Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing

Sun, Heng; Zeng, Jianming; Miao, Zhengqiang; Lei, Kuan Cheok; Huang, Chen; Hu, Lingling; Su, Sek Man; Chan, Un In; Miao, Kai; Zhang, Xu; Zhang, Aiping; Guo, Sen; Chen, Si; Meng, Ya; Deng, Min; Hao, Wenhui; Lei, Haipeng; Lin, Ying; Yang, Zhonglin; Tang, Dongjiang; Wong, Koon Ho; Zhang, Xiaohua Douglas; Xu, Xiaoling; Deng, Chu-Xia

doi:10.7150/thno.63995

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Theranostics 2021; 11(20):9967-9987. doi:10.7150/thno.63995 This issue Cite

Research Paper

Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing

Heng Sun^1,2,3,4, Jianming Zeng^1,2, Zhengqiang Miao^1,2, Kuan Cheok Lei^1,2, Chen Huang^1,2, Lingling Hu^1,2, Sek Man Su^1,2, Un In Chan^1,2, Kai Miao^1,2,3, Xu Zhang^1,2, Aiping Zhang^1,2, Sen Guo^1,2, Si Chen^1,2, Ya Meng^1,2,5, Min Deng^1,2, Wenhui Hao^1,2, Haipeng Lei^1,2, Ying Lin⁶, Zhonglin Yang^7,8, Dongjiang Tang^7,8, Koon Ho Wong^1,2, Xiaohua Douglas Zhang^1,2,3, Xiaoling Xu^1,2,3, Chu-Xia Deng^1,2,3✉

1. Cancer Center, Faculty of Health Sciences, University of Macau, Macau SAR, China.
2. Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau SAR, China.
3. MOE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China.
4. Zhuhai Research Institute, University of Macau, China.
5. Zhuhai Precision Medical Center, Zhuhai People's Hospital, Jinan University, Zhuhai, China.
6. Breast Disease Center, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
7. Zhuhai SanMed Biotech Ltd, Zhuhai, China.
8. Joint Research Center of Liquid Biopsy in Guangdong, Hong Kong and Macao, Zhuhai, China.

Citation:

Sun H, Zeng J, Miao Z, Lei KC, Huang C, Hu L, Su SM, Chan UI, Miao K, Zhang X, Zhang A, Guo S, Chen S, Meng Y, Deng M, Hao W, Lei H, Lin Y, Yang Z, Tang D, Wong KH, Zhang XD, Xu X, Deng CX. Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing. Theranostics 2021; 11(20):9967-9987. doi:10.7150/thno.63995. https://www.thno.org/v11p9967.htm

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Abstract

Background: BRCA1 plays critical roles in mammary gland development and mammary tumorigenesis. And loss of BRCA1 induces mammary tumors in a stochastic manner. These tumors present great heterogeneity at both intertumor and intratumor levels.

Methods: To comprehensively elucidate the heterogeneity of BRCA1 deficient mammary tumors and the underlying mechanisms for tumor initiation and progression, we conducted bulk and single cell RNA sequencing (scRNA-seq) on both mammary gland cells and mammary tumor cells isolated from Brca1 knockout mice.

Results: We found the BRCA1 deficient tumors could be classified into four subtypes with distinct molecular features and different sensitivities to anti-cancer drugs at the intertumor level. Whereas within the tumors, heterogeneous subgroups were classified mainly due to the different activities of cell proliferation, DNA damage response/repair and epithelial-to-mesenchymal transition (EMT). Besides, we reconstructed the BRCA1 related mammary tumorigenesis to uncover the transcriptomes alterations during this process via pseudo-temporal analysis of the scRNA-seq data. Furthermore, from candidate markers for BRCA1 mutant tumors, we discovered and validated one oncogene Mrc2, whose loss could reduce mammary tumor growth in vitro and in vivo.

Conclusion: Our study provides a useful resource for better understanding of mammary tumorigenesis induced by BRCA1 deficiency.

Keywords: Brca1/BRCA1, single cell RNA-seq, tumor heterogeneity, mammary tumor, Mrc2

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APA

Sun, H., Zeng, J., Miao, Z., Lei, K.C., Huang, C., Hu, L., Su, S.M., Chan, U.I., Miao, K., Zhang, X., Zhang, A., Guo, S., Chen, S., Meng, Y., Deng, M., Hao, W., Lei, H., Lin, Y., Yang, Z., Tang, D., Wong, K.H., Zhang, X.D., Xu, X., Deng, C.X. (2021). Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing. Theranostics, 11(20), 9967-9987. https://doi.org/10.7150/thno.63995.

ACS

Sun, H.; Zeng, J.; Miao, Z.; Lei, K.C.; Huang, C.; Hu, L.; Su, S.M.; Chan, U.I.; Miao, K.; Zhang, X.; Zhang, A.; Guo, S.; Chen, S.; Meng, Y.; Deng, M.; Hao, W.; Lei, H.; Lin, Y.; Yang, Z.; Tang, D.; Wong, K.H.; Zhang, X.D.; Xu, X.; Deng, C.X. Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing. Theranostics 2021, 11 (20), 9967-9987. DOI: 10.7150/thno.63995.

NLM

CSE

Sun H, Zeng J, Miao Z, Lei KC, Huang C, Hu L, Su SM, Chan UI, Miao K, Zhang X, Zhang A, Guo S, Chen S, Meng Y, Deng M, Hao W, Lei H, Lin Y, Yang Z, Tang D, Wong KH, Zhang XD, Xu X, Deng CX. 2021. Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing. Theranostics. 11(20):9967-9987.

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