Cellular and molecular mechanisms underlying planar cell polarity pathway contributions to cancer malignancy

Abstract

While the mutational activation of oncogenes drives tumor initiation and growth by promoting cellular transformation and proliferation, increasing evidence suggests that the subsequent re-engagement of largely dormant developmental pathways contributes to cellular phenotypes associated with the malignancy of solid tumors. Genetic studies from a variety of model organisms have defined many of the components that maintain epithelial planar cell polarity (PCP), or cellular polarity in the axis orthogonal to the apical-basal axis. These same components comprise an arm of non-canonical Wnt signaling that mediates cell motility events such as convergent extension movements essential to proper development. In this review, we summarize the increasing evidence that the Wnt/PCP signaling pathway plays active roles in promoting the proliferative and migratory properties of tumor cells, emphasizing the importance of subcellular localization of PCP components and protein-protein interactions in regulating cellullar properties associated with malignancy. Specifically, we discuss the increased expression of Wnt/PCP pathway components in cancer and the functional consequences of aberrant pathway activation, focusing on Wnt ligands, Frizzled (Fzd) receptors, the tetraspanin-like proteins Vangl1 and Vangl2, and the Prickle1 (Pk1) scaffold protein. In addition, we discuss negative regulation of the Wnt/PCP pathway, with particular emphasis on the Nrdp1 E3 ubiquitin ligase. We hypothesize that engagement of the Wnt/PCP pathway after tumor initiation drives malignancy by promoting cellular proliferation and invasiveness, and that the ability of Wnt/PCP signaling to supplant oncogene addiction may contribute to tumor resistance to oncogenic pathway-directed therapeutic agents.

Frizzled-dependent Planar Cell Polarity without Wnt Ligands

“…In a wide range of metazoans, PCP contributes to cell proliferation, cell fate decisions, body axis elongation and morphogenesis, as well as to the orientation of cellular protrusions such as hairs (Goodrich and Strutt, 2011;Adler, 2012;Yang and Mlodzik, 2015;Butler and Wallingford, 2017;Lawrence and Casal, 2013). Moreover, aberrant PCP has been linked to disease such as polycystic kidney disease, deafness, and cancer (Yates et al, 2010;Lu and Sipe, 2016;VanderVorst et al, 2018). Understanding the molecular basis of PCP establishment and maintenance is therefore important from both a fundamental and a biomedical perspective.…”

Wnt/PCP Signaling Contribution to Carcinoma Collective Cell Migration and Metastasis

“…Dysregulation of core Wnt/PCP components has been reported to promote cell migration, invasion, or metastasis in breast (95-101), brain (84), ovarian (102), prostate (103), gastric (104), and colorectal cancers (105,106). The contribution of Wnt/PCP signaling to the progression of such diverse tumor types suggests that pathway dysregulation may be a common feature of solid tumor malignancy (30). Importantly, mechanistic studies of Wnt/PCP in development and cancer contexts suggests that Wnt/PCP component localization may be critical to the defining features of collective cell migration, including cell polarization at the leading edge of a migrating collective and maintenance of cell-cell contact within the migrating collective.…”

“…In vitro motility studies An abundance of evidence suggests that Wnt/PCP signaling is a major driver of migration, invasion, and metastasis in a wide Cancer Research variety of solid tumor types (30), and likely mediates both single and collective migratory modes. Historically, in vitro assays such as the scratch migration and Boyden chamber methods have been used to explore mediators of cell motility in numerous cell types, but these results are likely skewed toward the single-cell migratory mode.…”

“…Dvl serves as both a scaffold and activator of downstream effector components such as Rho family GTPases and JNK, which in turn modulate actin cytoskeleton organization to promote cellular motility. Adapted with permission from Elsevier (30). C, Findings from both developmental and cancer contexts demonstrate that collective migration is at least partially dependent upon asymmetric localization of Wnt/PCP core component complexes within leader and follower cells.…”

“…In both static epithelial tissues and migrating cells, noncanonical Wnt ligands provide global instructional cues necessary for proper Wnt/PCP signaling (27)(28)(29). Importantly, core Wnt/PCP components are dysregulated in a variety of solid tumors and have been directly implicated in promoting tumor cell migration and metastasis (30).…”