cell-08-00054 Feb ua y 11, 2020 Time: 16:43 # 1
REVIEW
published: 11 Feb ua y 2020
doi: 10.3389/ cell.2020.00054
Edi ed by:
Shamik Sen,
Indian Ins i u e o Technology
Bombay, India
Re iewed by:
Zhizhan Gu,
Dana-Fa be Cance Ins i u e,
Uni ed S a es
Takashi Ka o,
Johns Hopkins Uni e si y,
Uni ed S a es
*Co espondence:
Man ed Radmache
[email p o ec ed]
†ORCID:
Ped o L. G anja
o cid.o g/0000-0003-2761-4929
Special y sec ion:
This a icle was submi ed o
Cell Adhesion and Mig a ion,
a sec ion o he jou nal
F on ie s in Cell and De elopmen al
Biology
Recei ed: 15 July 2019
Accep ed: 21 Janua y 2020
Published: 11 Feb ua y 2020
Ci a ion:
B ás MM, Radmache M,
Sousa SR and G anja PL (2020)
Melanoma in he Eyes
o Mechanobiology.
F on . Cell De . Biol. 8:54.
doi: 10.3389/ cell.2020.00054
Melanoma in he Eyes o
Mechanobiology
M. Manuela B ás1,2,3, Man ed Radmache 4*, Susana R. Sousa1,2,5 and
Ped o L. G anja1,2,3†
1Ins i u o de In es igação e Ino ação em Saúde, Uni e sidade do Po o, Po o, Po ugal, 2Ins i u o de Engenha ia
Biomédica, Uni e sidade do Po o, Po o, Po ugal, 3Faculdade de Engenha ia, Uni e sidade do Po o, Po o, Po ugal,
4Ins i u e o Biophysics, Uni e si y o B emen, B emen, Ge many, 5Ins i u o Supe io de Engenha ia do Po o, Ins i u o
Poli écnico do Po o, Po o, Po ugal
Skin is he la ges o gan o he human body wi h se e al impo an unc ions ha
can be impai ed by inju y, gene ic o ch onic diseases. Among all skin diseases,
melanoma is one o he mos se e e, which can lead o dea h, due o me as iza ion.
Mechano ansduc ion has a c ucial ole o mo ili y, in asion, adhesion and me as iza ion
p ocesses, since i deals wi h he esponse o cells o physical o ces. Signaling
pa hways a e impo an o unde s and how physical cues p oduced o media ed
by he Ex acellula Ma ix (ECM), a ec heal hy and umo cells. Du ing hese
p ocesses, se e al molecules in he nucleus and cy oplasm a e ac i a ed. Melanocy es,
ke a inocy es, ib oblas s and he ECM, play a c ucial ole in melanoma o ma ion. This
manusc ip will add ess he syne gy among melanocy es, ke a inocy es, ib oblas s cells
and he ECM conside ing hei mechanical con ibu ion and ele ance in his disease.
Mechanical p ope ies o melanoma cells can also be in luenced by pigmen a ion,
which can be associa ed wi h changes in s i ness. Mechanical changes can be ela ed
wi h he adhesion, mig a ion, o in asi eness po en ial o melanoma cells p omo ing a
high me as iza ion capaci y o his cance . Mechanosensing, mechano ansduc ion, and
mechano esponse will be highligh ed wi h espec o he mo ili y, in asion, adhesion and
me as iza ion in melanoma cance .
Keywo ds: melanoma, mechanobiology, melanocy es, ke a inocy es, in asion, adhesion, mig a ion,
me as iza ion
MELANOMA
Melanoma is one o he mos se e e skin cance s in humans wi h a mo ali y a e o 80%
(Ho sch oe e al., 2017), due o he high esis ance o his umo o adio he apy and chemo he apy
(Uong and Zon, 2010). The esis ance o hose ea men s is due o high numbe o mu a ions
(app ox. 75%) a ec ing speci ic genes, which lead o an inc easing p oli e a ion and su i al (Koza
e al., 2019). Immuno he apy is being exploi ed and in es iga ed, and can be g ouped in i e ypes:
(i) a ge ed an ibodies (Sanlo enzo e al., 2014;He zbe g and Fishe , 2016); (ii) adop i e cell he apy
(Sanlo enzo e al., 2014); (iii) oncoly ic i us he apy (F anklin e al., 2017); (i ) cance accines
(Tue enbe g e al., 2007;Rod iguez-Ce dei a e al., 2017); and ( ) immunomodula o s (Johnson
e al., 2014;Fa ies, 2016;Cance Resea ch Ins i u e, 2019). Chemo he apy and immuno he apy,
can be combined (biochemo he apy) ega ding he s age disease (Sanlo enzo e al., 2014;Koza
e al., 2019). The disease appea s due o he malignan ans o ma ion o melanocy es loca ed in
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B ás e al. Melanoma in he Eyes o Mechanobiology
he s a um basale o he epide mis al hough i is no clea
how a melanocy e becomes malignan (Uong and Zon, 2010).
Banda chi e al. (2010) sugges ed ha a combina ion o up
and down egula ion o ac o s in se e al molecula pa hways,
seem o be he mechanism o ans o ma ion o no mal in o
malignan melanocy es. I he disease is de ec ed in an ea ly
s age, he e is a high p obabili y o disease con ol, howe e ,
when me as iza ion occu s, he 5 yea s li e expec ancy d ops
o 14%. Some epidemiological e idence ela ed o melanoma
incidences in whi e and da k skinned popula ion (Banda chi
e al., 2013) was p esen ed by he au ho s whe eas B ad o d
(2009) p esen ed epidemiological da a abou he o al numbe s
o melanoma incidences in he wo ld. Da k skin esul s in a
lowe incidence o skin cance due o he p o ec ion o he
inc eased epide mal melanin, which il e s UV ligh wice as good
as whi e skin o Caucasian people (B ad o d, 2009). Malignan
melanoma a e diagnosed by he ABCD ule, whe e A s ands
o asymme y, B o bo de s i egula i y, C o colo a ia ion
and D o diame e highe han 6 mm (Banda chi e al., 2010).
Melanoma shows h ee pe cep ible s eps in umo p og ession:
(i) one only a ec ing he epide mis; (ii) a second one a ec ing
bo h he epide mis and he supe icial papilla y o he de mis; and
(iii) a hi d one a ec ing he epide mis, de mis and hypode mis
( e ical g ow h melanoma) (Banda chi e al., 2010). Haass e al.
