Molecular mechanisms underlying the development Genitourinary Cancers
Research #1: Role of p63 in development and renewal of the prostate epithelium
Unraveling the mechanisms regulating the development and renewal of normal tissues is not only one of the main goals of developmental biology but also an essential step for the elucidation of the mechanisms underlying the development of pathological processes, namely cancer. Although epithelial stem cells have been identified in the skin and intestine, the way the prostate and epithelium are formed and maintained remains unclear. The basal cell marker p63 is selectively expressed in the basal cells of several epithelia, including the prostate. My research group has previously demonstrated that p63-deficient (p63-/-) mice present defects in prostate buds indicating that p63-positive cells are required for normal prostate development (Signoretti et al., Am J Pathol 2000). We have more recently performed in vivo studies and found that ΔNp63-positive cells of the urogenital sinus generate all epithelial lineages of the prostate, indicating that these cells represent the stem/progenitor cells of this epithelium during development. We also observed ΔNp63 expression in caudal gut endoderm and the contribution of ΔNp63-positive cells to the stem/progenitor compartment of adult colorectal epithelium. Because p63 is a master regulator of stratified epithelial development, this finding provides a unique developmental insight into the cell of origin of squamous cell metaplasia and squamous cell carcinoma of the colon (Signoretti et al, Proc Natl Acad Sci U S A 2005; Pignon et al, Proc Natl Acad Sci U S A 2013). My current research aims at further defining stem cells and differentiation programs in the adult prostate epithelium. Specifically, we are performing genetic lineage tracing experiments to directly follow the fate of p63-positive cells in the adult prostate in vivo. The secondary goal of this endeavor is to identify molecular mechanisms mediating p63 function during both development and tumorogenesis. We have shown that prostate basal cells predominantly express the ΔNp63α isosform and that ΔNp63α is required for cell survival. Importantly, we have also demonstrated that Fatty Acid Synthase (FASN) is a functionally relevant target of p63 and is required for mediating its pro-survival effects (Sabbisetti, PLoS ONE, 2009). Our results establish a novel functional link between this p53 family member and lipid metabolism and suggest that maintenance of fatty acid synthesis is a key mechanism through which p63 acts as a pro-survival molecule in both development and cancer.
Research #2: Molecular Analysis Of Renal Cell Carcinoma
Clear cell renal cell carcinoma (cRCC) represents the most common and fatal form of renal cancer and accounts for 70-80% of cases. In patients with advanced disease, response rates to traditional chemotherapy and radiotherapy are, unfortunately, very low. The introduction of cytokine-based immunotherapy with interferon-α or interleukin-2 for patients with metastatic disease has shown survival improvements, but the treatment is often not well tolerated and only a limited subset of patients experience clinically meaningful benefit. Recently, tyrosine kinase inhibitors (TKIs) that target the VHL pathway have shown clear activity in metastatic cRCC and have received approval by the FDA. However, not all the patients treated with these targeted therapies experience a substantial clinical benefit and almost all of them eventually progress. Therefore, more effective treatments for cRCC are warranted. High-throughput genetic studies represent a unique opportunity to identify the tumor suppressor genes (TSGs) and oncogenes, upon which genetic subtypes of cRCC depend. In collaboration with Drs. Kaelin and Beroukhim at DFCI and the Broad Institute, we have performed integrated analysis of SNP array data describing chromosomal aberrations with matched gene expression data to identify candidate genes targeted by these aberrations in cRCC (Beroukhim et al, Cancer Res, 2009). We continue to carry out this work as part of the NCI-sponsored TCGA effort. Results from these studies will shed light on the molecular mechanisms underlying kidney cancer development and might eventually lead to more effective targeted therapies for this disease.