Our laboratory is interested in understanding the molecular mechanisms involved in the development and progression of genitourinary malignances, with particular emphasis on prostate, bladder and renal cancer.
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 bladder 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 and the bladder. My research group has previously demonstrated that p63-deficient (p63-/-) mice present defects in prostate buds and urothelial development (Signoretti et al., Am J Pathol 2000). We have more recently performed in vivo studies utilizing the p63-/- mouse as a tool to define cell lineages in the prostate epithelium and urothelium. Results from these studies show that when developmental defects of p63-/- embryos are abolished by injecting p63+/+ ES cells into 3.5dpc p63-/- blastocysts, only p63+/+ cells compose the normal prostate epithelium of 7-weeks old chimeric mice.
These findings indicate that prostate secretory cells of young adult mice derive from p63-positive progenitor cells that constitute the prostate buds. Surprisingly, in contrast with the prostate findings, analysis of the urothelium of the rescued p63-/- chimeras demonstrates that urothelial umbrella cells can develop independently from p63-positive basal and intermediate cells (Signoretti et al, Proc Natl Acad Sci U S A 2005).
My current research aims at further defining stem cells and differentiation programs in the adult prostate and bladder epithelia. Specifically, we are performing genetic lineage tracing experiments to directly follow the fate of p63-positive cells in the prostate and bladder epithelia in vivo.
The secondary goal of this endeavor is to identify molecular mechanisms mediating p63 function during both development and tumorigenesis. We have shown that prostate basal cells predominantly express the Np63 isoform and that Np63 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.
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-a 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, including sorafenib and sunitinib, 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.
Kinases are tractable therapeutic targets with multiple small molecule inhibitors in development. Identification of new kinases that play an important role in the development and progression of cRCC would enable rapid development of more effective therapeutic approaches. High-throughput genetic studies represent a unique opportunity to identify the tumor suppressor genes (TSGs) and oncogenes, including kinases, upon which genetic subtypes of cRCC depend. High-resolution single nucleotide polymorphism (SNP) arrays are able simultaneously to delineate regions of copy-number gain and loss and loss-of-heterozygosity (LOH) at high resolution throughout the genome.
In collaboration with Drs. Kaelin and Beroukhim at DFCI and the Broad Institute, we are currently performing integrated analysis of SNP array data describing chromosomal aberrations with matched gene expression data to identify candidate kinases targeted by these aberrations in cRCC (Beroukhim et al, Cancer Res, 2009). 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.