(2005) di ided he p ocess o melanoma de elopmen in he
ollowing s eps: (i) he damage o adhesion be ween ke a inocy es
by down- egula ion o E-cadhe in, P-cadhe in, desmoglein, and
connexins, which is in luenced by g ow h ac o s p oduced by
ib oblas s o ke a inocy es; (ii) he in e ac ion o melanoma
wi h ib oblas s and/o melanoma wi h melanoma cells no mally
no ound in melanocy es, is up- egula ed by MCAM and
N-cadhe in; and (iii) al e a ion o in eg in exp ession, inducing
he loss o basemen memb ane ancho age (Haass e al., 2005).
Acco ding o he A Melanoma Founda ion (AIM), melanoma
de elops in a simila way han o he cance s: he DNA o a
gene ha con ols cell di ision and p oli e a ion is mu a ed.
This damaged gene esul s in a lack o con ol o cell di ision
and g ow h. This DNA mu a ion is passed o he daugh e
cell du ing di ision. Melanoma is o igina ed om a melanocy e
ha expe ienced oo many mu a ions g owing in an abno mal
way. In he case o melanoma, his DNA mu a ion is caused
by an o e exposu e o UV adia ion, a ec ing he melanocy es
(A Melanoma Founda ion, 2014). When he e is DNA damage,
se e al genes may be a ec ed, esul ing in encoding e o s
o se e al molecules hampe ing hei unc ion (A Melanoma
Founda ion, 2014;Kunz, 2014) and he e is a isk o a
melanocy e o gene a e a melanoma. I he melanoma is no
supp essed o ea ed, i will sp ead along he epide mis, a e
pene a ing he de mis and hypode mis, ge ing in con ac wi h
he lymph and he blood essels (A Melanoma Founda ion,
2014). The main unc ion o melanocy es is o p oduce melanin
( esponsible o skin pigmen a ion) ha abso b UV ligh o a oid
ke a inocy es’ DNA damage (Hi obe, 2014). Ke a inocy es will
dis ibu e melanin o he uppe pa s o he skin laye (Wang
e al., 2017). Wang e al. (2017) also men ioned ha ho monal
ac o s, amily his o y and cosme ics a e he h ee main igge ing
and agg a a ing ac o s o melanoma de elopmen . When a
p ima y melanoma is o med, i ac i a es some signals, which
will p o ide condi ions ha make he p ima y umo s ong such
as: (i) a achmen o he wall o he blood and/o lympha ic
essels, enabling he mo emen h ough a new o gan; (ii) enough
nu ien s o g ow; and (iii) i is esis an o he immune sys em.
Wi h he h ee condi ions men ioned be o e he p ima y umo
has he capaci y o p omo e he me as iza ion (A Melanoma
Founda ion, 2014). Why can melanoma de elop in some body
pa s ha a e no exposed o sunligh ? I was sugges ed ha he e
a e di e en changes occu ing in genes o issue cells exposed,
compa ed wi h he changes o genes o issue cells no exposed
o UV ligh . These mu a ions a e ansmi ed in o he nex
gene a ions. Some genes appea du ing melanoma de elopmen ,
being no gene ic. The ans o ma ion o melanocy es in o
melanoma cells is a e y complex p ocess, which in ol es se e al
signaling pa hways e iewed by Paluncic e al. (2016). B ie ly,
melanocy es a e o med om hei p ecu so s: melanoblas s.
Melanoblas s di e en ia e in o melanocy es, which ge ma u e
and s a melanin p oduc ion on melanosomes, which will be
ans e ed o ke a inocy es. Melanomagenesis depends on he
mic oen i onmen , gene ic and en i onmen al ac o s. Al hough
gene ic ac o s a e c ucial, hey a e no su icien o induce
melanomagenesis (Paluncic e al., 2016). Melanoma umo s
a e di e en om pa ien o pa ien . The en i onmen , whe e
melanoma umo s g ow, is e y complex depending on he
in e ac ions wi h ECM, mic o ascula u e, ib oblas ic cells and
changing concen a ion o g ow h ac o , cy okines, and nu ien s
like glucose, oxygen, e c (Paluncic e al., 2016). Some signaling
pa hways a e mo e in ol ed in umo de elopmen , whe eas
o he signals a e mo e c ucial in he me as iza ion p ocess.
The desc ip ion o biochemical pa hways signaling is beyond
o his e iew, howe e he eade s can ind mo e in o ma ion
in di e en sou ces (Dissanayake e al., 2007;S aussman e al.,
2012;Mo iceau e al., 2015;S a k e al., 2015;Wang e al., 2016;
Ahmed and Haass, 2018;Kode e al., 2018). Melanoma can be
pigmen ed o no pigmen ed. The colo o melanoma is due o
he exis ence o melanin, sec e ed and s o ed in melanosomes in
he cy oplasm o melanocy es. The e a e wo ypes o melanin:
eumelanin (has a black colo ) and pheomelanin (has a ed/yellow
colo ). No mal melanocy es may o may no sec e ei he ype
o melanin (Lassalle e al., 2003). Mechanical p ope ies and cell
pigmen a ion a e co ela ed (Sa na e al., 2013, 2014).
As melanoma needs a high amoun o i on and coppe , he
de elopmen o subs ances ha a ge hese ions could be ano he
me hodology (Go ode sky e al., 1986).
MECHANOBIOLOGY OF SKIN CELLS
Cu en ly, mechanobiology b ings oge he biologis s and
biophysicis s in o de o be e unde s and he ole o mechanical
o ces in cell mo ili y, adhesion and in asion. Fo de eloping
he apies ha a oid he in asi eness o cance cells, i is c ucial o
unde s and he mechanisms o umo in asion. The mechanical
s i ness o umo s is co ela ed wi h i s in asi eness, which was
demons a ed by a s udy wi h cance o a ian cells: mo e in asion
co esponds o so e cells esul ing in de o ma ion and shape
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B ás e al. Melanoma in he Eyes o Mechanobiology
changes, being sui able o me as iza ion (Swamina han e al.,
2011). Makale (2007) aised h ee hypo heses co ela ing cance
and cell mechanobiology: (i) he cell biology o umo in asion
is a key o unde s and cance ea men ; (ii) cance cells ac i a e
physiological mechanisms and mig a o y p ocesses ha a e used
by cells usually du ing emb yo mo phogenesis; and (iii) o ces
ha a e sensed by he issue and cells igge he di e en ia ion
and sp eading o umo s. In ac , mechanical o ces a e gene a ed
by issues, being sensed by cells, du ing emb yogenesis and umo
expansion (Makale, 2007).
