Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

Robert E. Hynds; Ariana Huebner; David R. Pearce; Mark S. Hill; Ayse U. Akarca; David A. Moore; Sophia Ward; Kate H.C. Gowers; Takahiro Karasaki; Maise Al Bakir; Gareth A. Wilson; Oriol Pich; Carlos Martínez-Ruiz; A. S.Md Mukarram Hossain; Simon P. Pearce; Monica Sivakumar; Assma Ben Aissa; Eva Grönroos; Deepak Chandrasekharan; Krishna K. Kolluri; Rebecca Towns; Kaiwen Wang; Daniel E. Cook; Leticia Bosshard-Carter; Cristina Naceur-Lombardelli; Andrew J. Rowan; Selvaraju Veeriah; Kevin Litchfield; Philip A.J. Crosbie; Caroline Dive; Sergio A. Quezada; Sam M. Janes; Mariam Jamal-Hanjani; Teresa Marafioti; Maise Al Bakir; Jason F. Lester; Amrita Bajaj; Apostolos Nakas; Azmina Sodha-Ramdeen; Mohamad Tufail; Molly Scotland; Rebecca Boyles; Sridhar Rathinam; Claire Wilson; Domenic Marrone; Sean Dulloo; Dean A. Fennell; Gurdeep Matharu; Jacqui A. Shaw; Hugo J.W.L. Aerts; TRACERx Consortium

doi:10.1038/s41467-024-47547-3

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

Robert E. Hynds^*, Ariana Huebner, David R. Pearce, Mark S. Hill, Ayse U. Akarca, David A. Moore, Sophia Ward, Kate H.C. Gowers, Takahiro Karasaki, Maise Al Bakir, Gareth A. Wilson, Oriol Pich, Carlos Martínez-Ruiz, A. S.Md Mukarram Hossain, Simon P. Pearce, Monica Sivakumar, Assma Ben Aissa, Eva Grönroos, Deepak Chandrasekharan, Krishna K. KolluriRebecca Towns, Kaiwen Wang, Daniel E. Cook, Leticia Bosshard-Carter, Cristina Naceur-Lombardelli, Andrew J. Rowan, Selvaraju Veeriah, Kevin Litchfield, Philip A.J. Crosbie, Caroline Dive, Sergio A. Quezada, Sam M. Janes, Mariam Jamal-Hanjani, Teresa Marafioti, Maise Al Bakir, Jason F. Lester, Amrita Bajaj, Apostolos Nakas, Azmina Sodha-Ramdeen, Mohamad Tufail, Molly Scotland, Rebecca Boyles, Sridhar Rathinam, Claire Wilson, Domenic Marrone, Sean Dulloo, Dean A. Fennell, Gurdeep Matharu, Jacqui A. Shaw, Hugo J.W.L. Aerts, TRACERx Consortium

^*Corresponding author for this work

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

Abstract

Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

Original language	English
Article number	4653
Number of pages	21
Journal	Nature Communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-47547-3
Publication status	Published - 1 Dec 2024

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Hynds, R. E., Huebner, A., Pearce, D. R., Hill, M. S., Akarca, A. U., Moore, D. A., Ward, S., Gowers, K. H. C., Karasaki, T., Al Bakir, M., Wilson, G. A., Pich, O., Martínez-Ruiz, C., Hossain, A. S. M. M., Pearce, S. P., Sivakumar, M., Ben Aissa, A., Grönroos, E., Chandrasekharan, D., ... TRACERx Consortium (2024). Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models. Nature Communications, 15(1), Article 4653. https://doi.org/10.1038/s41467-024-47547-3

