UCCC P30 Supplement: Human Endogenous Retrovirus-H as a Target for Early-Onset Colorectal Cancer

About This Grant

Abstract Early-onset colorectal cancer (EOCRC), defined as diagnosis before age 50, has shown a significant rise in incidence, contrasting with declining rates in late-onset CRC. EOCRC tumors frequently exhibit microsatellite stability and harbor TP53 mutations. Despite extensive RNA sequencing efforts in colorectal cancer (CRC), the expression of retroelements (REs), particularly human endogenous retroviruses (HERVs), in CRC remains largely underexplored. Members of the HERV-H family can be reactivated in CRC and may contribute to an immunosuppressive tumor microenvironment (TME). However, it is not currently known if TP53 mutations, found at higher incidence in EOCRC, contribute to increased HERV-H expression which drives tumor metastasis and immune evasion. We propose that the increased expression of specific HERV-H loci in patients with TP53- mutated EOCRC enhances tumor growth and suppresses the immune response, and that anti-retroviral therapy will decrease HERV-H expression, resulting in improved immune control of the tumor. This project aims to identify and characterize HERV-H loci with increased expression in TP53-mutant EOCRC and evaluate their impact on the TME and tumor progression. Long-read RNA sequencing will be used to detect full-length RE transcripts in patient-derived xenograft (PDX) models from EOCRC and late-onset CRC cases expressing wild-type or mutant TP53. Spatial transcriptomics and multiplexed immunofluorescence will localize RE expression within tumor tissues and define associated immune phenotypes using a panel of 20 immune markers. Differential expression analysis will prioritize candidate loci based on enrichment in TP53-mutant EOCRC (compared to late onset and wild-type P53 CRC) and tumor-specific or immune cell expression. Functional validation will include RNA in situ hybridization and quantitative PCR in tumor and immune cell populations. The influence of RE expression on immune cell infiltration, activation, and phenotype will be assessed, with particular focus on B cells, T cells, and innate immune components. Therapeutic modulation of RE expression will be tested using an FDA-approved antiretroviral therapy (3TC) with tumor growth and RE transcript levels as primary endpoints. Integration of transcriptomic and spatial data will provide a comprehensive view of RE-driven immunomodulation in EOCRC. The proposed research seeks to establish a mechanistic link between TP53 mutations, HERV-H expression, and EOCRC progression. Findings may inform the development of diagnostic markers and targeted therapies, including repurposed antiretroviral agents, for personalized treatment of EOCRC patients.