Regulation of epithelial cell fate decisions in tissue homeostasis and cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications & trials

Abstract

Non-melanoma skin cancers, like Basal Cell Carcinoma (BCC), are the most common human cancers. BCC arises from dysregulated Hedgehog signaling, often caused by mutations that hyperactivate Smoothened (SMO), a G-protein-coupled receptor (GPCR). This hyperactivation leads to uncontrolled proliferation of basal cells and impaired differentiation, resulting in tumor formation. In the United States alone, over 3 million BCC cases are diagnosed annually, creating a significant healthcare burden. While most BCCs are treated through surgical removal, some cases present challenges due to their quantity, location, or spread. Alternative therapies, such as SMO inhibitors or immunotherapy, have severe side effects and therapeutic resistance. These facts highlight the need for additional treatment options for BCC. Since Hedgehog signaling is active in numerous other types, developing novel therapeutic strategies for Hedgehog-driven cancers is crucial. BCC serves as a prime example of a GPCR-driven cancer. GPCRs, the most diverse family of cell-surface receptors, signal through heterotrimeric G-protein subunits or G-protein-independent pathways. While classic stem cell regulatory signals like Hedgehog and WNT employ G protein-independent pathways, our research has revealed a novel Galpha protein-dependent pathway that is crucial for coordinating epithelial cell fate and Hedgehog signaling. We discovered that Galphas and its downstream effector, protein kinase A (PKA), inhibit basal cell differentiation, and their inhibition induces BCC formation. Understanding how Galphas and PKA signaling regulate tumor formation could lead to new pharmacological targets for modulating somatic stem cell activity to inhibit cancer growth. For the past years, my research program has focused on untangling the signaling and transcriptional mechanisms that govern BCC initiation and progression. We have focused on the interplay between GPCR-Galphas/PKA signaling and the canonical Hedgehog pathway, as well as the role of Hippo signaling in tumor cell fate. Our goal is to identify new pharmacological targets that can intervene in somatic stem cell activity, potentially reducing cancer growth or enhancing tissue regeneration. A key factor in the success of our program has been the pioneering development and application of unique organotypic and signaling disruption mechanisms, which enable us to investigate the precise mechanisms of signaling pathways in cell proliferation and differentiation.