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<p>Non-small cell lung cancer (NSCLC), the most common type of lung cancer, is essentially the leading cause of cancer related deaths in United States. Only 24% of NSCLC patients survive 5-years post diagnosis, largely attributed to the lack of efficient treatment strategies at the metastatic stage. Thus, understanding the biological mechanisms that promote NSCLC metastasis is critical for the development of effective cancer-specific therapeutic agents. The development of cancer metastasis is greatly driven and influenced by intercellular communication. Key mediators of cell-to-cell communication are extracellular vesicles (EVs). For the past years, the study of EVs released by tumor cells have gained attention, given their impact in modulating the tumor immunity, supporting tumorigenesis, and contributing to the development of metastasis. However, the mechanisms though which tumor EVs contribute to tumor development are still understudied. In this study, we isolated and characterized small EVs, also referred as exosomes, from NSCLC cell lines (H358, Calu6, H460, SKMES-1) and investigated their release, uptake, and impact in non-tumorigenic lung epithelial cells recipient cells (BEAS-2B and HBEC). Our results demonstrated that EVs from NSCLC can induce migration and invasion of non-tumorigenic epithelial cells, and impair epithelial barrier permeability, suggesting their role in supporting tumorigenesis and metastasis. Furthermore, we assessed the immunomodulatory effects of NSCLC EVs on anti-tumor immune cells, particularly T cells. Our findings revealed a suppressive effect of EVs derived from mutant KRASG12C NSCLC (H358) on T-cell proliferation, suggesting their contribution to immune evasion mechanisms in mutant KRAS tumors. To dissect the underlying mechanisms, we employed a dual approach utilizing genetic manipulation (shRNA knockdown) and a small molecule inhibitor (ARS-1620) targeting the oncogenic KRASG12C. Our data demonstrated that targeting KRASG12C impaired the EV-driven cancer phenotypes, highlighting the pivotal role of KRAS oncogenic signaling in tumorigenesis and immune suppression mediated by EVs. Overall, our study sheds light on the crucial involvement of tumor derived EVs in NSCLC progression, both in terms of promoting cellular migration and invasion, as well as dampening anti-tumor immune responses. By elucidating the mechanisms underlying EV-driven tumorigenesis and highlighting the therapeutic potential of targeting KRAS signaling, our findings pave the way for the development of novel and effective therapeutic agents for NSCLC.</p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/23740263 |
| Date | 26 July 2023 |
| Creators | Zulaida Soto-Vargas (16642911) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/thesis/UNRAVELING_THE_IMPACT_OF_ONCOGENIC_SIGNALING_IN_EXTRACELLULAR_VESICLES_MEDIATED_CANCER_PHENOTYPES_IN_NON-SMALL_CELL_LUNG_CANCER/23740263 |
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