In melanoma he Epi helial o Mesenchymal T ansi ion
(EMT) swi ching, and o ces behind his p ocess (Wei e al.,
2015) a e c ucial p ocesses ega ding he loss o connec ions
be ween melanocy e and ke a inocy es; melanocy es acqui ed
he emb yonic pheno ype, p omo ing cells in asion, hei
in a asa ion in body luids and he ex a asa ion o o he
o gans. A i ing a hei a ge des ina ion, umo cells a e
e e ed o hei o iginal pheno ype known as Mesenchymal
o Epi helial T ansi ion (MET), es ablishing seconda y umo s.
The p oduc ion o me allop o einases (MMP) will induce ECM
deg ada ion, a o ing me as iza ion (Paluncic e al., 2016).
Mig a ion o collec i e cells in e ac wi h he ex acellula
en i onmen ia in eg ins (Hege eld e al., 2002). When no mal
cells a e comp essed because o a umo , hese o ces will be
sensed by cell body, h ough memb ane molecules, he in eg ins,
which a e connec ed o he cy oskele on, and o he nucleus.
All cells espond o hese ex e nal o ces o ganizing cellula
componen s in he cell and gene a ing biochemical signals ha
will help hem o adap o ex e nal physical p essu e. The
no mal ECM p oduced by ib oblas s also induces p essu e on
umo cells ia i s cy oskele on, esul ing in cell and nucleus
de o ma ion. A consequence o nucleus comp ession could be he
modula ion o gene exp ession ha may induce changes in cell
iabili y, p omo ing locomo ion, due o he adop ion o a mo e
malignan pheno ype. In spi e o high umo s oma s i ness,
umo cells a e de o mable and ha e some deg ee o plas ici y
(Makale, 2007). In melanoma, he ela ion among melanocy es,
ke a inocy es, ib oblas s and he ECM media e and con ol his
disease. In he nex pa ag aphs, mechanobiology o hese cell
ypes and ECM con ibu ion o melanoma will be add essed.
The Role o Melanocy es
Melanocy es a e loca ed in he basal laye o he epide mis, eyes,
ea s, hai and meninges (Banda chi e al., 2013). Melanocy es
ha e a dend i ic shape (Figu e 1). They a e o igina ed om
mig a o y emb yonic cells, called neu al c es cells, which ha e a
high capaci y o mig a ion (Uong and Zon, 2010). Melanocy es
a e he cells esponsible o skin pigmen a ion, h ough he
p oduc ion o melanin, also named melanogenesis (Lassalle
e al., 2003). They a e p esen in he epide mis and exhibi
long dend i ic p o usions, which a e ex ended h ough he
epide mal ke a inocy es. Melanocy es syn hesize melanosomes
and anspo hem o he ke a inocy es (Zhang e al., 2004).
Melanocy es adhe e o ke a inocy es h ough E-cadhe ins,
Desmoglein (DSg)/Desmocollin (DSc), Connexins (CX)
molecules (Li e al., 2003) and o he basemen memb ane
h ough in eg ins (Wang e al., 2016). The a io o melanocy es
and ke a inocy es is a ound 1:36/1:40. 8 o 12% o malignan
melanoma a e associa ed wi h mu a ions on CDKN2A (cyclin-
dependen kinase Inhibi o 2) gene (Banda chi e al., 2013). Uong
and Zon (2010) also men ioned ha he pa hways in ol ed in
melanocy e de elopmen and p oli e a ion s a o be sub e ed
in melanoma o ma ion. BRAF and NRAS (a gene o he RAS
amily iden i ied o he i s ime a human neu oblas oma)
(Pugh e al., 2013) o e ac i e mu a ions a e ound in 65 and 20%
o melanomas, espec i ely. CDKN2A is lacking by melanoma
cells, consequen ly he encoding supp esso genes (INK4a and
ARF) a e no ac i e (Banda chi e al., 2010).
Malignan melanocy es a e cha ac e ized by changes o
biophysical p ope ies (like shape, elas ici y and s i ness) which
will con ibu e o he cell locomo ion, in asion and me as iza ion
in o he o gans. In his case, he plas ici y o melanocy es
is e y impo an , since hey need o be highly de o mable.
Since he mechanical p ope ies o melanoma cells may be
a ec ed by he p oduc ion o melanin, his has o be conside ed
(Sa na e al., 2013). Melanin and melanogenesis may ac in
wo di e en di ec ions: melanin ac as a p o ec ion shield
o adia ion, howe e i also a enua es he e ec i eness o
adio he apy, chemo he apy and pho o he apy in he case o
melano ic melanoma. This cha ac e is ic can p o ide umo
g ow h and p og ession (Slominski e al., 2015).
AFM was used o obse e he shape o human epide mis
melanocy es in cul u e and o obse e he melanosome ans e
in i o. Filopodia o igina ed om he dend i e ips o he
cell body o melanocy es, which con ained melanosomes ha e
been obse ed (Zhang e al., 2004). Van Den Bossche e al.
(2006) hypo hesized di e en mechanisms o melanin ans e :
(i) ke a inocy es phagocy e he melanocy e dend i es; (ii) he
melanosomes elease melanin in o he ex acellula space by
melanosome exocy osis, being in e nalized by he ke a inocy es;
(iii) melanosomes a e anspo ed ia memb ane nano ubes; and
(i ) he melanocy es en iched o melanosomes a e phagocy osed
by he ke a inocy es (Van Den Bossche e al., 2006).
Wu e al. (2012) s udied melanocy es o mice lacking myosin
Va (Myo5a). This p o ein is in ol ed in he accumula ion
o melanosomes in he melanocy e dend i es. When myosin
Va is p esen , melanosomes s ay concen a ed in he cen e
o cance ous melanocy es educing melanosome ans e o
ke a inocy es (Wu e al., 2012). Wäs e e al. (2016) s udied
he ela ion be ween UV skin adia ion and skin pigmen a ion
esponse. They concluded ha when pigmen ed skin is exposed
o UVA, he e is a spillage o ex acellula esicles om he
melanocy e’s plasma memb ane. This does no happen when
pigmen ed skin is exposed o UVB (Wäs e e al., 2016).
