Abstract 1383: Investigation of biological role and cytokine axis of cancer-associated fibroblast (CAF) in lung cancer brain metastasis

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Abstract Background: Brain metastases (BM) are among the most lethal forms of cancer globally. Lung cancer BM are frequently encountered and are associated with poor prognosis, decreased survival rates, and therapeutic resistances. Cancer-associated fibroblasts (CAFs) have emerged as important players of the brain metastases tumor microenvironment (TME). Mechanistic roles of brain metastases CAFs (hBM-CAFs) in tumorigenesis and therapeutic resistances remain unclear. Material and Methods: In the present study, the patient's BM surgical sample was subjected to primary culture to isolate CAF. The hBM-CAF induced EMT and stemness phenotype was investigated by western blot. Biological role of hBM-CAF in tumorigenesis was evaluated using indirect co-culture method in vitro. FACS analysis was performed to investigate the changes in cisplatin cytotoxicity and radiation susceptibility of lung cancer cell lines when co-cultured with hBM-CAF. CX3CL1 and IL26 expression was confirmed by ELISA along with transcriptomic analysis of hBM-CAF. Molecular events were validated by using neutralizing CX3CL1 and IL26. The tumorigenicity and response to chemotoxicity of lung cancer cells were examined by co-injecting them with hBM-CAF in a mouse xenograft model. Results: Our experiments demonstrated that hBM-CAFs significantly enhanced EMT and stemness phenotype by upregulating transcription factor SNAIL1, TWIST1, Slug and CD133, CD44 respectively in lung cancer cells. We also observed that hBM-CAFs decreased cisplatin cytotoxicity and enhanced radiation resistance, as measured by FACS analysis of apoptotic cells. In vivo experiments using xenograft mouse models revealed that co-injection of lung cancer cells with hBM-CAFs led to faster tumor growth and increased cisplatin resistance. Transcriptomic analysis of hBM-CAFs revealed a distinct genomic signature compared to normal fibroblast (hNFs), with significant overexpression of IL26 and CX3CL1 genes in the hBM-CAFs secretome, as validated by ELISA. Moreover, we found that lung cancer cells expressed high levels of the IL26 receptor IL10Rβ and ILR20α, and CX3CL1 receptor CX3CR1. Our hBM-CAF significantly upregulated JAK-STAT3 and Akt-mTOR pathway. Eventually, we have confirmed that neutralizing IL26 and CX3CL1 inhibit phosphorylation of JAK-STAT3 and Akt-mTOR respectively and revoked the IL26-CX3CL1 induced EMT and stemness phenotype of lung cancer cells. Conclusion: Patient derived hBM-CAF promote aggressive phenotype of lung cancer cells by upregulating EMT and stemness transcriptome factors. Overexpression of IL26 and CX3CL1 cytokine led to the therapeutic resistance through JAK-STAT3 and Akt-mTOR signaling pathway respectively. Targeting IL26-CX3CL1 might be a novel therapeutic efficacy for lung cancer brain metastasis patients. Citation Format: Nah Ihm Kim, SM Abdus Salam, Eshrat Jahan, Eun-Jeong Ahn, Tae-Young Jung, Jae-Hyuk Lee, Joon Haeng Rhee, Sung Sun Kim, Kyung-Hwa Lee, Kyung-Sub Moon. Investigation of biological role and cytokine axis of cancer-associated fibroblast (CAF) in lung cancer brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1383.

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