Abstract
Abstract Lung cancer is the second most diagnosed type of cancer and is the leading cause of cancer-related deaths in both men and women. An estimated 235,760 new cases of lung cancer and 131,880 lung cancer deaths are expected this year accounting for 12% of new cancer cases and 22% of cancer deaths in the United States. Exosomes are secreted vesicles that contain selectively packaged biomaterials (protein, lipids, and RNA) and serve as a form of extracellular communication between cells in the tumor microenvironment. Previous studies have shown the effects of cancer-derived exosomes on specific cell types or gross tumor response in vivo yet, the competitive nature and dynamics of exosomal uptake in the tumor microenvironment remains largely unknown. This work seeks to identify molecular responses induced by cancer-derived exosomes on cells residing in the tumor microenvironment. In order to control tumor cell exposure to cancer-derived exosomes, heterogeneous ex vivo cultures derived from subcutaneous Lewis lung carcinoma (LLC) tumors in C57BL6 mice were exposed to fluorescently dyed LLC exosomes for up to 72 hours. Flow cytometric analysis was performed to identify preferential uptake of cancer exosomes into the stromal subpopulations of tumor cells. Increased uptake was observed throughout the duration of the exposure and preferential uptake was observed into neutrophils, macrophages, and endothelial cells while cancer cells, fibroblasts, and lymphocytes were underrepresented in the exosome uptaken population. Additionally, single cell RNA-sequencing was performed 24 hours post-exosomal exposure to identify transcriptional changes promoted by cancer exosome uptake. We found tumor-derived cancer cells to up-regulate transcripts associated with proliferation and down-regulated genes associated with interferon signaling in response to exosome uptake. These preliminary findings suggest that cancer-derived exosomes have targeted effects on specific cell types in the tumor microenvironment. Specifically in cancer cells, exosomal uptake can elicit protumor (cancer proliferation and immune suppression via decreased interferon signaling) effects that may serve as mediators of disease progression. An understanding of both cancer and host-derived exosomal response to disease progression may identify novel biomarkers and potential therapeutic targets previously undiscovered using canonical discovery methods. This study received funding from LLNL LDRD grant 21-LW-028. This work was conducted under the auspices of the USDOE by LLNL (DE-AC52-07NA27344). LLNL-ABS-829271 Citation Format: Nicholas R. Hum, Nicole F. Leon, Aimy Sebastian, Kelly A. Martin, Gabriela G. Loots. Molecular characterization of the effects of cancer-derived exosomes on murine lung cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3136.
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