Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

IMAXT Consortium

doi:10.1038/s41467-021-22303-z

Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

IMAXT Consortium

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

44 Scopus citations

Abstract

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

Original language	English
Article number	1998
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22303-z
State	Published - 1 Dec 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021, The Author(s).

Funding

This research was supported with funding from Cancer Research UK (Caldas Core Grant A16942 and CRUK Cambridge Institute Core Grant A29580), the Cancer Research UK IMAX-T Grand Challenge (C9545/A24042), an ERC Advanced Grant to C.C. from the European Union’s Horizon 2020 research and innovation programme (ERC-2015-AdG-694620), and an unrestricted research grant from AstraZeneca administered by the University of Cambridge. M.C. received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie Research Fellowship (grant agreement no. 660060). A.B., O.M.R., V.S., and C.C. are members of the EurOPDX Consortium. We are very grateful for the generosity of all the patients that donated samples for implantation. We are also deeply indebted to all the staff at the Cambridge Breast Cancer Research Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Core Facilities (Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Biorepository) for support during the execution of this project. C.C. is a member of AstraZeneca’s iMED External Science Panel, of Illumina’s Scientific Advisory Board, and is a recipient of research grants (administered by the University of Cambridge) from AstraZeneca, Genentech, Roche, and Servier. L.S.C. and S.S.C. are employees and shareholders of AstraZeneca. V.S. received research support from AstraZeneca, Novartis, Genentech and Tesaro. The remaining authors declare no competing interests.

Funders	Funder number
Cancer Research UK IMAX-T	C9545/A24042
National Cancer Institute	P30CA008748
AstraZeneca
Genentech
Roche
Horizon 2020 Framework Programme	ERC-2015-AdG-694620
H2020 Marie Skłodowska-Curie Actions	660060
Cancer Research UK	A29580, A16942
University of Cambridge
Servier

UN SDGs

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

SDG 3 Good Health and Well-being

Access to Document

10.1038/s41467-021-22303-z

Cite this

@article{3da6fefeb73e4582a150dcf8b7a4f713,

title = "Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response",

abstract = "The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.",

author = "\{IMAXT Consortium\} and Dimitra Georgopoulou and Maurizio Callari and Rueda, \{Oscar M.\} and Abigail Shea and Alistair Martin and Agnese Giovannetti and Fatime Qosaj and Ali Dariush and Chin, \{Suet Feung\} and Carnevalli, \{Larissa S.\} and Elena Provenzano and Wendy Greenwood and Giulia Lerda and Elham Esmaeilishirazifard and Martin O{\textquoteright}Reilly and Violeta Serra and Dario Bressan and Ali, \{H. R.\} and \{Al Sa{\textquoteright}d\}, M. and S. Alon and S. Aparicio and G. Battistoni and S. Balasubramanian and R. Becker and B. Bodenmiller and Boyden, \{E. S.\} and D. Bressan and A. Bruna and Marcel Burger and Carlos Caldas and M. Callari and Cannell, \{I. G.\} and H. Casbolt and N. Chornay and Y. Cui and A. Dariush and K. Dinh and A. Emenari and Y. Eyal-Lubling and J. Fan and A. Fatemi and E. Fisher and Gonz{\'a}lez-Solares, \{E. A.\} and C. Gonz{\'a}lez-Fern{\'a}ndez and D. Goodwin and W. Greenwood and F. Grimaldi and Hannon, \{G. J.\} and O. Harris and S. Harris",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

month = dec,

day = "1",

doi = "10.1038/s41467-021-22303-z",

language = "אנגלית",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

AU - IMAXT Consortium

AU - Georgopoulou, Dimitra

AU - Callari, Maurizio

AU - Rueda, Oscar M.

AU - Shea, Abigail

AU - Martin, Alistair

AU - Giovannetti, Agnese

AU - Qosaj, Fatime

AU - Dariush, Ali

AU - Chin, Suet Feung

AU - Carnevalli, Larissa S.

AU - Provenzano, Elena

AU - Greenwood, Wendy

AU - Lerda, Giulia

AU - Esmaeilishirazifard, Elham

AU - O’Reilly, Martin

AU - Serra, Violeta

AU - Bressan, Dario

AU - Ali, H. R.

AU - Al Sa’d, M.

AU - Alon, S.

AU - Aparicio, S.

AU - Battistoni, G.

AU - Balasubramanian, S.

AU - Becker, R.

AU - Bodenmiller, B.

AU - Boyden, E. S.

AU - Bressan, D.

AU - Bruna, A.

AU - Burger, Marcel

AU - Caldas, Carlos

AU - Callari, M.

AU - Cannell, I. G.

AU - Casbolt, H.

AU - Chornay, N.

AU - Cui, Y.

AU - Dariush, A.

AU - Dinh, K.

AU - Emenari, A.

AU - Eyal-Lubling, Y.

AU - Fan, J.

AU - Fatemi, A.

AU - Fisher, E.

AU - González-Solares, E. A.

AU - González-Fernández, C.

AU - Goodwin, D.

AU - Greenwood, W.

AU - Grimaldi, F.

AU - Hannon, G. J.

AU - Harris, O.

AU - Harris, S.

PY - 2021/12/1

Y1 - 2021/12/1

N2 - The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

AB - The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.

UR - https://www.scopus.com/pages/publications/85103744076

U2 - 10.1038/s41467-021-22303-z

DO - 10.1038/s41467-021-22303-z

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 33790302

AN - SCOPUS:85103744076

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1998

ER -

Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this