*2.1.3 Wnt pathway*

Wnt signaling cascades regulate multiple cellular processes including cell polarity, migration, adhesion, proliferation, and developmental events, such as embryogenesis and tissue morphogenesis [33, 55]. The two main Wnt pathways, non-canonical and canonical, are characterized by the involvement of β-catenin, which is one of the key components in cell-cell adhesion and cell migration, in addition to its role in Wntmediated gene transcription. In non-canonical signaling, small GTPases of the Rho family or heterotrimeric G proteins, independently from β-catenin, are activated to

control cell polarity and calcium signaling, respectively [56, 57]. The Wnt/β-catenin pathway (a.k.a. canonical pathway) is initiated via the activation of the frizzled receptor by Wnt proteins [58]. Activated receptors recruit and activate the cytoplasmic protein Disheveled, which inactivates the β-catenin destruction complex that is composed of proteins, including Axin, Adenomatous Polyposis Coli (APC) and GSK-3β. Since β-catenin levels are kept low by the destruction complex, the inactivation of the complex enables cytoplasmic accumulation of β-catenin. Accumulated β-catenin then translocates to the nucleus and interacts with the TCF/LEF family proteins to control transcription [55, 56].

In cancer, Wnt signaling becomes dysregulated and Wnt target genes can regulate tumor progression and drug resistance [55, 58, 59]. The Wnt/β-catenin pathway is associated with poor prognosis in ovarian tumors and has been shown to be a key regulator of chemoresistance in different cancer types including ovarian, colon, prostate, and pancreatic [60–63]. In a study by Viscarra *et al*., transcriptomic sequencing analysis of parental and carboplatin-resistant A2780 cells revealed 156 differentially expressed genes, among which those related to the Wnt/β-catenin pathway and integrin signaling were the most enriched (15.2 and 10.9%, respectively) [64]. Upregulation of one of the integrin signaling pathway members, COL11A1, in carboplatin-resistant A2780 cells is important to note because COL11A1 overexpression has been reported to be an indicator of poor prognosis, metastasis, and drug resistance in ovarian cancer. Interestingly, Viscarra *et al.* also reported that, compared to carboplatin-resistant A2780 cells, parental A2780 cells showed significant increases in caspase-3/7 cleavage, which are indicators of apoptosis. Together these findings suggest that integrins and the Wnt/β-catenin pathway can synergistically regulate carboplatin resistance in A2780 cells [64, 65]. In accordance with these findings, a study by Crampton *et al.* revealed that integrin-mediated signals can synergize with the Wnt pathway through the adapter protein growth factor Grb2 [33]. Additionally, Burkhalter *et al.* found that integrin clustering and binding to collagen increased nuclear β-catenin levels, thereby promoting transcriptional activation of Wnt/βcatenin pathway target genes [66].
