Background: The progression of colorectal carcinoma (CRC) to metastasis is an inefficient process that involves coordinated interactions between tumor and its immune microenvironment. We have found that a CRC secreted peptide hormone, progastrin (PG), promotes CRC metastatic dissemination in an experimental mouse model. Preliminary studies demonstrate that PG has a novel immune regulatory effect characterized by increase systemic neutrophil accumulation and survival. PG's effect on neutrophils is indirect and requires production of GM-CSF by T-cells. Objective/Hypothesis: We hypothesize that the immune regulatory effect of PG creates a permissive environment for metastasis. Hence, the main goal of this proposal is to understand PG's effect on the T-cells and neutrophils that promote CRC metastatic dissemination in mouse models and in human disease.
Specific Aims : 1. To establish the effect of progastrin in colorectal carcinoma metastasis and on T-cell and neutrophils 2. To test the effect of progastrin on human immune cells and correlate progastrin expression in human colorectal carcinoma and metastasis 3. Identify the T-cell subset that respond to progastrin and explore the underlying signaling mechanism 4. To characterize the effect of progastrin on neutrophil function in the colorectal carcinoma tumor microenvironment Method: We will perform loss of function studies to establish the role of PG in CRC metastasis and further investigate the role of T-cells in PG's effect on metastasis in vivo. We will measure the expression of PG in CRC and metastasis from patient samples and correlate the findings with clinical outcome. We will identify the T-cell subset(s) that produces GM-CSF and understand its signaling mechanism by genetic, molecular, and biochemical approaches. We will characterize PG's effect on neutrophil functions and perform single-cell gene expression studies of intratumoral neutrophils from patient CRC samples. Cancer Relevance: Little is known about the how colorectal carcinoma regulates immunity to affect the dissemination of CRC metastasis. We have identified a novel immune regulatory function of PG in CRC metastasis and we aim to characterize its significance and mechanism, which may lead to new therapeutic or preventive approaches against metastatic dissemination.
Colorectal carcinoma remains a leading cause of cancer associated mortality and metastasis is the biggest predictor of poor outcome. We aim to understand how carcinoma alter its immune environment to promote its survival and metastatic dissemination and have identified a key factor, progastrin, involved in this process. Better understanding of the underlying mechanism could provide novel preventive or therapeutic approaches against colorectal carcinoma metastasis.
