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. Glenn Prestwich (Department of Medicinal Chemistry) and 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.