AFM was used o s udy he mo phological changes o
melanocy es exposed o he melanocy e s imula ed ho mone
α-MSH, which induces melaniza ion (Shin e al., 2014). The
au ho s ound ha he oughness inside he po e-like s uc u es
on dend i es inc eased and MSH p oduced an inc ease in he
size and densi y o he melanosomes. Howe e , ega ding he
esponse o he p esence o α-MSH, mo e s udies a e needed
o co ela e mo phological shape al e a ions wi h he mo emen
o melanosomes (Shin e al., 2014). Human melanocy e’s
pigmen a ion in melanoma cells a e also impo an in egula ion
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B ás e al. Melanoma in he Eyes o Mechanobiology
FIGURE 1 | Schema ic ep esen a ion o skin and cell popula ion. Melanocy es a e loca ed in he basal laye o epide mis. Each melanocy e is connec ed o se e al
ke a inocy es. Melanosomes (black spo s) a e dis ibu ed in he den i es, p oduce and s o e melanin. The dend i es allow he ans e o he melanin o
ke a inocy es, which will be ans e ed o he s a um co neum laye o he epide mis.
o elas ic p ope ies acco ding o Choi e al. (2014). The
au ho s s udied he e ec o subs a es wi h di e en s i ness
on he pigmen a ion, using no mal human melanocy es (NHM)
and melanoma cells (MNT1) cul u ed on polydime hylsiloxane
(PDMS) coa ed wi h laminin. They obse ed a educ ion o
dend i e o ma ion in bo h cell ype as well as a di e ence
on he ans e ence a e o melanosomes o bo h cell ype
on so e subs a es. Cells cul u ed on s i e subs a es showed
lowe mig a ion capaci y once ac ion o ces o ma ion a e
mo e e iden h ough ia ocal adhesion in eg in complexes
(Choi e al., 2014).
Based on some s udies o cell elas ici y, cance cells ypically
show a dec ease in s i ness ela i ely o no mal cells. Sa na
e al. (2013) desc ibed a s udy o elas ic p ope ies compa ing
melanoma cells and heal hy melanocy es. Basically, he au ho s
used AFM o de e mine he s i ness o human melanoma cells
SKMEL-188 wi h di e en s ages o pigmen a ion and compa ed
wi h SKMEL-188 cells no pigmen ed and wi h NHMs heal hy
human melanocy es (Sa na e al., 2013). They ound ha heal hy
melanocy es we e so e han cance cells. This ea u e could
be ela ed wi h he amoun o melanin p esen in melanoma
cells, esul ing in some limi a ions o cance diagnosis using he
s i ness. Lazo a and Pawelek (2009) men ioned ha melanoma
cells do no exc e e he pigmen like heal hy melanocy es do,
which may esul in pigmen accumula ion in melanoma cells in
ela ion o melanocy es. This could explain he highe s i ness o
cance cells, since hey a e o en highly pigmen ed (Lazo a and
Pawelek, 2009). In conclusion, by AFM nanoinden a ion assays i
is no possible o dis inguish melanoma cells om melanocy es.
AFM can be used as a complemen a y echnique, howe e , his
s udy was use ul in unde s anding be e pigmen ed cell elas ici y.
Sa na e al. (2014) also men ioned he need o unde s and i he e
is a co ela ion be ween he pigmen a ion o melanoma cells and
he me as iza ion pheno ype p ocess. In his p ocess, malignan
cells mus pass he epi helial ba ie , ha ing he capaci y o
de o m hei cell body, including he nucleus o mig a e h ough
issue. Cells wi h low Young’s moduli exhibi a g ea po en ial
o in ade issue (Sa na e al., 2014), so his is why biophysical
p ope ies, as cell elas ici y, mus be aken in o accoun . The
au ho s showed ha melanin g anules inhibi he ansmig a ion
po en iali ies o melanoma cells. Fo non-pigmen ed melanoma
cells, he s i ness was lowe , and he ansmig a ion e iciency
was highe . This s udy con ibu ed wi h new insigh s abou he
ela ionship be ween pigmen a ion and elas ici y o melanoma
cells in e ms o mig a ion and in asion.
Some subs ances a e esponsible o he e ac ion o
melanocy e dend i es. I o e al. (2006) ha e s udied he e ec
o dend i e e ac ion using a la onoid subs ance. In his
case, TYRP-1 signaling pa hway is in e up ed, once his
molecule is impo an o melanosome mig a ion. Rho signaling
molecule, when ac i a ed induces dend i ic e ac ion, educing
he melanosome ans e o he ke a inocy es bu does no
a ec he amoun o melanin p oduc ion. Howe e , his melanin
will no be ans e ed due o he dend i e’s e ac ion. The
mechanism o dend i e e ac ion ia RhoA in ol es changes
in cy oskele on and mic o ubules o ganiza ion due o ac in and
ubulin-βdisassembly. These changes will induce s ess ibe
o ma ion p omo ing ac in polyme iza ion and eo ganiza ion
o mic o ubules (I o e al., 2006). Rac is in ol ed in melanocy e
dend i e g owing, inducing he appea ing o lamellipodia (Sco ,
2002). The dend i e ips o melanocy es a e also s imula ed by
he α-MSH and endo helin – 1 p o eins om ke a inocy es
ha a e su ounding he melanocy es and he ECM p oduced
by he ke a inocy e (Kippenbe ge e al., 1998). Kippenbe ge
e al. (1998) demons a ed ha co-cul u es o melanocy es
and ke a inocy es in he p esence o high concen a ion o
calcium, showed shee s o ke a inocy es o ma ion, su ounding
by melanocy es wi h pola dend i es ex ended a ound he
di e en ia ed ke a inocy es. Di e en ia ed ke a inocy es will
ha e s able a eas o con ac wi h melanocy es due o he calcium
g adien . The no mal melanocy es ha lose hei dend i es soon
will be in an apop osis s a e (Kippenbe ge e al., 1998). The
senescence o p ima y melanocy es could also be impo an
in he melanoma appea ance (Feue e e al., 2019), howe e ,
he e a e no s udies ha co ela e melanocy es’ senescence wi h
mechanical p ope ies measu ed by AFM. Some s udies showed
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B ás e al. Melanoma in he Eyes o Mechanobiology
a co ela ion be ween he melanocy es aging and senescence
bioma ke s (Wang and D eesen, 2018) and exposi ion o
melanocy es o ligh (Benne e al., 2017). AFM is a powe ul ool
o assess he mo phological and elas ic p ope ies ega ding he
in e ace be ween p ima y melanocy es and p ima y melanoma
wi h and wi hou senescence. In opposi ion o he melanoma
cell lines ha a e immo alized and hus, submi ed o se e al
passages, he p ima y melanocy es and p ima y melanoma cells
should be assessed in o de o e alua e wha passage he
senescence will no in e e e wi h mechanical p ope ies. The
quan i ica ion o senescence le el can be pe o med using he
quan i ica ion o he Popula ion Double Le el (PDL) me hod
(K use and Pa e son, 1973).