@article{7b99e80c16914f6db92fd4d2e1a1a04d,

title = "Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models",

abstract = "Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.",

author = "Hynds, {Robert E.} and Ariana Huebner and Pearce, {David R.} and Hill, {Mark S.} and Akarca, {Ayse U.} and Moore, {David A.} and Sophia Ward and Gowers, {Kate H.C.} and Takahiro Karasaki and {Al Bakir}, Maise and Wilson, {Gareth A.} and Oriol Pich and Carlos Mart{\'i}nez-Ruiz and Hossain, {A. S.Md Mukarram} and Pearce, {Simon P.} and Monica Sivakumar and {Ben Aissa}, Assma and Eva Gr{\"o}nroos and Deepak Chandrasekharan and Kolluri, {Krishna K.} and Rebecca Towns and Kaiwen Wang and Cook, {Daniel E.} and Leticia Bosshard-Carter and Cristina Naceur-Lombardelli and Rowan, {Andrew J.} and Selvaraju Veeriah and Kevin Litchfield and Crosbie, {Philip A.J.} and Caroline Dive and Quezada, {Sergio A.} and Janes, {Sam M.} and Mariam Jamal-Hanjani and Teresa Marafioti and {Al Bakir}, Maise and Lester, {Jason F.} and Amrita Bajaj and Apostolos Nakas and Azmina Sodha-Ramdeen and Mohamad Tufail and Molly Scotland and Rebecca Boyles and Sridhar Rathinam and Claire Wilson and Domenic Marrone and Sean Dulloo and Fennell, {Dean A.} and Gurdeep Matharu and Shaw, {Jacqui A.} and Aerts, {Hugo J.W.L.} and {TRACERx Consortium}",

note = "Funding Information: The authors thank the staff of the Advanced Sequencing Facility at The Francis Crick Institute, as well as the members of the TRACERx consortium for their contributions to this study. TRACERx (Clinicaltrials.gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and was approved by an independent research ethics committee (REC 13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK; C11496/A17786) and is coordinated by CRUK and the UCL Cancer Trials Centre. The authors thank Sharon Vanloo for administrative support and members of the EpiCENTR, Swanton and McGranahan labs for their comments on draft manuscripts. Schematic diagrams were created with BioRender.com. R.E.H. was supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust; WT209199/Z/17) and received additional funding for this project from the CRUK Lung Cancer Centre of Excellence, the Roy Castle Lung Cancer Foundation and the James Tudor Foundation. T.K. is supported by the Japan Society for the Promotion of Science (JSPS) overseas research fellowships program (202060447). PDX derivation and WES for the samples used to validate the NSG-adapted reference genome were funded through a grant from the Moulton Charitable Foundation (to P.A.J.C). M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, the Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from CRUK, the Rosetrees Trust, the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041), and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); CRUK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007 & RF\\ERE\\231118)); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the CRUK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US) (BCRF-22-157); CRUK Early Detection and Diagnosis Primer Award (Grant EDDPMA-Nov21/100034); and The Mark Foundation for Cancer Research Aspire Award (Grant 21-029-ASP). This work was supported by a Stand Up To Cancer (SU2C)\u2010LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement no. 835297). For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Funding Information: The authors thank the staff of the Advanced Sequencing Facility at The Francis Crick Institute, as well as the members of the TRACERx consortium for their contributions to this study. TRACERx (Clinicaltrials.gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and was approved by an independent research ethics committee (REC 13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK; C11496/A17786) and is coordinated by CRUK and the UCL Cancer Trials Centre. The authors thank Sharon Vanloo for administrative support and members of the EpiCENTR, Swanton and McGranahan labs for their comments on draft manuscripts. Schematic diagrams were created with BioRender.com. R.E.H. was supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust; WT209199/Z/17) and received additional funding for this project from the CRUK Lung Cancer Centre of Excellence, the Roy Castle Lung Cancer Foundation and the James Tudor Foundation. T.K. is supported by the Japan Society for the Promotion of Science (JSPS) overseas research fellowships program (202060447). Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

