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, C.
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 - Mills, Gordon B.
N1 - Funding Information:
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.
Funding Information:
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.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
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 - http://www.scopus.com/inward/record.url?scp=85103744076&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85103744076&partnerID=8YFLogxK
U2 - 10.1038/s41467-021-22303-z
DO - 10.1038/s41467-021-22303-z
M3 - Article
C2 - 33790302
AN - SCOPUS:85103744076
VL - 12
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1998
ER -