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Vanderbilt-Ingram Cancer CenterVanderbilt-Ingram Cancer Center

Albert B.  Reynolds

Albert B. Reynolds, Ph.D.

Ingram Professor of Cancer Research
Professor of Cancer Biology
Executive Director, Vanderbilt Antibody and Protein Resource (VAPR)
Program Director, VICC Signal Transduction & Cell Proliferation Research Program
VICC Member

Contact Information:

Vanderbilt University Medical Center
440-C Preston Building
Nashville, TN 37232-6840

Research Specialty

p120-catenin and Kaiso function in cell-cell adhesion and cancer

Research Description

My laboratory combines molecular and biochemical approaches with 3D culture and mouse models of colon and breast cancer to study the roles of p120-catenin (p120) in cell-cell adhesion, tumorigenesis and metastasis. Most proteins linked physically or functionally to p120 are, in fact, tumor suppressors or oncogenes (eg, Src, Receptor Tyrosine kinases, Rho GTPases, E-cadherin, B-catenin, Adenomatous Polyposis Coli), implying a role for p120 in cancer. Previously, we showed that p120 interaction is essential for cadherin stability at the cell surface. For example, p120 knockdown in many epithelial cell lines (eg, MCF10A, A431) causes rapid degradation of the entire E-cadherin complex and partial or complete loss of cell-cell adhesion. These observations have led to the notion that p120 itself is a tumor and/or metastasis suppressor - on its own, or in collaboration with E-cadherin. Indeed, E-cadherin is broadly established as a tumor and metastasis suppressor and p120 is frequently downregulated and/or mislocalized in most major human cancers (e.g. colon, breast, lung, pancreas, prostate).

We are heavily invested in mouse models of colon cancer. Using conditional p120 KO in APC mutant mice, we recently found that p120 is, in fact, a haploinsufficient tumor suppressor in the colon (and probably other tissues). Interestingly, loss of one p120 allele increases tumor number by 10 fold. Although biallic loss is well tolerated in wild type intestinal epithelium, it is not permitted in the context of the tumor. Based on data from Sleeping Beauty insertional mutagenesis screens (in collaboration with Neal Copeland) we have extended these findings to a-catenin and E-cadherin, and to several different oncogenic backgrounds (e.g., K-Ras, Smad4, p53). Thus, it appears that loss of E-cadherin complex components is not restricted to late stage tumors. Instead, very early loss of any single allele for p120, a-catenin or E-cadherin likely comprises a major bottleneck to tumor progression, exceeded only by the mandatory initiating mutation in APC.

In the mammary gland, we are using a well-characterized MMTV-mT breast cancer model to examine the role of p120 in metastasis. Interestingly, in contrast to the intestine, the mammary gland does not form at all in the absence of p120. Transformation by mT, on the other hand, rescues the epithelium and gives rise to p120 null primary tumors. However, tumor cells lacking p120 cannot metastasize to the lung. Thus, we have arrived at a unique and powerful system for examining not only the role of p120 (and p120 isoforms) in metastasis, but also recently postulated roles for EMT and ???stemness??? as they pertain to the metastatic process. The system is complemented by mechanistic studies based on ex-vivo manipulation of cells follow by reconstitution in vivo or in in vitro 3D cell cultures.

Finally, A third line of research focuses on the transcription factor Kaiso, discovered some time ago in our lab as a direct p120 binding partner. The interaction is reminiscent of Wnt-pathway mediated B-catenin ??? TCF4 interactions and may connect p120 to the nucleus. The Kaiso landscape is evolving rapidly in the wake of whole genome sequencing technologies such as ChipSEQ. We are examining different aspects of Kaiso activity in intestinal and mammary systems and moving into exciting new areas including epigenetics, transcription and genome maintenance. Kaiso is going to be an exciting place to be over the next decade.