Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

Karsten Bach; Sara Pensa; Marija Zarocsinceva; Katarzyna Kania; Julie Stockis; Silvain Pinaud; Kyren A. Lazarus; Mona Shehata; Bruno M. Simões; Alice R. Greenhalgh; Sacha J. Howell; Robert B. Clarke; Carlos Caldas; Timotheus Y. F. Halim; John C. Marioni; Walid T. Khaled

doi:10.1038/s41467-021-21783-3

Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

Karsten Bach, Sara Pensa, Marija Zarocsinceva, Katarzyna Kania, Julie Stockis, Silvain Pinaud, Kyren A. Lazarus, Mona Shehata, Bruno M. Simões, Alice R. Greenhalgh, Sacha J. Howell, Robert B. Clarke, Carlos Caldas, Timotheus Y. F. Halim, John C. Marioni, Walid T. Khaled

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

Abstract

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.

Original language	English
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-21783-3
Publication status	Published - 9 Mar 2021

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Manchester Cancer Research Centre

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Bach, K., Pensa, S., Zarocsinceva, M., Kania, K., Stockis, J., Pinaud, S., Lazarus, K. A., Shehata, M., Simões, B. M., Greenhalgh, A. R., Howell, S. J., Clarke, R. B., Caldas, C., Halim, T. Y. F., Marioni, J. C., & Khaled, W. T. (2021). Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors. Nature Communications, 12(1). https://doi.org/10.1038/s41467-021-21783-3

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title = "Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors",

abstract = "It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.",

author = "Karsten Bach and Sara Pensa and Marija Zarocsinceva and Katarzyna Kania and Julie Stockis and Silvain Pinaud and Lazarus, {Kyren A.} and Mona Shehata and Sim{\~o}es, {Bruno M.} and Greenhalgh, {Alice R.} and Howell, {Sacha J.} and Clarke, {Robert B.} and Carlos Caldas and Halim, {Timotheus Y. F.} and Marioni, {John C.} and Khaled, {Walid T.}",

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doi = "10.1038/s41467-021-21783-3",

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Bach, K, Pensa, S, Zarocsinceva, M, Kania, K, Stockis, J, Pinaud, S, Lazarus, KA, Shehata, M, Simões, BM, Greenhalgh, AR, Howell, SJ , Clarke, RB, Caldas, C, Halim, TYF, Marioni, JC & Khaled, WT 2021, 'Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors', Nature Communications, vol. 12, no. 1. https://doi.org/10.1038/s41467-021-21783-3

TY - JOUR

T1 - Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

AU - Bach, Karsten

AU - Pensa, Sara

AU - Zarocsinceva, Marija

AU - Kania, Katarzyna

AU - Stockis, Julie

AU - Pinaud, Silvain

AU - Lazarus, Kyren A.

AU - Shehata, Mona

AU - Simões, Bruno M.

AU - Greenhalgh, Alice R.

AU - Howell, Sacha J.

AU - Clarke, Robert B.

AU - Caldas, Carlos

AU - Halim, Timotheus Y. F.

AU - Marioni, John C.

AU - Khaled, Walid T.

PY - 2021/3/9

Y1 - 2021/3/9

N2 - It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.

AB - It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.

U2 - 10.1038/s41467-021-21783-3

DO - 10.1038/s41467-021-21783-3

M3 - Article

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors

Abstract

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