day = "1",

doi = "10.1038/s41467-024-47547-3",

language = "English",

volume = "15",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

Hynds, RE, Huebner, A, Pearce, DR, Hill, MS, Akarca, AU, Moore, DA, Ward, S, Gowers, KHC, Karasaki, T, Al Bakir, M, Wilson, GA, Pich, O, Martínez-Ruiz, C, Hossain, ASMM, Pearce, SP, Sivakumar, M, Ben Aissa, A, Grönroos, E, Chandrasekharan, D, Kolluri, KK, Towns, R, Wang, K, Cook, DE, Bosshard-Carter, L, Naceur-Lombardelli, C, Rowan, AJ, Veeriah, S, Litchfield, K, Crosbie, PAJ, Dive, C, Quezada, SA, Janes, SM, Jamal-Hanjani, M, Marafioti, T, Al Bakir, M, Lester, JF, Bajaj, A, Nakas, A, Sodha-Ramdeen, A, Tufail, M, Scotland, M, Boyles, R, Rathinam, S, Wilson, C, Marrone, D, Dulloo, S, Fennell, DA, Matharu, G, Shaw, JA, Aerts, HJWL & TRACERx Consortium 2024, 'Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models', Nature Communications, vol. 15, no. 1, 4653. https://doi.org/10.1038/s41467-024-47547-3

TY - JOUR

T1 - Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

AU - Hynds, Robert E.

AU - Huebner, Ariana

AU - Pearce, David R.

AU - Hill, Mark S.

AU - Akarca, Ayse U.

AU - Moore, David A.

AU - Ward, Sophia

AU - Gowers, Kate H.C.

AU - Karasaki, Takahiro

AU - Al Bakir, Maise

AU - Wilson, Gareth A.

AU - Pich, Oriol

AU - Martínez-Ruiz, Carlos

AU - Hossain, A. S.Md Mukarram

AU - Pearce, Simon P.

AU - Sivakumar, Monica

AU - Ben Aissa, Assma

AU - Grönroos, Eva

AU - Chandrasekharan, Deepak

AU - Kolluri, Krishna K.

AU - Towns, Rebecca

AU - Wang, Kaiwen

AU - Cook, Daniel E.

AU - Bosshard-Carter, Leticia

AU - Naceur-Lombardelli, Cristina

AU - Rowan, Andrew J.

AU - Veeriah, Selvaraju

AU - Litchfield, Kevin

AU - Crosbie, Philip A.J.

AU - Dive, Caroline

AU - Quezada, Sergio A.

AU - Janes, Sam M.

AU - Jamal-Hanjani, Mariam

AU - Marafioti, Teresa

AU - Al Bakir, Maise

AU - Lester, Jason F.

AU - Bajaj, Amrita

AU - Nakas, Apostolos

AU - Sodha-Ramdeen, Azmina

AU - Tufail, Mohamad

AU - Scotland, Molly

AU - Boyles, Rebecca

AU - Rathinam, Sridhar

AU - Wilson, Claire

AU - Marrone, Domenic

AU - Dulloo, Sean

AU - Fennell, Dean A.

AU - Matharu, Gurdeep

AU - Shaw, Jacqui A.

AU - Aerts, Hugo J.W.L.

