Machine Learning Discoveries of WNT10B-X Synergy in ETC-1922159 Treated Colorectal Cancer Cells

Machine learning discoveries of WNT10B-X synergy in ETC-1922159 treated colorectal cancer cells shriprakash sinha Independent Researcher; Orcid ID : orcid.org/0000-0001-7027-5788 104-Madhurisha Heights Phase 1, Risali, Bhilai-490006, India Abstract Wnt family member 10B (WNT10B) is a cysteine-rich glycoprotein, that is a part of the WNT signaling pathway and is implicated in a range of cancers. In colorectal cancer (CRC) cells treated with ETC-1922159, WNT10B was found to be down regulated along with other genes. A recently developed search engine ranked combinations of WNT10B-X (X, a particular gene/protein) at 2nd order level after drug administration. Some of these combinations have been tested in wet lab, however many have been pointed out by the search engine that are yet to be explored/tested. These rankings reveal which WNT10B-X combinations might be working synergistically in CRC. In this research work, I cover combinations of WNT10B with mitogen-activated protein kinase (MAPK), GATA zinc finger containing domain antisense RNA (GATA-AS), fatty acid binding protein (FABP), helicase like transcription factor (HLTF), long intergenic non-protein coding RNA (LINC-xxxxx), frizzled class receptor (FZD), homeobox (HOX), cytochrome c oxidase assembly factor (COX), fibroblast growth factor (FGF), interleukin (IL), Rac GTPase (RAC), transforming growth factor beta (TGFB), low density lipoprotein receptor-related protein (LRP), notch receptor (NOTCH), SET and MYND domain containing (SMYD) and forkhead box (FOX) family. Keywords: WNT10B, Porcupine inhibitor ETC-1922159, Sensitivity analysis, Machine learning, Colorectal cancer. 1. Introduction 1.1. WNT10B WNT10B has been found to be implicated in a range of cancers. In gastric cancer, the knockdown of WNT10B showed reduced expression of cell proliferation and migration IML dicoveries of WNT10B-X synergy in ETC-1922159 treated CRC cells Email address: [email protected] (shriprakash sinha) 1Aspects of unpublished work were presented in a poster session at the first Wnt Gordon Research Conference, from 6-11 August 2017, held in Stowe, VT 05672, USA. Preprint submitted to Preprint January 8, 2025 as well as inhibition of epithelial-mesenchymal transition Wu et al. [1]. On the other hand, WNT10B is also involved in the formation of bone mass and progenitor maintenance of various kinds of tissue, while deletion of the same leads to loss of bone mass and mesenchymal progenitor cells Stevens et al. [2]. Their contribution is also reported in axonal regeneration in injured CNS Tassew et al. [3]. Furthermore, like WNT10B, WNT10A and WNT6 have shown to play a major role in inhibiting adipogenesis and stimulates osteoblastogenesis while regulating the mesenchymal stem cells Cawthorn et al. [4] & Collins et al. [5]. Involvement in heptocellular carcinoma of WNT10B has been found wherein it is shown that stable silencing of WNT10B leads to significant reduction in proliferation, colony formation, migration and invasion in HepG2 HCC cell line Wu et al. [6]. Its implication in breast cancer Wend et al. [7] & Chen et al. [8] as well as endometrial cancer Chen et al. [9] has also been reported. In colorectal cancer, WNT10B has shown to play a dual function of both oncogenesis promotion via β-catenin/TCF pathway and the inhibition of cell growth, possibly via FGF family of proteins Yoshikawa et al. [10]. Methylation of WNT10B has been found in the some of the cancer cell lines while its reversal has lead to over-expression of the WNT10B. However, the over-expression of WNT10B has lead to reduced cell growth in cancer, indicating a β-catenin independent component to be behind such a phenomena. Methylation of over-expressed WNT10B and synergistic work with FGF family of proteins later indicate the promotion of oncogenesis, as has been demonstrated in Yoshikawa et al. [10]. WNT10B works in tandem with multiple components and some combinations of WNT10B have been confirmed in wet lab. However, many of the combinations have not been explored/tested or are known. To reveal these combinations, I use a modification of a recently published machine learning based search engine, details of which are given in the next section. 