The Role o Ke a inocy es
Ke a inocy es a e he p edominan cell ype in he epide mis,
mos o hem (90%) being loca ed a he ou mos epide mis laye
(McG a h e al., 2004). Ke a inocy es a e connec ed o each o he
h ough ac in cell junc ions (Hsu e al., 2018).
The main unc ion o ke a inocy es is o o m a ba ie agains
pa hogenic mic oo ganisms, hea , UV adia ion and wa e loss.
They also p oduce cy okines ha a ac leukocy es o he
loca ion o pa hogen in asion (Hall e al., 2014). Ke a inocy es
also p oduce di e en ke a ins. Ke a ins ( ype 1, 5, 10, and 14)
a e he main s uc u al p o ein o hei cy oskele on, all o which
play an impo an ole in he mechanics o hese cells (Ramms
e al., 2013). Ke a ins become al e ed when esponding o s esses,
esul ing in i s modi ica ion and eo ganiza ion (Ka an za, 2011).
Ke a inocy es become co neocy es, when hey a e comple ely
di e en ia ed, losing hei nucleus and cy oplasmic o ganelles
(Mi, 2009). Di e en ia ion o ke a inocy es is d i en by a calcium
g adien , which is es ablished be ween he in e io o he cell
and he ECM (P oksch e al., 2008) and egula ed by i amin
D3 (Bikle, 2004), ca hepsin E (Kawakubo e al., 2011), TALE
homeodomain ansc ip ion ac o s (Jackson e al., 2011), and
hyd oco isone (Rheinwald and G een, 1975). Ke a inocy es a e
a ec ed by senescence, losing hei biological unc ion wi h
age (O ioli and Dellamb a, 2018). Ke a in, ac in ilamen s and
mic o ubules o m he cy oskele on ne wo k o ke a inocy es,
p o iding shape and s uc u e o cells allowing ansmission o
mechanical loads (Sil e and Sipe ko, 2003). Fo ke a inocy es
mig a ion one o he mos impo an pa ame e s is he subs a e
s i ness (Ramms e al., 2013), since i is expec ed ha he
ke a inocy es mus change hei shape du ing mig a ion h ough
he epide mis un il hey each he ou mos laye and become
co neocy es (Za koob e al., 2015). This change in shape will
a ec also he componen s exis ing inside he cy oplasm, namely
he cy oskele on, in which ke a in ibe s a e c ucial (Ramms e al.,
2013). Ramms e al. (2013) used AFM o p obe ke a inocy es
(in he nuclea egion and in he cell body) de icien in
ke a ins inding ha hey a e so e han heal hy ones. In
addi ion, wi h magne ic weeze s, he iscous con ibu ion o
he displacemen o magne ic beads inc eased, co obo a ing he
esul s achie ed by AFM. These au ho s also ound ha he
so ening was e e sible and could depend on he e-exp ession
o wo ypes o Ke a ins (K4 and K15) only (Ramms e al., 2013).
Ba e al. (2014) epo ed he skin agili y in mice and hampe ed
desmosomes adhesion when he e is a lack o all ke a ins
Ba e al., 2014. AFM showed a educ ion o adhesi e o ces
and memb ane s abili y in mu ine ke a inocy es when lacking
ke a in ilamen s (Vielmu h e al., 2018). Adhe en junc ions (AJ)
ha e unc ions in mechanosensing and ansducing mechanical
o ces be ween he plasma memb ane and he ac omyosin
cy oskele on. Desmosomes and in e media e ilamen s p omo e
he mechanical s abili y o main ain issue a chi ec u e and
in eg i y when hey a e submi ed o mechanical s ess. Bo h (AJ
and desmosomes) connec he ac in and ke a in ilamen ne wo k
o adjacen cells. Desmosomes a e impo an o in e cellula
cohesion, whe e ke a ins de e mine cell mechanics bu a e
no in ol ed in ension gene a ion (Ha z eld e al., 2017).
Za koob e al. (2015) in es iga ed he ole o subs a e s i ness
on ke a inocy e colony o ma ion (in i o) du ing epi helial
o ma ion, due o calcium exchange du ing ke a inocy e cell
cul u e. Ke a inocy es cul u ed on so polyac ylamide subs a es
(E= 1.2 KPa) p esen ed small con ac a eas, an inc ease
in mig a ion eloci y and in colony o ma ion compa ed o
hose cul u ed on s i polyac ylamide gels (E= 24 KPa)
(Za koob e al., 2015). How melanoma cells escape he
ke a inocy e’s con ol in ading o he issues and o m me as asis,
is s ill unclea . In a heal hy issue, he e is a homeos asis
main ained by each cell. In his no mal issue, ke a inocy es a e
he “su eyo s” o melanocy es, con olling hei g ow h and
beha io h ough complex pa ac ine g ow h ac o s and cell-cell
adhesion molecules. When al e a ions occu o his homeos a ic
balance, cell-cell adhesion and cell communica ion molecules
change and induce melanoma de elopmen esul ing in he
damage o he epide mal melanin uni , inducing he con inuous
melanocy e p oli e a ion, and e en ually leading o melanoma
de elopmen (Haass e al., 2005). Chung e al. (2011) sugges ed
ke a inocy es-de i ed ECM ac o s may ac as egula o s o
melanocy es. The au ho s showed ha laminin-332, a componen
o basemen memb ane, plays a c ucial ole in he adhesion
and mig a ion o melanocy es and melanoma. I is known
ha ke a inocy es egula e he beha io o melanocy es such as
p oli e a ion, melanin syn hesis and dend i e o ma ion and he
ECM also egula es di e en cell beha io s (Chung e al., 2011).
The Role o Fib oblas s and he ECM
Fib oblas s a e p oduced in he bone ma ow. They
syn hesize he componen s o he ECM, o ins ance collagen,
glycosaminoglycans and elas ic ibe s. Fib oblas s also p oduce a
s uc u al ne wo k called “s oma” in animal issues (connec i e
issue), playing an impo an ole in cance and in wound
healing (Desja dins-Pa k e al., 2018). Kwa e al. (2019)
men ioned ha cance is associa ed wi h ib oblas s and how
hese ib oblas s a ec me as iza ion. Fib oblas s p oduce
high amoun s o ECM molecules, cy okines and g ow h
ac o s con ibu ing o he s oma, cance p og ession and
me as iza ion due o se e al pa hways. These pa hways could
be a a ge o new cance ea men s a egies o be de eloped.
