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Scott Kuwada

Associate Professor of Oncological Sciences and of Medicine

B.A.Whitman College

M.D. University of Hawaii

Research

References

Scott Kuwada's Lab Page

Research

Cell adhesion is central not only to normal cell function but to cancer metastasis as well. The extracellular matrix exerts strong selective pressures on genetically unstable neoplastic cells. The existence of these selective pressures is manifested by tumor cell invasion through the underlying stroma, a process that defines cancer. Our laboratory studies the mechanisms by which normal cell adhesion-induced signaling and regulation is usurped in gastrointestinal cancer.

Integrins are the largest and most diverse class of adhesion molecules expressed by gastrointestinal epithelial cells. ß1 integrins comprise the most diverse subclass of integrins expressed by gastrointestinal epithelial cells, and, integrin expression is specifically lost during colorectal tumorigenesis.

Our lab has two main areas of interest:

1) Integrin mediated growth factor signaling:  In order to understand the roles of integrins in gastrointestinal cancers, one must first understand their roles in normal gastrointestinal epithelial biology. The study of the mechanism(s) by which ß1 integrins regulate epithelial proliferation in vivo is limited, so we have utilized the Cre-lox genetic system in mice to conditionally delete ß1 integrins in the intestinal epithelial cells. ß1 integrin homodimerizes with several alpha integrins to form cell surface receptors that bind to collagens, fibronectin, laminins, and vitronectin, which are principal constituents of the intestinal basement membrane.  Conditional deletion of ß1 integrins in the intestinal epithelium causes epithelial hyperproliferation, dysplasia, polyp formation, and, stromal expansion-features in common with intestinal tumors. The mice die shortly after birth due to severe malnutrition from defective epithelial cell differentiation. Surprisingly, deletion of ß1 integrins had no effects on intestinal epithelial anchorage or survival. We have found that loss of ß1 integrin expression results in a loss of paracrine (epithelial-stromal) Hedgehog and Bone Morphogenetic Protein signaling which leads to a intestinal epithelial hyperproliferation and tumor formation in these mice.  We are currently utilizing in vivo genetic mouse models and in vitro co-culture systems to understand the dynamic epithelial-stromal crosstalk mediated by ß1 integrins.

 

2) The role of cell adhesion in metastasis:  Every step of cancer cell metastasis involves dynamic changes in cell adhesion. During invasion, a hallmark of cancers, the cancer cells migrate through the underlying extracellular matrix and intravasate into the circulatory system where they must survive in the absence of cell adhesion. Normal epithelial cells cannot survive without adhesion and rapidly undergo apoptosis when placed in suspension (a process coined "anoikis"). To successfully form metastases, the cancer cells must eventually extravasate from the circulatory system and readhere in distant tissues.

We recently found that colon cancer cells transiently activate NF-kB signaling during readhesion, a major rate-limiting step in metastasis.  Treatment of suspended colon cancer cells with novel NF-kB inhibitors during readhesion resulted in massive induction of apoptosis. We further demonstrated that these NF-kB inhibitors could prevent colon cancer cell implantation of the connective tissues covering the abdominal cavity and intraabdominal organs such as the liver (the most favorite site for colon cancer metastasis). We have found that integrins and cytokine receptors of the TNF alpha superfamily are important for NF-kB activation during colon cancer cell readhesion and are studying how these signaling pathways activate NF-kB.

These studies are being performed in collaboration with Dr. Courtney Scaife (Department of Surgery) to determine if these novel NF-kB inhibitors can prevent metastasis of primary cancers of the pancreas, stomach, ovaries, and colon in more accurate mouse models of metastasis. We are currently studying FDA-approved NF-kB inhibitors in order to rapidly translate this work into human clinical trials.

 

References