Regulation of epithelial cell fate decisions in tissue homeostasis and cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

Non-melanoma skin cancers, including Basal Cell Carcinoma (BCC), are the most frequently diagnosed human cancers. BCC is caused by dysregulated Hedgehog signaling, stemming from mutations that over-activate the G-protein coupled receptor (GPCR) Smoothened (SMO). SMO causes uncontrolled basal cell proliferation and blockage of differentiation, leading to tumor formation. More than 3 million cases of BCC are diagnosed each year in the US alone, causing a significant burden to the healthcare system. Most BCCs are easily treated by surgical removal, although some can be difficult due to their high numbers, location, or localized tumor spread. Alternative therapies in these cases involve using SMO inhibitors or immunotherapy, although side effects and therapeutic resistance undermine their use. The deficiency of additional therapies for BCC and the fact that Hedgehog signaling is an oncogenic pathway in other tumor types makes it a priority to find novel therapeutic options for targeting Hedgehog-driven tumors. BCC is a prototypical GPCR-driven cancer. GPCRs are the most diverse family of cell-surface receptors, relaying their signaling by coupling to heterotrimeric Galpha, beta, and gamma subunits or by G-protein independent pathways. Classic stem cell regulatory signals like Hedgehog and WNT rely on G protein-independent pathways to regulate cell proliferation and differentiation. Nevertheless, I found a novel Galpha protein-dependent pathway vital to coordinating epithelial cell fate and Hedgehog signaling. Gs and Gi heterotrimeric Galpha proteins either stimulate (Gs) or inhibit (Gi) production of the second-messenger cyclic AMP (cAMP). In mouse skin, inactivating Gs or its downstream target protein kinase A (PKA) blocks basal cell differentiation and triggers BCC formation. Gs or PKA disruption alone can activate Hedgehog GLI and Hippo YAP1, revealing a high degree of overlap between these signaling pathways. Understanding how Gs and PKA signaling regulate Hedgehog and BCC formation could reveal new targets for the pharmacological intervention of somatic stem cell activity to reduce cancer growth. Hence, my current research plan focuses on dissecting the crosstalk between Gs-PKA and Hedgehog signaling and characterizing cell fate regulation by the downstream signals of these pathways. Beyond BCC, we are exploring the role of PKA inactivation by protein kinase A inhibitor proteins (PKIs) in tumor growth and metastasis in other organs, particularly in prostate cancer. Prostate cancer shows amplifications on the PKIalpha gene, and we have demonstrated that PKIalpha is involved in prostate cancer cell growth. We are characterizing the molecular mechanisms regulated by PKI in this tumor type.