Dr. Beauchemin’s research deals with colon cancer and focuses on the molecular mechanisms of pathways involving CEACAM1 in cancer progression. Colon cancer remains a leading cause of death in Canada. It is estimated that 9,600 of Canadians will die of this disease in 2010. Dr. Beauchemin’s team analyzes:
1) Whether the CEACAM1 gene, an Ig and carcinoembryonic antigen (CEA) family member, represents a good target for colorectal cancer treatment options. CEACAM1 (CC1) is dysregulated in many human tumors, including colon. Its expression pattern is paradoxical: it is absent in the very early stages of tumor development, but strongly overexpressed later in stages C and D human colon cancer. Dr. Beauchemin’s team has shown that Ceacam1-/- normal colonocytes exhibit increased proliferation and decreased apoptosis. This leads to increased colon tumor multiplicity in azoxymethane (AOM)-induced carcinogenesis compared to wild-type littermate controls. Deletion of CC1 also contributes to development of Adenomatous polyposis coli (Apc)-driven intestinal cancer with Ceacam1-/- intestine having decreased intestinal apoptosis, Wnt signaling dysregulation of GSK-3ß activity, increased nuclear ß-catenin expression and increased TCF-Lef transcription program. Importantly, CEACAM1 deletion has more impact on tumor progression leading to increased tumor size and more advanced staging.
In addition, lung and colon cancer cells were tested in WT and Ceacam1-/- mice in experimental metastasis assays. CC1 deletion favored a significant reduction in the number of metastatic nodules in the liver. This correlates to elevated CC1 expression in advanced staged patients. Ceacam1-/- mice have decreased mobilization and migration of bone marrow-derived cells to the periphery under metastatic conditions with a significant decrease of cytokines. CEACAM1-mediated mechanisms involved in this phenotype are currently under investigation. Furthermore, members of this laboratory are developing new CEACAM1-based inhibitory compounds that would prevent such dramatic cancer progression.
2) Ceacam1-/- mice present a major defect in lipogenesis with increased visceral adiposity, upregulation of a number of lipogenic enzymes and insulin resistance. Dr. Beauchemin’s laboratory therefore is currently evaluating the links between CC1 and regulation of metabolism, crucial for its role in colon cancer progression and immunity. This project is developed in collaboration with Dr. André Marette in Québec city.
3) In addition, CEACAM1 acts as angiogenic factor, as potent as VEGF in humans. Dr. Beauchemin’s team has shown that CEACAM1 expression plays a causal role in vascular remodelling in vivo. The group has demonstrated how CEACAM functions as a regulator of normal and tumor angiogenesis and postulates that it modulates key signaling pathways. The group has shown that CEACAM1 plays a crucial role in the eNOS signalling pathway by recruiting the tyrosine phosphatase SHP-1. Ablation of the Ceacam1 gene therefore leads to vascular hyperpermeability both in normal and tumor blood vessels. The research team is currently evaluating whether CEACAM1-deficient hypermeability can be exploited for more efficient delivery of chemotherapeutic drugs.
4) Dr. Beauchemin has also developed a long-standing collaboration with Dr. Philippe Gros to identify and characterize colon cancer susceptibility genes using the power of reverse genetics. A novel gene locus has been identify for azoxymethane-induced colorectal cancer development using A/J-B6 congenic mice and another locus has also been found with a gene(s) responding to azoxymethane and sodium dextran sulfate-induced treatment for inflammation-CRC.