Howe e , i is di icul o cha ac e ize his sub ype o ib oblas s
and o iden i y speci ic molecules in ol ed in his p ocess
(Kwa e al., 2019). Mechanosensing has a la ge impac in
Cance -Associa ed Fib oblas s (CAFs). Fib oblas s sense
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B ás e al. Melanoma in he Eyes o Mechanobiology
mechanical s esses and ac i a e mechanosignaling p ocesses,
which use mechano ecep o s loca ed in he cell memb ane,
he cy oskele on and ansc ip ion ac o s. The ECM s i ness
is de e minan in he mechanosignaling, which by i sel can
ac i a e he mechanosensing pa hways in CAFs, leading o ECM
p oduc ion and s i ness inc easing, suppo ing di e en CAFs
di e en ia ion (Kwa e al., 2019).
The s udy o mechanosignaling and ib oblas s esponse o
he ECM s i ness was conduc ed using hyd ogels, o mimic
pa hologically he ECM o issues. Viji Babu e al. (2018) ha e
used he AFM o s udy he s i ness and iscoelas ici y o no mal,
sca and Dupuy en’s disease ib oblas s, g owing on op o
so (1 KPa) and s i (50 KPa) hyd ogels. Basically, a MLCT-
Bio py amidal can ile e (nominal sp ing cons an o 0.01 N/m,
B uke , Uni ed S a es) was used o inden he ib oblas s, using
he z-s ep esponse me hodology, in which he elas ici y and
iscosi y was assessed (Figu e 2). The au ho s wan ed o e alua e
he e ec o TGF-αin he ib oblas ’s elas ici y. The au ho s
concluded ha Dupuy en’s ib oblas s inc eased hei elas ic
moduli and became s i e in TGF-β1 p esence, whe eas hey
did no ind signi ican changes in he elas ic moduli o sca
and no mal ib oblas s, be o e and a e addi ion o TGF-
β1. Dupuy en’s ib oblas s p esen ed a wide numbe o well-
o ganized s ess ibe s and bundles o s ess ibe s we e e en
hicke in p esence o TGF-β1 (Viji Babu e al., 2018).
RhoA signaling is he key o he ib oblas ’s eac ion
o ECM s i ness. RhoA is ac i a ed by a s i ma ix,
causing cell con ac ion and ac in polyme iza ion, inducing he
di e en ia ion o ib oblas s in myo ib oblas s. The e o e, CAFs
need he ac i a ion o his pa hway, since i is equi ed o
hei con ac ile and in asi e p ope ies. I has been men ioned
ha he e a e se e al CAF sub ypes, howe e , he e is a lack o
in o ma ion abou hei plas ici y, which could be impo an o
he p og ession and me as iza ion o cance (Kwa e al., 2019).
AFM could gi e new insigh s ega ding he cha ac e iza ion o
ib oblas s sub ype based in hei mo phome ic cha ac e is ics
(shape ac o , olume and a ea) and mechanical p ope ies. As
a as we know, he e is no any speci ic s udy in li e a u e, which
FIGURE 2 | Basic componen s o (A) AFM and (B) o ce cu e wi h (C) iscoelas ic c eep esponse measu emen . (A) The basic ou componen s o AFM (i) a lase
diode, (ii) a can ile e o 0.01 N/m sp ing cons an wi h 30 nm adius AFM py amidal ip, (iii) a posi ion-sensi i e pho o de ec o (PSPD), and (i ) xyz-piezo s age.
(B) Sample inden a ion by he AFM ip ob ains he o ce cu e ha gi es he app oach ( ed a ow) and e ac (blue a ow) cu e on de lec ion s. Z-heigh g aph,
and appa en Young modulus was calcula ed by applying He z model o he app oach cu e. In c eep esponse cu e (C), he Z-heigh p o ile (i) shows he
app oach and e ac amp owa d he cell o 3 s, and in-be ween, he e is a z s ep, which is applied a = 1.5, which is enla ged in panel (ii).(iii) The de lec ion
da a show global c eep o he cell, which includes he c eep a e loading and unloading s ep, which is enla ged in panel (i ), and global c eep was de e mined by
he exponen ial i (black cu e) and was sub ac ed o quali a i e analysis ( ep oduced wi h pe mission om John Wiley and Sons wi h Copy igh Clea ance Cen e ’s
Righ , Jou nal o Molecula Recogni ion, 2018) (Viji Babu e al., 2018).
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B ás e al. Melanoma in he Eyes o Mechanobiology
could be use ul o he de elopmen o he apies di ec ed o a
speci ic ib oblas sub ype ela ed wi h melanoma. This s udy
could also p omo e new insigh s o de elop he apeu ic s a egies
o o he cance ypes.
The ECM is composed by (i) he s uc u al p o eins collagen
and elas in; (ii) adhesion p o eins such as ib illin, ib onec in,
i onec in and laminin; and (iii) he p o eoglycans (which ha e
a p o ein co e bound o glycosaminoglycans) (Makale, 2007). The
ECM is esponsible o cellula suppo . Va ia ions in i s s uc u e
and composi ion al e he mechanical p ope ies o he ECM.
Gene ally, he ex e nal o ces applied o cell-ma ix complexes
a e ansmi ed o he in e io o he cell by in eg ins acco ding
o h ee s eps (Roca-Cusachs e al., 2009): (i) in eg ins binding
o ECM molecules; (ii) ansmission o o ces o he in e io
o he cells, h ough in eg ins, whe e hey a e ans o med in o
biochemical signals (mechano ansduc ion); and (iii) in eg ins
binding o cy oskele on, ansmi ing he o ces all o e he cell,
and ein o cing hei adhesion p ope ies o esis he o ce.
The in eg ins inside o cell ec ui se e al o he molecules,
which bind o he cy oskele on and/o signaling p o eins o o m
wha is called “ ocal adhesion” o esis o he ex e nal o ce
(Roca-Cusachs e al., 2009).
