A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

Alejandra Bruna; Oscar M. Rueda; Wendy Greenwood; Ankita Sati Batra; Maurizio Callari; Rajbir Nath Batra; Katherine Pogrebniak; Jose Sandoval; John W. Cassidy; Ana Tufegdzic-Vidakovic; Stephen John Sammut; Linda Jones; Elena Provenzano; Richard Baird; Peter Eirew; James Hadfield; Matthew Eldridge; Anne McLaren-Douglas; Andrew Barthorpe; Howard Lightfoot; Mark J. O'Connor; Joe Gray; Javier Cortes; Jose Baselga; Elisabetta Marangoni; Alana L. Welm; Samuel Aparicio; Violeta Serra; Mathew J. Garnett; Carlos Caldas

doi:10.1016/j.cell.2016.08.041

A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

Alejandra Bruna, Oscar M. Rueda, Wendy Greenwood, Ankita Sati Batra, Maurizio Callari, Rajbir Nath Batra, Katherine Pogrebniak, Jose Sandoval, John W. Cassidy, Ana Tufegdzic-Vidakovic, Stephen John Sammut, Linda Jones, Elena Provenzano, Richard Baird, Peter Eirew, James Hadfield, Matthew Eldridge, Anne McLaren-Douglas, Andrew Barthorpe, Howard LightfootMark J. O'Connor, Joe Gray, Javier Cortes, Jose Baselga, Elisabetta Marangoni, Alana L. Welm, Samuel Aparicio, Violeta Serra, Mathew J. Garnett, Carlos Caldas

Biomedical Engineering

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Abstract

The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

Original language	English (US)
Pages (from-to)	260-274.e22
Journal	Cell
Volume	167
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2016.08.041
State	Published - Sep 22 2016

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2016.08.041

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Bruna, A., Rueda, O. M., Greenwood, W., Batra, A. S., Callari, M., Batra, R. N., Pogrebniak, K., Sandoval, J., Cassidy, J. W., Tufegdzic-Vidakovic, A., Sammut, S. J., Jones, L., Provenzano, E., Baird, R., Eirew, P., Hadfield, J., Eldridge, M., McLaren-Douglas, A., Barthorpe, A., ... Caldas, C. (2016). A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds. Cell, 167(1), 260-274.e22. https://doi.org/10.1016/j.cell.2016.08.041

Bruna, A, Rueda, OM, Greenwood, W, Batra, AS, Callari, M, Batra, RN, Pogrebniak, K, Sandoval, J, Cassidy, JW, Tufegdzic-Vidakovic, A, Sammut, SJ, Jones, L, Provenzano, E, Baird, R, Eirew, P, Hadfield, J, Eldridge, M, McLaren-Douglas, A, Barthorpe, A, Lightfoot, H, O'Connor, MJ, Gray, J, Cortes, J, Baselga, J, Marangoni, E, Welm, AL, Aparicio, S, Serra, V, Garnett, MJ & Caldas, C 2016, 'A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds', Cell, vol. 167, no. 1, pp. 260-274.e22. https://doi.org/10.1016/j.cell.2016.08.041

@article{8868f92d3abd44d291f76bcc541e50f8,

title = "A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds",

abstract = "The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.",

author = "Alejandra Bruna and Rueda, {Oscar M.} and Wendy Greenwood and Batra, {Ankita Sati} and Maurizio Callari and Batra, {Rajbir Nath} and Katherine Pogrebniak and Jose Sandoval and Cassidy, {John W.} and Ana Tufegdzic-Vidakovic and Sammut, {Stephen John} and Linda Jones and Elena Provenzano and Richard Baird and Peter Eirew and James Hadfield and Matthew Eldridge and Anne McLaren-Douglas and Andrew Barthorpe and Howard Lightfoot and O'Connor, {Mark J.} and Joe Gray and Javier Cortes and Jose Baselga and Elisabetta Marangoni and Welm, {Alana L.} and Samuel Aparicio and Violeta Serra and Garnett, {Mathew J.} and Carlos Caldas",