1.2. Combinatorial search problem and a possible solution In a recently published work Sinha [11], a frame work of a search engine was developed which can rank combinations of factors (genes/proteins) in a signaling pathway. Readers are requested to go through the adaptation of the above mentioned work for gaining deeper insight into the working of the pipeline and its use of published data set generated after administration of ETC-1922159, Sinha [12]. The work uses SVM package by Joachims [13] in https://www.cs.cornell.edu/people/tj/svm_light/ svm_rank.html. I use the adaptation to rank 2nd order gene combinations. 2. Results & Discussion 2.1. WNT10B related synergies 2.1.1. WNT10B - MAPK15 / GATA6-AS1 / FABP5 / HLTF Chen et al. [14] demonstrate that WNT10B provides defense mechanisms against doxorubicininduced cardiotoxicity and apoptosis, via MAPK signaling. Khalid et al. [15] show that in GATA4 knockout mice bone marrow derived mesenchymal stem cells had reduction 2 in WNT ligands, particularly WNT10B as compared to control cells. They demonstrated that GATA4 is recruited to enhancers near WNT10B, thus regulating the WNT signalosome. In glioblastoma cells, Li et al. [16] exhibited a high level of FABP4 expression, and down-regulation of FABP4 suppressed tumor cell growth and metastasis. Further it was found that WNT10b, a regulator gene of FABP4, restored the effects of FABP4 down-regulation in glioblastoma cells. Helmer et al. [17] observe that HLTF regulates WNT10B signaling in brain. All these experimental validations point to existing combinatorial synergy between the involved members and WNT10B. In colorectal cancer cells treated with ETC-1922159, individual family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these individual members along with WBT10B. Table 1 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 2 generated from analysis of the ranks in table 1. The table 1 shows rankings of individual members w.r.t WNT10B. HLTF - WNT10B shows low ranking of 1162 (linear) and 1137 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Interestingly, MAPK15, GATA6-AS1 and FABP5 showed high ranking with WNT10B, thus indicating that they might not be working synergistically with WNT10B, before the drug treatment. RANKING INDIVIDUAL MEMBERS VS WNT10B RANKING OF INDIVIDUAL MEMEBRS W.R.TWNT10B laplace linear rbf MAPK15 - WNT10B 574 2470 2147 GATA6-AS1 - WNT10B 475 2031 2240 FABP5 - WNT10B 277 2222 2461 HLTF - WNT10B 1816 1162 1137 Table 1: 2nd order interaction ranking between WNT10B VS individual members. One can also interpret the results of the table 1 graphically, with the following influences - •individual members w.r.t WNT10B with WNT10B −>HLTF. UNEXPLORED COMBINATORIAL HYPOTHESES Individual members w.r.t WNT10B HLTF WNT10B Table 2: 2nd order combinatorial hypotheses between WNT10B and individual members. 3 2.1.2. WNT10B - LINC-xxxxx In colorectal cancer cells, Xi et al. [18] demostrated that inhibition of LINC00261 caused an increase in microRNA-148a expression and a decrease in expression of WNT10B and β-catenin. These indicate that LINC00261 may affect colon cancer progression by modulating the miR-148a/WNT10b axis. In colorectal cancer cells treated with ETC-1922159, LINC-xxxxx family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these LINC-xxxxx members along with WBT10B. Table 3 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 4 generated from analysis of the ranks in table 3. The table 3 shows rankings of LINC-xxxxx members w.r.t WNT10B. LINC00261 - WNT10B shows low ranking of 651 (laplace) and 1513 (rbf). LINC01123 - WNT10B shows low ranking of 1126 (laplace) and 1528 (rbf). LINC00888 - WNT10B shows low ranking of 1216 (laplace), 961 (linear) and 898 (rbf). LINC00338 - WNT10B shows low ranking of 530 (linear) and 543 (rbf). LINC00242 - WNT10B shows low ranking of 754 (linear) and 1001 (rbf). LINC00858 - WNT10B shows low ranking of 860 (linear) and 769 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, LINC01106 showed high ranking with WNT10B, thus indicating that they might not be working synergistically with WNT10B, before the drug treatment. RANKING LINC-XXXXX FAMILY VS WNT10B RANKING OF LINC-XXXXX FAMILY W.R.TWNT10B laplace linear rbf laplace linear rbf LINC01106 - WNT10B 503 2295 1998 LINC00261 - WNT10B 651 1767 1513 LINC01123 - WNT10B 1126 1787 1528 LINC00888 - WNT10B 1216 961 898 LINC00338 - WNT10B 1651 530 543 LINC00242 - WNT10B 2258 754 1001 LINC00858 - WNT10B 2364 860 769 Table 3: 2nd order interaction ranking between WNT10B VS LINC-xxxxx members. One can also interpret the results of the table 3 graphically, with the following influences - •LINC-xxxxx members w.r.t WNT10B with WNT10B −>LINC-00261 / 01123 / 00888 / 00338 / 00242 / 00858. UNEXPLORED COMBINATORIAL HYPOTHESES LINC-xxxxx members w.r.t WNT10B LINC-00261/01123/00888/00338/00242/00858 - WNT10B Table 4: 2nd order combinatorial hypotheses between WNT10B and LINC-xxxxx members. 