WNT-mediated regulation of regeneration and oncogenesis

Abstract

WNT signaling is a key cell-cell communication pathway that regulates essential cellular processes such as cell fate determination and proliferation. Accordingly, WNT signaling plays critical roles during embryogenesis, adult tissue homeostasis and regeneration. WNT signaling is initiated via interactions of secreted WNT proteins with Frizzled (FZD) receptors and different co-receptors, activating either canonical (β-catenin-dependent) or non-canonical intracellular pathways. The diversity of ligands (19 WNT genes) and receptors (10 FZD genes) creates potential for combinatorial signaling via temporally and spatially regulated ligand and receptor expression patterns. In this thesis, we explore the central role of two developmental WNT proteins, WNT7B and WNT10A, that are typically absent during adult tissue homeostasis but become re-expressed during tissue regeneration and tumorigenesis. Upon tissue damage, WNT signaling is activated to drive injury-induced reprogramming and regeneration during the process of tissue repair. For instance, wounding of the intestinal epithelium mediates a transient reprogramming of epithelial cells into a fetal-like state, which enables uniform cell proliferation, tissue remodeling, and the restoration of tissue homeostasis. These steps are coordinated by WNT and YAP signaling, although the exact mechanism remains unclear. We describe that WNT7B and WNT10A are re-expressed during injury and regeneration of multiple epithelial tissues, indicating that these WNTs mediate a conserved pathway for tissue repair. Our findings indicate that these WNTs not only promote β-catenin target gene activation but also regulate YAP-driven injury-associated transcriptional programs, thereby playing a central role in the coordination of the intestinal regenerative process upon injury. In cancer, hyperactivated WNT signaling is a hallmark of tumorigenesis. In line, some cancers acquire elevated expression of WNT proteins to drive their own proliferation, of which WNT7B and WNT10A are prime examples. Our work shows that their increased abundancy correlates with more aggressive epithelial cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, we find that these WNTs are heterogeneously expressed in PDAC organoids and promote cancer cell survival and proliferation, while shifting tumor cells towards a more aggressive, basal-like PDAC expression profile. Besides, WNT-positive cells drive the survival and proliferation of neighboring WNT-negative cells within tumors via short-range signaling. These findings suggest that WNT inhibition could induce a shift toward a less aggressive cancer subtype, potentially improving therapeutic responses. FZD receptors are central to WNT signal transduction, with their expression patterns and roles varying across tissues. In this thesis, we uncover that PDAC cancer cells employ a subset of FZD receptors to drive a classical -catenin-dependent program of WNT signaling for cell proliferation and survival. By contrast, we uncover another subset of FZD receptors that activate a previously unknown -catenin-independent program for cancer cell survival and aggressiveness when PDAC organoids are placed under challenging growth conditions. These insights suggest that targeting specific FZD subsets in cancer may offer therapeutic potential for treatment of aggressive cancers. In conclusion, this thesis highlights the conserved and context-specific roles of WNT signaling in development, regeneration, and disease. By advancing our understanding of specific WNT proteins and FZD receptors, this work opens avenues for regenerative medicine and cancer therapy.