Wha a e he mechanical cues sensed by cells when o ces
a e applied om he ou side? In eg in-associa ed complexes
(IACs) in cellula memb anes es ablish he connec ion be ween
he ECM and he cy oskele on o he cell, ia ac in ilamen s
(Haase e al., 2016). Haase e al. (2016) ound ha physical
o ces s emming om he ECM ha e a huge impac on
gene egula ion; i has been hypo hesized ha gene exp ession
is a ec ed by nucleus de o ma ion, which was obse ed in
3T3 ib oblas s. The ac in and mic o ubule ne wo k gene a es
nuclea de o ma ion. The de o ma ion o he nucleus will
be aniso opic being obse ed along he sho e axis and is
in insic o he nucleus. This beha io is due o he ch oma in
o ganiza ion and lamin-A exp ession (Haase e al., 2016). The
ECM uses he concep o “ enseg i y,” which employs ensile
o ces and igid suppo s uc u es o dis ibu e and manage
he loads media ed by he cellula cy oskele on complex. In
he cy oskele on mic o ilamen s and mic o ubules, which a e
connec ed o he ECM, he e a e o ces in be ween (Makale,
2007). This means ha he p essu e exe ed on he ECM
will in luence he cell’s beha io in e ms o di e en ia ion,
mo ili y, adhesion, in asion, and me as asis (Makale, 2007).
ECM mechanical p ope ies a e di ec ly ela ed wi h elas in
ibe s, collagens, glycosaminoglycans (GAGs) and p o eoglycans.
Elas in ibe s con ibu e o cyclic s e ching du ing li e; collagen
ibe s con ibu e o he issue s i ness and mechanical s eng h
o issues and GAGs a ec ECM iscoelas ici y, o ming b idges
be ween he collagen ibe s and con ibu ing o he comp essi e
issue s i ness. Cells sense he o ces exe ed by he ECM,
con e ing hese s imuli in o in acellula signal pa hway, which
u he downs eam egula e ansc ip ional changes (Hsu e al.,
2018). Se e al mechanosenso s a e iden i ied in cells: glycocalyx,
lipid a /ca eolin-1, cell adhesion s uc u es (in eg in, hemi-
desmosomes and ocal adhesion), ion channels (calcium-sensing
ecep o ), ansien ecep o po en ial channels, connexins,
in e cellula complexes (desmosomes o cadhe in) and he
cy oskele on (pa icula ly he ac in ilamen s) (Hsu e al., 2018).
Any abno mali y ha causes changes in he ECM mechanical
p ope ies, cell in e ac ions, o cellula esponse o mechanical
s imuli will induce ensional homeos asis, con ibu ing o se e al
diseases like cance and ib osis (Hsu e al., 2018). In eg ins
( ansmemb ane p o eins) a e esponsible o ansmission o
o ces be ween ECM and he in e io o he cell. Tumo cells
exp essed he a b3 in eg in and he in asi eness o melanoma
cells depends on he exp ession o β-3 and β-1 in eg ins,
which a e ela ed wi h hei agg essi e p ope ies (Pe i cle c
e al., 1999;Hege eld e al., 2002). The e o e, one he apeu ic
s a egy could con ibu e o he educ ion o hese in eg ins
exp ession (Makale, 2007). S i ness o umo s is impo an
since i ac i a es biochemical pa hways ega ding he cell cycle,
EMT, cell mo ili y and leads o comp ession in neighbo ing
heal hy cells. These heal hy cells may hen ac i a e umou ogenic
pa hways (B ode s-Bondon e al., 2018).
Cell sp eading depends on subs a e s i ness, which, in u n,
depends on he complex adhesion ype. A7 melanoma cells we e
seeded in polyac ylamide gels lamina ed wi h collagen ype I (Coll
I), ib onec in (FN) and a mix u e o Coll I and FN (Wine e al.,
2011). Figu e 3 shows he s i ening and sp eading o ilamin
A-exp essing A7 human melanoma cells and is compa ed wi h
di e en s i nesses subs a es coa ed wi h FN o Coll I. S i ening
bu no sp eading o A7 melanoma cells depends e y s ongly
on whe he in eg ins speci ic o FN o Coll I a e engaged. When
A7 cells a e pla ed on gels coa ed wi h sa u a ing amoun s o
ei he FN o Coll I, hey sp ead o app oxima ely he same ex en
(Figu e 3B), bu he cells on Coll I a e much s i e han hose
adhe en o FN (Figu e 3A). When bo h FN and Coll I a e
p esen , allowing bo h α1 and β3 in eg ins o bind, adhe en a ea
inc eases, bu cell s i ness eaches an in e media e alue be ween
hose ound on FN o Coll I alone (Kandow e al., 2007).
CELL MIGRATION AND PROGRESSION
IN MELANOMA
Mo ili y
Melanoma s a s wi h he los binding in e cellula connec ions
be ween melanocy es and ke a inocy es (Figu e 4).
In he p ocess o melanoma de elopmen , due o EMT,
cells acqui ed a mesenchymal s em cell pheno ype, con ibu ing
o cell mig a ion (Banda chi e al., 2010). The EMT model
is e y well explained by Nie o e al. (2016) and B able z
e al. (2018), he o ces in ol ed in EMT and i s ela ion
wi h cance me as asis a e desc ibed by Wei e al. (2015).
A e losing hei connec ions, melanocy es mo e due o a
mo ili y p ocess.
Mo ili y is he capaci y o a li ing sys em o mo e
independen ly, using me abolic ene gy o pe o m mechanical
wo k and should no be con used wi h mobili y (Allen, 1981;
Figu e 5). Fo cell mig a ion, he e is he con ibu ion o
he in e nal o ces (which a e gene a ed by some s uc u es
p esen inside each cell, such as he cy oskele al ilamen s)
and he ex e nal o ces ( he shea low o blood o lympha ic
luids con ibu ions). The mo ili y o cells h ough issues is
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B ás e al. Melanoma in he Eyes o Mechanobiology
FIGURE 3 | Melanoma s i ness (A) and sp eading (B) in unc ion o Collagen
ype I (Coll I) and Fib onec in (FN) p esence in hyd ogels. When A7 cells a e
pla ed on gels coa ed wi h sa u a ing amoun s o ei he FN o Coll I, hey
sp ead o app oxima ely he same ex en (B), bu he cells on Coll I a e much
s i e han hose adhe en o FN (A). When bo h FN and Coll I a e p esen ,
allowing bo h α1 and β3 in eg ins o bind, adhe en a ea inc eases, bu cell
s i ness eaches an in e media e alue be ween hose ound on FN o Coll I
alone. Each ace d awing inside he cells co esponds o 1 KPa (based on
Kandow e al., 2007).
a p ocess media ed by in e nal o ces, which a e ela ed wi h
he pola iza ion o he cell body wi hin he ECM. This mo ion
depends on shape changes, cell-subs a e in e ac ion, and he
gene a ion o o ces om he cells media ing h ough he issue.
