Defining the mechanism of inositol 1,4,5-triphosphate receptor-mediated metastatic liver colonization in colorectal cancer

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PROJECT SUMMARY/ABSTRACT Metastatic progression is the predominant cause of death from solid organ tumors like colorectal cancer but is poorly understood at the molecular level. While modern systemic therapy has incrementally improved outcomes, survival in metastatic colorectal cancer remains dismal, with less than 15 percent of patients alive at five years. Therefore, there is an urgent need to identify and characterize the key genes and pathways that facilitate metastatic colonization. Using a genome-scale in vivo short hairpin RNA (shRNA) screen, the PI and his collaborators have identified several putative metastasis promoters including the type 3 inositol 1,4,5- triphosphate receptor (ITPR3), which mobilizes intracellular calcium from the endoplasmic reticulum. ITPR3 deletion in colorectal cancer cells reduces liver metastatic capacity in vivo, implicating ITPR3 as a key driver of metastasis. Preliminary data suggest that ITPR3 may allow disseminating cancer cells to overcome physiological barriers inherent to the metastatic microenvironment, such as the loss of normal extracellular attachment to the primary epithelial site, potentially through shutting down energetically demanding processes such as protein translation. In addition, ITPR3 may regulate pro-metastatic non-canonical NF-kB signaling and the associated transcription factor RELB, which was also identified as a robust metastasis promoter in the shRNA screen. These studies have led to the hypothesis that ITPR3 is a central coordinator of multiple pathways to support survival during early and late phases of metastatic colonization. Experiments are proposed to (1) define the mechanisms by which ITPR3 regulates translation and cellular metabolism through polysome/ribosome profiling, proteomics and metabolomics, (2) elucidate the mechanism by which ITPR3 controls RELB and non-canonical NF-kB signaling to facilitate metastasis, and (3) determine whether ITPR3 can be therapeutically targeted using novel organoids derived from highly metastatic patient-derived xenografts. Successful completion of the proposed work will improve understanding of the mechanisms underlying metastatic colonization in colorectal cancer and reveal avenues to develop more effective therapeutic strategies to block metastatic progression. The applicant, Dr. Ryan Moy, is a Medical Oncology Fellow and member of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center (MSKCC). Dr. Moy has outlined a 5-year career development plan that expands on his background in molecular biology and clinical training in oncology to acquire vital skills for becoming an independent physician-scientist. He will perform the proposed studies under the mentorship of Dr. Sohail Tavazoie, a physician-scientist and leading expert in metastasis biology with a strong track record of training successful scientists. Dr. Moy will develop new skills in bioinformatics, metabolomics, proteomics and the generation of patient-derived cancer models. In addition to this training plan and strong scientific background, the combined institutional environments of MSKCC and The Rockefeller University ideally position Dr. Moy to successful develop into an independent laboratory-based physician-scientist with R01 funding.