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NIH grant 1R01CA288410-01A1: Preventing Malignant Transformation of Colorectal Adenomas
Institute: {'code': 'CA', 'abbreviation': 'NCI', 'name': 'National Cancer Institute', 'admin_org_id': '12500008', 'admin_funding_url': ''}. PI: Subbaya Subramanian. Award: $625415.
Start: 2026-09-19T00:00:00.
Preventing the malignant transformation of colorectal adenomas is essential to reducing colorectal cancer (CRC) incidence
and mortality. Despite advances in screening, up to 11% of patients harbor residual invasive disease after complete polyp
resection, highlighting a critical need for novel prevention strategies beyond polypectomy. We will investigate the molecular
drivers of adenoma transformation and evaluate a first-in-class extracellular vesicle (EV)-based immunoprevention strategy
to prevent CRC.
Our preliminary data identify miR-503/424 as a key oncogenic factor in colorectal adenomas. Our data suggest that miR503/424 drives transformation by suppressing the tumor suppressor FBXW7, a regulator of MYC, thereby enhancing
adenoma cell proliferation. Additionally, tumor-derived EVs enriched in miR-503/424 downregulate CD28 on T cells,
impairing immune surveillance. Remarkably, inhibiting miR-503/424 restores FBXW7 expression in adenoma cells,
enhances CD28-mediated T-cell activation, and suppresses tumor progression. Notably, prophylactic treatment with EVs
engineered to lack miR-503/424 exhibits strong immunogenicity and effectively prevents tumor development in preclinical
models. Based on these findings, we hypothesize that the miR-503/424/FBXW7 and miR-503/424/CD28 axes act through
complementary cell-autonomous and non-autonomous mechanisms to drive adenoma transformation and that tumor EVs
lacking miR-503/424 can restore antitumor immunity and prevent CRC development.
Aim 1 will define the oncogenic role of miR-503/424 in driving malignant transformation in adenoma cells and colon organoid
models; Aim 2 will elucidate the cell-autonomous effects of the miR-503/424/FBXW7 axis and the non-autonomous effects
of EV-associated miR-503/424 on malignant transformation; and Aim 3 will evaluate the cancer-preventive potential of miR503/424-deficient EVs in spontaneous and inflammation-induced adenoma models.
Animal use justification. Vertebrate animals are required to determine whether miR-503/424 promotes adenoma-tocarcinoma progression and whether EV-based intervention can prevent this process within an intact physiological and
immune microenvironment. Mouse orthotopic, spontaneous genetic, and inflammation-induced adenoma models permit
longitudinal assessment of tumor progression and evaluation of tumor-immune interactions and antigen-specific T-cell
responses that cannot be adequately modeled using isolated cells or organoids alone. We will use both male and female
mice and employ the minimum numbers necessary to achieve statistically rigorous results.
Impact. Our findings will reveal previously unrecognized mechanisms governing adenoma transformation and validate a
novel EV-based immunoprevention approach. By directly targeting early transformation pathways and restoring antitumor
immune surveillance, this work has the potential to establish innovative interventions to reduce CRC incidence and mortality.document fetched 2026-09-27 02:45