4 2.1.3. WNT10B - FZD In Tcell acute lymphoblastic leukemia, using MOLT4 and MUTZ-2 as leukemic cell models characterized by the expression of WNT10BIVS1, Cassaro et al. [19] observed that WNT10B drives WNT activation via FZD6 receptor ligand binding. In colorectal cancer cells treated with ETC-1922159, FZD family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these FZD members along with WBT10B. Table 5 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 6 generated from analysis of the ranks in table 5. The table 5 shows rankings of FZD members w.r.t WNT10B. FZD7 - WNT10B shows low ranking of 1121 (laplace), 1331 (linear) and 1395 (rbf). FZD3 - WNT10B shows low ranking of 724 (linear) and 727 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. RANKING FZD FAMILY VS WNT10B RANKING OF FZD FAMILY W.R.TWNT10B laplace linear rbf FZD7 - WNT10B 1121 1331 1395 FZD3 - WNT10B 1805 724 727 Table 5: 2nd order interaction ranking between WNT10B VS FZD members. One can also interpret the results of the table 5 graphically, with the following influences - •FZD members w.r.t WNT10B with WNT10B −>FZD-7/3. UNEXPLORED COMBINATORIAL HYPOTHESES FZD members w.r.t WNT10B FZD-7/3 - WNT10B Table 6: 2nd order combinatorial hypotheses between WNT10B and FZD members. 2.1.4. WNT10B - HOX In oral squamous cell carcinoma cells, Dai et al. [20] found an enhanced migration ability induced by WNT10B, but it was reversed by HOXC10 knockdown. In colorectal cancer cells treated with ETC-1922159, HOX family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these HOX members along with WBT10B. 5 Table 7 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 8 generated from analysis of the ranks in table 7. The table 7 shows rankings of HOX members w.r.t WNT10B. HOXB8 - WNT10B shows low ranking of 1233 (laplace), 1144 (linear) and 1487 (rbf). HOXB9 - WNT10B shows low ranking of 1413 (laplace), 1264 (linear) and 1321 (rbf). HOXB4 - WNT10B shows low ranking of 1554 (laplace), 1579 (linear) and 1354 (rbf). HOXA9 - WNT10B shows low ranking of 1556 (laplace), 518 (linear) and 668 (rbf). HOXB5 - WNT10B shows low ranking of 296 (linear) and 481 (rbf). HOXA11 - WNT10B shows low ranking of 74 (linear) and 584 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, HOXB13, HOXB7, HOXB3 and HOXA11-AS showed high ranking with WNT10B, thus indicating that they might not be working synergistically with WNT10B, before the drug treatment. RANKING HOX FAMILY VS WNT10B RANKING OF HOX FAMILY W.R.TWNT10B laplace linear rbf laplace linear rbf HOXB13 - WNT10B 82 2417 2583 HOXB7 - WNT10B 84 2709 2705 HOXB3 - WNT10B 838 1950 1912 HOXA11-AS - WNT10B 860 2021 1866 HOXB8 - WNT10B 1233 1144 1487 HOXB9 - WNT10B 1413 1264 1321 HOXB4 - WNT10B 1554 1579 1354 HOXA9 - WNT10B 1556 518 668 HOXB5 - WNT10B 1950 296 481 HOXA11 - WNT10B 2612 74 584 Table 7: 2nd order interaction ranking between WNT10B VS HOX members. One can also interpret the results of the table 7 graphically, with the following influences - •HOX members w.r.t WNT10B with WNT10B −>HOX-B8/B9/B4/A9/B5/A11. UNEXPLORED COMBINATORIAL HYPOTHESES HOX members w.r.t WNT10B HOX-B8/B9/B4/A9/B5/A11 WNT10B Table 8: 2nd order combinatorial hypotheses between WNT10B and HOX members. 2.1.5. WNT10B - COX WNT10B can promote bone morphogenetic protein 9 (BMP9) induced osteogenic differentiation via the COX2/p-CREB dependent manner, as obaerved by Liao et al. [21]. In colorectal cancer cells treated with ETC-1922159, COX family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these COX members along with WBT10B. Table 9 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 10 generated from analysis of the ranks in table 9. 