Colon cancer is the third most common cancer in veterans; one-third of those with colon cancer are anticipated to die, largely from metastases. Current therapeutic options for advanced colon cancer are limited. The focus of our work is to elucidate the role of M3 muscarinic receptor (M3R) activation in colon cancer dissemination, and to use this knowledge to develop novel biomarkers and innovative therapies. M3R (encoded by CHRM3 ) are commonly over-expressed in colon cancer and our prior work identified the molecular mechanisms whereby M3R activation regulates colon cancer cell proliferation and survival. Now, we intend to build on our exciting finding that M3R activation induces robust expression of matrix metalloproteinase 1 (MMP1), a collagenase whose expression in colon cancer correlates strongly with advanced stage, metastasis and poor prognosis. Notably, blocking either M3R or MMP1 activation strongly attenuates cancer cell invasion in vitro. New preliminary data for this VA Merit application show that combined over-expression of M3R and MMP1 is a novel biomarker for a more aggressive colon cancer phenotype, that M3R-induced MMP1 expression is governed by newly-identified cross-talk between EGFR/ERK and protein kinase C/p38 signaling, and that specific neutralizing anti-MMP1 antibody, proposed as a novel therapeutic, can be administered safely to mice. Based on our published and preliminary data, we formulated the central hypothesis that targeting the M3R/MMP1 axis in colon cancer has therapeutic potential and ask the following key questions: How are M3R (CHRM3) and MMP1 expression connected in colon cancer? How does M3R activation induce MMP1 expression? Does blocking the MMP1 expression and activation attenuate colon cancer invasion and dissemination in vivo? To answer these questions and test our central hypothesis, we propose three Specific Aims: (1) Test the hypothesis that co-expression of M3R and MMP1 is a biomarker for an aggressive colon cancer phenotype. (2) Test the hypothesis that cross-talk between post-M3R signaling pathways potentiates MMP1 gene induction and colon cancer cell invasion. (3) Test the hypothesis that targeting MMP1 expression and activation attenuates colon cancer invasion and spread. Expected outcomes/impact: Building on our discovery that the M3R/MMP1 axis plays a key role in colon cancer progression, we will elucidate its molecular underpinnings and use innovative animal models relevant to human disease to reveal the translational potential of targeting MMP1. The clinical goal of this application, diminishing the morbidity and mortality associated with colon cancer by blocking its dissemination, is an important health concern in veterans and directly relevant to the VA mission.
Each year in the US, approximately 150,000 people are diagnosed and 50,000 die from colon cancer, the third most common cause of cancer death in veterans. Cancer limited to the bowel is readily treated by surgery. However, treatment for colon cancer that spread to other organs is usually ineffective; these patients are likely to die from the disease. With prior VA research support we found that muscarinic receptor activation plays an important role in colon cancer progression and that M3 muscarinic receptor (M3R) activation induced expression of matrix metalloproteinase 1 (MMP1), an enzyme that breaks down barriers to cell invasion. We will show that combined expression of M3R and MMP1 is a biomarker for aggressive colon cancer. We will elucidate novel cross-talk between signaling pathways leading from M3R activation to induction of MMP1 expression and cell invasion, and demonstrate that inhibiting MMP1 expression and activation blocks colon cancer invasion and dissemination.