AU - TRACERx Consortium

N1 - Funding Information: The authors thank the staff of the Advanced Sequencing Facility at The Francis Crick Institute, as well as the members of the TRACERx consortium for their contributions to this study. TRACERx (Clinicaltrials.gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and was approved by an independent research ethics committee (REC 13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK; C11496/A17786) and is coordinated by CRUK and the UCL Cancer Trials Centre. The authors thank Sharon Vanloo for administrative support and members of the EpiCENTR, Swanton and McGranahan labs for their comments on draft manuscripts. Schematic diagrams were created with BioRender.com. R.E.H. was supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust; WT209199/Z/17) and received additional funding for this project from the CRUK Lung Cancer Centre of Excellence, the Roy Castle Lung Cancer Foundation and the James Tudor Foundation. T.K. is supported by the Japan Society for the Promotion of Science (JSPS) overseas research fellowships program (202060447). PDX derivation and WES for the samples used to validate the NSG-adapted reference genome were funded through a grant from the Moulton Charitable Foundation (to P.A.J.C). M.J.H. is a CRUK Fellow and has received funding from CRUK, NIHR, the Rosetrees Trust, UKI NETs and the NIHR University College London Hospitals Biomedical Research Centre. N.M. is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (211179/Z/18/Z), and also receives funding from CRUK, the Rosetrees Trust, the NIHR BRC at University College London Hospitals and the CRUK University College London Experimental Cancer Medicine Centre. C.S. is a Royal Society Napier Research Professor (RSRP\\R\\210001). His work is supported by the Francis Crick Institute that receives its core funding from Cancer Research UK (CC2041), the UK Medical Research Council (CC2041), and the Wellcome Trust (CC2041). C.S. is funded by CRUK (TRACERx (C11496/A17786), PEACE (C416/A21999) and CRUK Cancer Immunotherapy Catalyst Network); CRUK Lung Cancer Centre of Excellence (C11496/A30025); the Rosetrees Trust, Butterfield and Stoneygate Trusts; NovoNordisk Foundation (ID16584); Royal Society Professorship Enhancement Award (RP/EA/180007 & RF\\ERE\\231118)); National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre; the CRUK-University College London Centre; Experimental Cancer Medicine Centre; the Breast Cancer Research Foundation (US) (BCRF-22-157); CRUK Early Detection and Diagnosis Primer Award (Grant EDDPMA-Nov21/100034); and The Mark Foundation for Cancer Research Aspire Award (Grant 21-029-ASP). This work was supported by a Stand Up To Cancer (SU2C)\u2010LUNGevity-American Lung Association Lung Cancer Interception Dream Team Translational Research Grant (Grant Number: SU2C-AACR-DT23-17 to S.M. Dubinett and A.E. Spira). Stand Up To Cancer is a division of the Entertainment Industry Foundation. Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. C.S. is in receipt of an ERC Advanced Grant (PROTEUS) from the European Research Council under the European Union\u2019s Horizon 2020 research and innovation programme (grant agreement no. 835297). For the purpose of open access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. Funding Information: The authors thank the staff of the Advanced Sequencing Facility at The Francis Crick Institute, as well as the members of the TRACERx consortium for their contributions to this study. TRACERx (Clinicaltrials.gov no: NCT01888601) is sponsored by University College London (UCL/12/0279) and was approved by an independent research ethics committee (REC 13/LO/1546). TRACERx is funded by Cancer Research UK (CRUK; C11496/A17786) and is coordinated by CRUK and the UCL Cancer Trials Centre. The authors thank Sharon Vanloo for administrative support and members of the EpiCENTR, Swanton and McGranahan labs for their comments on draft manuscripts. Schematic diagrams were created with BioRender.com. R.E.H. was supported by a Sir Henry Wellcome Postdoctoral Fellowship (Wellcome Trust; WT209199/Z/17) and received additional funding for this project from the CRUK Lung Cancer Centre of Excellence, the Roy Castle Lung Cancer Foundation and the James Tudor Foundation. T.K. is supported by the Japan Society for the Promotion of Science (JSPS) overseas research fellowships program (202060447). Publisher Copyright: © The Author(s) 2024.

PY - 2024/12/1

Y1 - 2024/12/1

N2 - Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

AB - Patient-derived xenograft (PDX) models are widely used in cancer research. To investigate the genomic fidelity of non-small cell lung cancer PDX models, we established 48 PDX models from 22 patients enrolled in the TRACERx study. Multi-region tumor sampling increased successful PDX engraftment and most models were histologically similar to their parent tumor. Whole-exome sequencing enabled comparison of tumors and PDX models and we provide an adapted mouse reference genome for improved removal of NOD scid gamma (NSG) mouse-derived reads from sequencing data. PDX model establishment caused a genomic bottleneck, with models often representing a single tumor subclone. While distinct tumor subclones were represented in independent models from the same tumor, individual PDX models did not fully recapitulate intratumor heterogeneity. On-going genomic evolution in mice contributed modestly to the genomic distance between tumors and PDX models. Our study highlights the importance of considering primary tumor heterogeneity when using PDX models and emphasizes the benefit of comprehensive tumor sampling.

U2 - 10.1038/s41467-024-47547-3

DO - 10.1038/s41467-024-47547-3

M3 - Article

SN - 2041-1723

VL - 15

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4653

ER -

Representation of genomic intratumor heterogeneity in multi-region non-small cell lung cancer patient-derived xenograft models

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