Abstract 3639: Impact of KRAS oncogenic signaling in tumorigenesis and immune evasion driven by extracellular vesicles (EVs)

Abstract

Abstract Mutations in Kristen rat sarcoma homolog (KRAS) occur in about 25% of cancers, making this protein one of the most frequently altered genes in cancer. KRAS mutations are not only associated with poor patient survival, but also with increased tumor aggressiveness and metastasis. Tumor development and metastasis are impacted by intercellular communication. Key mediators of cell-to-cell communication include vesicles secreted by cells, also known as extracellular vesicles (EVs). EVs released by cancer cells can mediate malignant transformation of non-cancerous cells as well as influence pre-metastatic niche formation. Conversely, inhibiting the secretion and release of EVs by cancer cells decreases tumor growth and metastasis. However, the mechanisms through which EVs drive tumorigenesis in KRAS mutant tumors are still understudied. Our lab recently reported that EVs from lung cancer cells drive invasion of non-tumorigenic lung epithelial cells. Here, we found that KRAS oncogenic signaling in the donor cells contributes to the EV-driven migration and invasion of non-tumorigenic lung epithelial cells. Previous studies have demonstrated that KRAS signaling drives immune evasion and promotes an “immune cold” tumor microenvironment. Our preliminary studies showed that EVs derived from KrasG12C lung cancer cells (H358) inhibit T cell proliferation and that blocking KRASG12C signaling, using ARS-1620 (KrasG12C inhibitor), impairs EV-driven T cell immunosuppression. We performed a comprehensive proteomic comparison between EVs isolated from H358 treated with ARS-1620 and those isolated from cells treated with DMSO (vehicle) and identified proteins involved in migration and invasion, such as LAMB-3, to be downregulated in EVs isolated from ARS-1620 treated cells. Ongoing studies aim to pinpoint the detailed mechanisms by which cancer cells utilize mutant KRAS signaling to promote loading of oncogenic cargo into EVs, and the resulting contributions to tumorigenesis and immune evasion. Citation Format: Zulaida M. Soto Vargas, David C. Arteaga, Ikjot S. Sohal, Humna Hasan, Andrea L. Kasinski. Impact of KRAS oncogenic signaling in tumorigenesis and immune evasion driven by extracellular vesicles (EVs). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3639.