The in e nal o ces esponsible o cell mo ili y a e composed
by he ollowing s eps: (i) cy oskele al pola iza ion, o ming
ex ensions o ac in ilamen s loca ed in he leading edge; (ii)
cell p o usions connec o he ECM sca old by cell su ace
adhesion ecep o s; (iii) con ac ion o ac omyosin mo o s ha
a e connec ed wi h he ECM subs a es exe ing ac ion o ces;
(i ) bipola ension, which is ansmi ed h ough he subs a e,
allows he e ac ion o he cell ea comple ing he mo emen o
he cell; and ( ) when cells mo e, hey p oduce ECM deg ading
p o eases and he ansmig a ed ECM is emodeled by p o eolysis
(Tao e al., 2017). Tao e al. (2017) also e e s ha he ac in
cy oskele on exhibi s iscous and elas ic esponses, which can be
cha ac e ized by he elaxa ion ime obse ed in a c eep esponse
a e applying a s ess. The elaxa ion co esponds o he ime
scale whe e he cell cy oskele on can low and beha e in an
elas ic way. Cy oplasm is mo e han cy oskele on: i has a lo
o wa e con en (a ound 70%), which also play a ole in cell
mo ion, since wa e lows in be ween he cy oplasm o ganelles.
The ex e nal o ces a e ela ed wi h he wa e low and osmo ic
p essu e, as well o he luid shea s ess o he blood and lymph.
FIGURE 4 | Melanocy es – ke a inocy es adhesion molecules in heal hy and
in cance issues. In a heal hy s a e he melanocy e-ke a inocy e in e ac ions
a e cha ac e ized by he exis ence o E-cadhe in adhe en junc ions. The
ke a inocy es and melanocy es a e connec ed o he ECM h ough he
in eg ins. In a cance s a e, he E-cadhe ins a e los and N-cadhe ins a e he
adhe en junc ions s ablished be ween melanocy es. Melanocy e dend i es
e ac ed and melanocy es acqui ed a ound shape pheno ype.
The wa e can pass h ough he cell memb ane ia aquapo in in
bo h di ec ions, so he cell can change i s olume, ei he o ced
by ex e nal cues like he osmo ic p essu e di e ence be ween
inside and ou side o he cell o ac i ely con olled by ion pumps
(Tao e al., 2017).
Cy oskele on ea angemen occu s h ough he a angemen
o h ee p o eins: Rho, Rac and Cdc42. The Rho GTPase amily
since hey in luence he appea ance and s uc u e o ilopodia,
s ess ibe s and adhesion plaques o melanoma cells (Tao e al.,
2017) encou age ac in e ac ion; Rac was ea ed o encou age
lamellipodia ex ension bu block ac in depolyme iza ion; Cdc42
was assumed o encou age ilopodia elonga ion and block ac in
depolyme iza ion (Tao e al., 2017). Mo ili y is esul ing om
wha is calling he mechano ansduc ion “inside-ou ” combining
wi h a wa e low in and ou .
In human melanoma, by mic opo e il a ion, i was ound
ha imen in and ke a in in e media e ilamen exp ession
esul s in a mo e mig a o y and in asi e pheno ype (Gao,
2014). The au ho s also ound ha damage o ac in ilamen s
and mic o ubules inc eases he de o mabili y con ibu ing o
mo ili y and me as iza ion (Gao, 2014). Cell mo ion equi es
ha he cy oplasm iscosi y change in he cell pe iphe y
h ough he ans o ma ion o he gel s a e o a luidic one.
This mechanism also induces o ma ion o p o usions ha
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FIGURE 5 | Cell mo ili y: S age 0 (S eady s a e) -Cells main ain he connec ions o he ECM h ough he in eg ins; S age 1 (P o usion o he leading edge) -in e nal
o ces induce he F-ac in polyme iza ion and he wa e low en e s h ough he cell memb ane; he ac in polyme iza ion induce he o ma ion o p o usions; S age 2
(Adhesion o leading edge) - he co ex unde ension, accumula es new ac in, h ough he mo emen o unpolyme ized ac in o he p o usion edge, and new
adhesion molecules appea in he p o usion pa . S age 3 (Mo emen o he cell body) - he e is he con ac ion o he cell in he same di ec ion o he cell
mo emen , and he wa e low exi s om he cell in he opposi e di ec ion, con ibu ing o cell mo ili y; S age 4 (Deadhesion o he ailing edge) - Deadhesion on he
cell back edge: he in eg ins in he back o he cell dec eases, and new adhesion molecules appea ed in he on o he cell in he same di ec ion o cell mo emen
based on Tao e al. (2017).
acili a e cell locomo ion. Ac in ilamen s a e bond o he plasma
memb ane by a glycop o ein. In he p esence o his glycop o ein
cells a e s able, he p o usions a e well o ganized, occu ing
cell mo emen . I his glycop o ein is no p esen , as in he
case o ce ain human melanoma, locomo ion is impai ed,
and he plasma memb ane shows blebbing (because o he
cy oskele on ins abili y). I he p esence o he glycop o ein
is e-es ablished, blebbing disappea s and cell mo emen is
eco e ed. This glycop o ein also inc eases he s i ness o
no mal cells, meaning ha in melanoma cance he lack
o his p o ein inc eases he de o mabili y and con ibu es
o he e iciency o he mig a ion p ocess o umo cells
(Gao, 2014).
The whole cell, including he nucleus, mus p esen a ce ain
plas ici y. Inside he nucleus, he e is ch oma in oge he wi h
lamins in coo dina ion wi h he cy oskele on, main aining shape
and mechanical s abili y o he nucleus. Ch oma in wo ks like
an elas ic sp ing and is esponsible o he o ce esponse o
small de o ma ions o he nucleus. Lamin A de o ms easily
o small ex ensions and gi es s i ness o esis la ge nuclea
de o ma ions (S ephens e al., 2019). Mic o ubules in he cell
cy oskele on exe o ces gene a ed by dynein ha can de o m
o e en cause he up u e o he nucleus. Vimen in p o ec s
he nucleus gi ing i s abili y and pe inuclea s i ness, which
hinde s 3D mo ili y. Ac in also s abilizes he nucleus shape
oge he wi h mic o ubules (S ephens e al., 2019). Al e a ions
F on ie s in Cell and De elopmen al Biology | www. on ie sin.o g 9Feb ua y 2020 | Volume 8 | A icle 54
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B ás e al. Melanoma in he Eyes o Mechanobiology
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