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

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

doi:10.7150/THNO.63995

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

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

Research output: Contribution to journal › Article › peer-review

6 Scopus citations

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.

Original language	English
Pages (from-to)	9967-9987
Number of pages	21
Journal	Theranostics
Volume	11
Issue number	20
DOIs	https://doi.org/10.7150/THNO.63995
State	Published - 2021

Bibliographical note

Publisher Copyright:
© The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

Funding

We thank members of the Deng, Xu and Wong laboratories for helpful advice and discussion. We thank Dapeng Hao, Haitao Wang and Wei Qiao for their assistance of data analysis. We thank Yixiang Shi and Tiffany Nga Teng Iu for their assistance of scRNA-seq and dropseq. This work was supported by National Natural Science Foundation of China Grant 81602587 granted to HS, the Chair Professor Grant (CPG2019-00019-FHS and CPG2021-00021-FHS) granted to CD, Macao Science and Technology Development Fund (FDCT) grant 065/2015/A2, 0011/2019/AKP, and 0034/2019/AGJ to CD and FDCT grant 0004/2019/AFJ to XDZ, and Guangdong Science and Technology Department grant 2020A050515005 to DT.

Funders	Funder number
National Natural Science Foundation of China (NSFC)	81602587, CPG2019-00019-FHS, CPG2021-00021-FHS
National Natural Science Foundation of China (NSFC)
Fundo para o Desenvolvimento das Ciências e da Tecnologia	0034/2019/AGJ, 065/2015/A2, 0004/2019/AFJ, 0011/2019/AKP
Fundo para o Desenvolvimento das Ciências e da Tecnologia
Guangdong Science and Technology Department	2020A050515005
Guangdong Science and Technology Department

Keywords

Brca1/BRCA1
Mammary tumor
Mrc2
Single cell RNA-seq
Tumor heterogeneity

ASJC Scopus subject areas

Medicine (miscellaneous)
Pharmacology, Toxicology and Pharmaceutics (miscellaneous)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.7150/THNO.63995

Cite this

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., ... 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

@article{4f3e9f851def4c339e54e0526fc40065,

title = "Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing",

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, Mammary tumor, Mrc2, Single cell RNA-seq, Tumor heterogeneity",

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

note = "Publisher Copyright: {\textcopyright} The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.",

year = "2021",

doi = "10.7150/THNO.63995",

language = "English",

volume = "11",

pages = "9967--9987",

number = "20",

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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, vol. 11, no. 20, pp. 9967-9987. https://doi.org/10.7150/THNO.63995

TY - JOUR

T1 - Dissecting the heterogeneity and tumorigenesis of BRCA1 deficient mammary tumors via single cell RNA sequencing

AU - Sun, Heng

AU - Zeng, Jianming

AU - Miao, Zhengqiang

AU - Lei, Kuan Cheok

AU - Huang, Chen

AU - Hu, Lingling

AU - Su, Sek Man

AU - Chan, Un In

AU - Miao, Kai

AU - Zhang, Xu

AU - Zhang, Aiping

AU - Guo, Sen

AU - Chen, Si

AU - Meng, Ya

AU - Deng, Min

AU - Hao, Wenhui

AU - Lei, Haipeng

AU - Lin, Ying

AU - Yang, Zhonglin

AU - Tang, Dongjiang

AU - Wong, Koon Ho

AU - Zhang, Xiaohua Douglas

AU - Xu, Xiaoling

AU - Deng, Chu Xia

N1 - Publisher Copyright: © The author(s). This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

KW - Brca1/BRCA1

KW - Mammary tumor

KW - Mrc2

KW - Single cell RNA-seq

KW - Tumor heterogeneity

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M3 - Article

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SN - 1838-7640

VL - 11

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EP - 9987

JO - Theranostics

JF - Theranostics

IS - 20

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

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