6 The table 9 shows rankings of COX members w.r.t WNT10B. COX10-AS1 - WNT10B shows low ranking of 1429 (linear) and 1261 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, COX10, COX14 and COX18 showed high ranking with WNT10B, thus indicating that they might not be working synergistically with WNT10B, before the drug treatment. RANKING COX FAMILY VS WNT10B RANKING OF COX FAMILY W.R.TWNT10B laplace linear rbf COX10 - WNT10B 13 2300 2219 COX14 - WNT10B 448 2178 2186 COX18 - WNT10B 611 2224 2135 COX10-AS1 - WNT10B 1757 1429 1261 Table 9: 2nd order interaction ranking between WNT10B VS COX members. One can also interpret the results of the table 9 graphically, with the following influences - •COX members w.r.t WNT10B with WNT10B −>COX10-AS1. UNEXPLORED COMBINATORIAL HYPOTHESES COX members w.r.t WNT10B COX-10-AS1 WNT10B Table 10: 2nd order combinatorial hypotheses between WNT10B and COX members. 2.1.6. WNT10B - FGF Xiao et al. [22] support the hypothesis that the impaired anabolic response to parathyroid hormone in the absence of endogenous FGF2 is due in part to attenuated WNT signaling. WNT10B expression was altered by FGF2 deficiency. In colorectal cancer cells treated with ETC-1922159, FGF family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these FGF members along with WBT10B. Table 11 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 12 generated from analysis of the ranks in table 11. 7 The table 11 shows rankings of FGF members w.r.t WNT10B. FGF2 - WNT10B shows low ranking of 1020 (laplace), 1223 (linear) and 1155 (rbf). FGFBP3 - WNT10B shows low ranking of 740 (linear) and 384 (rbf). FGFR4 - WNT10B shows low ranking of 454 (linear) and 716 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. RANKING FGF FAMILY VS WNT10B RANKING OF FGF FAMILY W.R.TWNT10B laplace linear rbf FGF2 - WNT10B 1020 1223 1155 FGFBP3 - WNT10B 2353 740 384 FGFR4 - WNT10B 2403 454 716 Table 11: 2nd order interaction ranking between WNT10B VS FGF members. One can also interpret the results of the table 11 graphically, with the following influences - •FGF members w.r.t WNT10B with WNT10B −>FGF-2/BP3/R4. UNEXPLORED COMBINATORIAL HYPOTHESES FGF members w.r.t WNT10B FGF-2/BP3/R4 WNT10B Table 12: 2nd order combinatorial hypotheses between WNT10B and FGF members. 2.1.7. WNT10B - IL He et al. [23] observed high level of IL17A promoted mesenchymal stem cells-2 polarization through WNT10B/RUNX2 pathway in new bone formation developed in ankylosing spondylitis. In colorectal cancer cells treated with ETC-1922159, IL family members and WNT10B, were found to be down regulated and their regulation was recorded independently. I was able to rank 2nd order combination of these IL members along with WBT10B. Table 13 shows rankings of these combinations. Followed by this is the unexplored combinatorial hypotheses in table 14 generated from analysis of the ranks in table 13. The table 13 shows rankings of IL members w.r.t WNT10B. IL1RL2 - WNT10B shows low ranking of 991 (laplace) and 1502 (rbf). IL17D - WNT10B shows low ranking of 1546 (laplace), 762 (linear) and 706 (rbf). IL17RB - WNT10B shows low ranking of 825 (linear) and 573 (rbf). ILF3 - WNT10B shows low ranking of 343 (linear) and 412 8 (rbf). ILF3-AS1 - WNT10B shows low ranking of 591 (linear) and 631 (rbf). These rankings point to the synergy existing between the two components, which have been down regulated after the drug treatment. Further, IL17RD, ILF2 and IL33 showed high ranking with WNT10B, thus indicating that they might not be working synergistically with WNT10B, before the drug treatment. RANKING IL FAMILY VS WNT10B RANKING OF IL FAMILY W.R.TWNT10B laplace linear rbf IL17RD - WNT10B 330 2190 2407 ILF2 - WNT10B 529 2509 2338 IL1RL2 - WNT10B 991 1871 1502 IL33 - WNT10B 1118 1562 1694 IL17D - WNT10B 1546 762 706 IL17RB - WNT10B 1829 825 573 ILF3 - WNT10B 2231 343 412 ILF3-AS1 - WNT10B 2629 591 631 Table 13: 2nd order interaction ranking between WNT10B VS IL members. One can also interpret the results of the table 13 graphically, with the following influences - •IL members w.r.t WNT10B with WNT10B −>IL-1RL2/17D/17RB/F3/F3AS1. UNEXPLORED COMBINATORIAL HYPOTHESES IL members w.r.t WNT10B IL-1RL2/17D/17RB/F3/F3-AS1 WNT10B Table 14: 2nd order combinatorial hypotheses between WNT10B and IL members. 2.1.8. 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