Int J Biol Sci 2021; 17(10):2461-2475. doi:10.7150/ijbs.61790

Research Paper

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma

Chun-Guo Mao1*, Sha-sha Jiang1*, Xiao-yang Wang2, Shao-Lin Tao1, Bin Jiang1, Cheng-Yi Mao3, Yan-Lian Yang4, Zhi-Yuan Hu4,5, Tan Long1, Hua Jin1, Qun-You Tan1, Yi Huang2✉, Bo Deng1✉

1. Thoracic Surgery Department, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
2. Biomedical Analysis Center, Army Medical University, Chongqing 400038, China.
3. Department of Pathology, Daping Hospital, Army Medical University, Chongqing 400042, China.
4. CAS Key Laboratory of Standardization and Measurement for Nanotechnology, CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.
5. School of Nanoscience and Technology, Sino-Danish College, University of Chinese Academy of Sciences, Beijing 100049, P. R. China.
*These authors contributed equally to this work.

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Citation:
Mao CG, Jiang Ss, Wang Xy, Tao SL, Jiang B, Mao CY, Yang YL, Hu ZY, Long T, Jin H, Tan QY, Huang Y, Deng B. BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma. Int J Biol Sci 2021; 17(10):2461-2475. doi:10.7150/ijbs.61790. Available from https://www.ijbs.com/v17p2461.htm

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Abstract

Background: We investigated the roles of breast cancer anti-estrogen resistance 1 (BCAR1/p130Cas) in the formation and immunoevasion of invasive circulating tumor cells (CTCs) in lung adenocarcinoma (LUAD).

Methods: Biomarkers of CTCs including BCAR1 and CD274, were evaluated by the CanPatrol method. Proteomics analysis of LUAD cells and exosomes after BCAR1 overexpression (BCAR1-OE) was performed by mass spectrometry. Cell functions and relevant signaling pathways were investigated after BCAR1 knockdown (BCAR1-KO) or BCAR1-OE in LUAD cells. Lastly, in vitro and in vivo experiments were performed to confirm the roles of BCAR1 in the formation and immunoevasion of CTCs.

Results: High expression of BCAR1 by CTCs correlated with CD274 expression and epithelial-to-mesenchymal transition (EMT). RAC1, together with BCAR1, was found to play an important role in the carcinogenesis of LUAD. RAC1 functioned with BCAR1 to induce EMT and to enhance cell proliferation, colony formation, cell invasion and migration, and anoikis resistance in LUAD cells. BCAR1 up-regulated CD274 expression probably by shuttling the short isoform of BRD4 (BRD4-S) into the nucleus. CTCs, as well as tumor formation, were prohibited in nude mice xenografted with BCAR1-KO cells. The co-expression of BCAR1/RAC1 and BCAR1/CD274 was confirmed in LUAD. BCAR1 expression in LUAD is an indicator of poor prognosis, and it associates with immunoevasion.

Conclusion: BCAR1, as a new target for the treatment of LUAD, plays roles in the formation and immunoevasion of invasive CTCs. The mechanism includes triggering EMT via RAC1 signaling and up-regulating CD274 expression by shuttling BRD4-S into the nucleus.

Keywords: Breast cancer anti-estrogen resistance 1 (BCAR1/p130Cas), lung cancer, circulating tumor cells, prognosis, migration, invasion, Epithelial-to-mesenchymal transition, anoikis, CD274, RAC1, BRD4, exosome