Wednesday, December 4, 2024
12/4/2024
Project Summary While the 5-year survival rate for colorectal cancer (CRC) patients with localized stage disease (as defined by SEER) is 90%, this survival rate drops to 14% for patients diagnosed with metastatic CRC. Thus, there is an urgent need to define the mechanisms governing progression to advanced disease and its maintenance. Human CRCs harboring oncogenic mutations in the KRAS oncogene (designated hereafter as KRAS*) are 25% more likely to develop metastases. Similarly, our CRC mouse model, engineered with an inducible KRAS* transgene and conditional null alleles of APC and p53 alleles (iKAP), has revealed a role for KRAS* in driving cancer progression and metastasis. Mechanistically, KRAS*-driven cancer metastasis functions in part by activating cancer cell-intrinsic TGFβ signaling and suppressing anti-tumoral immunity via the IRF2-CXCL3 axis which recruits myeloid derived suppressor cells. Unfortunately, emerging therapies targeting either KRAS* or TGFβ pathways have shown limited efficacy in the clinic, motivating us to identify and validate additional KRAS*-driven cancer progression mechanisms with the goal of expanding the repertoire of therapeutic targets for metastatic CRC. Utilizing the iKAP model, functional gene set enrichment and histological analyses of KRAS*-expressing CRC metastases revealed a strong adipogenesis signature and preponderance of lipofibroblasts and angiogenesis in the tumor microenvironment. Correspondingly, co-culture of mouse embryonic fibroblasts with conditioned media from iKAP primary cell lines stimulated their differentiation into cells with adipocyte and fibroblast traits, i.e., “lipofibroblasts.” In the F99 phase of this proposal, I seek to define the molecular mechanisms by which KRAS*-expressing cancer cells drive lipofibrogenesis and to understand the tumor biological role of lipofibroblasts in KRAS*-driven CRC progression. As only a minority of human or mouse KRAS* CRC cases progress to metastatic disease, clearly genetic events beyond KRAS activation drive metastases. For example, patients with or without KRAS* mutation both show around a 40% lymph node metastatic rate. The study of such pro-metastasis events would be greatly facilitated by incorporating an inducible telomerase reverse transcriptase (LSL-mTERT) into our existing iAP model, thus modeling telomere-based crisis and genome instability followed by telomerase reactivation. In our telomerase-inducible mouse models of prostate cancer, crisis-telomerase sequence generates cancer-relevant genomic aberrations and increases metastatic potential. Although incorporation of genomic instability into the iAP model would not create a more human-like model, it would provide a platform to identify amplifications and deletions associated with the metastatic process. In the K00 phase of this proposal, I seek to engineer human- like telomere dynamics in the iAP model to assess the impact of telomere-based crisis and telomerase reactivation in driving metastasis and to survey the genomic alterations that may underlie the metastatic process. Such efforts may facilitate the discovery of new therapeutic targets for advanced CRC disease.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