note = "Funding Information: This research was supported with funding from Cancer Research UK and from the European Union to the EUROCAN Network of Excellence (FP7; grant number 260791). M.C. has received funding from the European Union{\textquoteright}s Horizon 2020 research and innovation program under the Marie Sk{\l}odowska-Curie grant agreement no. 660060 and was supported by the Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. R.N.B. is supported by the Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. S-J.S. is supported by the Wellcome Trust PhD Programme for Clinicians in Cambridge. A.Bruna, O.M.R., E.M., 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 (surgeons, pathologists, oncologists, theatre staff, and other ancillary personnel) at the Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Bio-repository Core Facilities for support during the execution of this project. Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = sep,

day = "22",

doi = "10.1016/j.cell.2016.08.041",

language = "English (US)",

volume = "167",

pages = "260--274.e22",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

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TY - JOUR

T1 - A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

AU - Bruna, Alejandra

AU - Rueda, Oscar M.

AU - Greenwood, Wendy

AU - Batra, Ankita Sati

AU - Callari, Maurizio

AU - Batra, Rajbir Nath

AU - Pogrebniak, Katherine

AU - Sandoval, Jose

AU - Cassidy, John W.

AU - Tufegdzic-Vidakovic, Ana

AU - Sammut, Stephen John

AU - Jones, Linda

AU - Provenzano, Elena

AU - Baird, Richard

AU - Eirew, Peter

AU - Hadfield, James

AU - Eldridge, Matthew

AU - McLaren-Douglas, Anne

AU - Barthorpe, Andrew

AU - Lightfoot, Howard

AU - O'Connor, Mark J.

AU - Gray, Joe

AU - Cortes, Javier

AU - Baselga, Jose

AU - Marangoni, Elisabetta

AU - Welm, Alana L.

AU - Aparicio, Samuel

AU - Serra, Violeta

AU - Garnett, Mathew J.

AU - Caldas, Carlos

N1 - Funding Information: This research was supported with funding from Cancer Research UK and from the European Union to the EUROCAN Network of Excellence (FP7; grant number 260791). M.C. has received funding from the European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement no. 660060 and was supported by the Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. R.N.B. is supported by the Wellcome Trust PhD Programme in Mathematical Genomics and Medicine. S-J.S. is supported by the Wellcome Trust PhD Programme for Clinicians in Cambridge. A.Bruna, O.M.R., E.M., 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 (surgeons, pathologists, oncologists, theatre staff, and other ancillary personnel) at the Cambridge Breast Unit, Cambridge University Hospital NHS Foundation Trust, for facilitating the timely collection of samples. We thank the Cancer Research UK Cambridge Institute Genomics, Bioinformatics, Histopathology, Flow Cytometry, Biological Resource, and Bio-repository Core Facilities for support during the execution of this project. Publisher Copyright: © 2016 The Authors

PY - 2016/9/22

Y1 - 2016/9/22

N2 - The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

AB - The inter- and intra-tumor heterogeneity of breast cancer needs to be adequately captured in pre-clinical models. We have created a large collection of breast cancer patient-derived tumor xenografts (PDTXs), in which the morphological and molecular characteristics of the originating tumor are preserved through passaging in the mouse. An integrated platform combining in vivo maintenance of these PDTXs along with short-term cultures of PDTX-derived tumor cells (PDTCs) was optimized. Remarkably, the intra-tumor genomic clonal architecture present in the originating breast cancers was mostly preserved upon serial passaging in xenografts and in short-term cultured PDTCs. We assessed drug responses in PDTCs on a high-throughput platform and validated several ex vivo responses in vivo. The biobank represents a powerful resource for pre-clinical breast cancer pharmacogenomic studies (http://caldaslab.cruk.cam.ac.uk/bcape), including identification of biomarkers of response or resistance.

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DO - 10.1016/j.cell.2016.08.041

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JO - Cell

JF - Cell

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ER -

A Biobank of Breast Cancer Explants with Preserved Intra-tumor Heterogeneity to Screen Anticancer Compounds

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