Emergence of a High-Plasticity Cell State during Lung Cancer Evolution

Nemanja Despot Marjanovic; Matan Hofree; Jason E. Chan; David Canner; Katherine Wu; Marianna Trakala; Griffin G. Hartmann; Olivia C. Smith; Jonathan Y. Kim; Kelly Victoria Evans; Anna Hudson; Orr Ashenberg; Caroline B.M. Porter; Alborz Bejnood; Ayshwarya Subramanian; Kenneth Pitter; Yan Yan; Toni Delorey; Devan R. Phillips; Nisargbhai Shah; Ojasvi Chaudhary; Alexander Tsankov; Travis Hollmann; Natasha Rekhtman; Pierre P. Massion; John T. Poirier; Linas Mazutis; Ruifang Li; Joo Hyeon Lee; Angelika Amon; Charles M. Rudin; Tyler Jacks; Aviv Regev; Tuomas Tammela

doi:10.1016/j.ccell.2020.06.012

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution

Nemanja Despot Marjanovic, Matan Hofree, Jason E. Chan, David Canner, Katherine Wu, Marianna Trakala, Griffin G. Hartmann, Olivia C. Smith, Jonathan Y. Kim, Kelly Victoria Evans, Anna Hudson, Orr Ashenberg, Caroline B.M. Porter, Alborz Bejnood, Ayshwarya Subramanian, Kenneth Pitter, Yan Yan, Toni Delorey, Devan R. Phillips, Nisargbhai ShahOjasvi Chaudhary, Alexander Tsankov, Travis Hollmann, Natasha Rekhtman, Pierre P. Massion, John T. Poirier, Linas Mazutis, Ruifang Li, Joo Hyeon Lee, Angelika Amon, Charles M. Rudin, Tyler Jacks^*, Aviv Regev^*, Tuomas Tammela^*

^*Corresponding author for this work

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

140 Scopus citations

Abstract

Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS. Cellular states capable of promoting tumor progression and resisting therapies exist in heterogeneous tumors. Marjanovic et al. discover that a high-plasticity cell state common to mouse and human lung tumors drives cellular heterogeneity, is highly tumorigenic and drug resistant, and associates with poor patient prognosis.

Original language	American English
Pages (from-to)	229-246.e13
Journal	Cancer Cell
Volume	38
Issue number	2
DOIs	https://doi.org/10.1016/j.ccell.2020.06.012
State	Published - 10 Aug 2020
Externally published	Yes

Bibliographical note

Funding Information:
We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals , the Howard Hughes Medical Institute , and, in part, by P01-CA42063 and the NIH / NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society , Rita Allen , Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association ; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI - CA187317. A.R. is supported by the Klarman Cell Observatory . J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207 ). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063 . P.P.M. is supported by NCI- CA196405 . L.M. is supported by The Alan and Sandra Gerry Foundation . We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748 , Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSKCC ; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute ; and the MIT Bio-Micro Center . A.R., T.J., and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar.

Funding Information:
We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals, the Howard Hughes Medical Institute, and, in part, by P01-CA42063 and the NIH/NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society, Rita Allen, Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI-CA187317. A.R. is supported by the Klarman Cell Observatory. J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063. P.P.M. is supported by NCI-CA196405. L.M. is supported by The Alan and Sandra Gerry Foundation. We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748, Cycle for Survival, and the Marie-Jos?e and Henry R. Kravis Center for Molecular Oncology at MSKCC; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute; and the MIT Bio-Micro Center. A.R. T.J. and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. conceived, designed, and directed the study. T.T. N.D.M. J.E.C. D.C. K.W. M.T. G.G.H. O.S. J.K. K.P. A.H. Y.Y. T.D. D.R.P. N.S. O.C. and T.H. performed the experiments. K.V.E. and J.-H.L. developed human tumor organoid culture methodology. M.H. O.A. C.B.M.P. A.S. A.T. and J.E.C. conducted bioinformatic analyses. P.P.M. J.T.P. N.R. and C.M.R. provided human tissues and clinical annotation. C.M.R. A.A. T.H. and L.M. provided conceptual advice. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. wrote the manuscript with comments from all authors. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. also received funding from Calico and currently receives funding from Johnson & Johnson, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder in Celsius Therapeutics and a SAB member for Thermo Fisher, Asimov, Neogene Therapeutics, and Syros Pharmaceuticals, and an equity holder of Immunitas Therapeutics. C.M.R. serves on the SAB of Bridge Medicines and Harpoon Therapeutics, and has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech, Ipsen, Loxo, Pharmamar, and Vavotek. None of the affiliations listed above represent a conflict of interest with the design or execution of this study or interpretation of data presented in this manuscript. Other authors have nothing to disclose.

Publisher Copyright:
© 2020 Elsevier Inc.

Keywords

cell state transition
chromatin state
differentiation
drug resistance
lung cancer
plasticity
single-cell transcriptomics
tumor evolution
tumor heterogeneity
tumor progression

UN SDGs

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

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10.1016/j.ccell.2020.06.012

Cite this

Marjanovic, N. D., Hofree, M., Chan, J. E., Canner, D., Wu, K., Trakala, M., Hartmann, G. G., Smith, O. C., Kim, J. Y., Evans, K. V., Hudson, A., Ashenberg, O., Porter, C. B. M., Bejnood, A., Subramanian, A., Pitter, K., Yan, Y., Delorey, T., Phillips, D. R., ... Tammela, T. (2020). Emergence of a High-Plasticity Cell State during Lung Cancer Evolution. Cancer Cell, 38(2), 229-246.e13. https://doi.org/10.1016/j.ccell.2020.06.012

@article{769311dffb73434283dc8065bd3c3eb2,

title = "Emergence of a High-Plasticity Cell State during Lung Cancer Evolution",

abstract = "Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS. Cellular states capable of promoting tumor progression and resisting therapies exist in heterogeneous tumors. Marjanovic et al. discover that a high-plasticity cell state common to mouse and human lung tumors drives cellular heterogeneity, is highly tumorigenic and drug resistant, and associates with poor patient prognosis.",

keywords = "cell state transition, chromatin state, differentiation, drug resistance, lung cancer, plasticity, single-cell transcriptomics, tumor evolution, tumor heterogeneity, tumor progression",

author = "Marjanovic, {Nemanja Despot} and Matan Hofree and Chan, {Jason E.} and David Canner and Katherine Wu and Marianna Trakala and Hartmann, {Griffin G.} and Smith, {Olivia C.} and Kim, {Jonathan Y.} and Evans, {Kelly Victoria} and Anna Hudson and Orr Ashenberg and Porter, {Caroline B.M.} and Alborz Bejnood and Ayshwarya Subramanian and Kenneth Pitter and Yan Yan and Toni Delorey and Phillips, {Devan R.} and Nisargbhai Shah and Ojasvi Chaudhary and Alexander Tsankov and Travis Hollmann and Natasha Rekhtman and Massion, {Pierre P.} and Poirier, {John T.} and Linas Mazutis and Ruifang Li and Lee, {Joo Hyeon} and Angelika Amon and Rudin, {Charles M.} and Tyler Jacks and Aviv Regev and Tuomas Tammela",

note = "Funding Information: We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals , the Howard Hughes Medical Institute , and, in part, by P01-CA42063 and the NIH / NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society , Rita Allen , Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association ; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI - CA187317. A.R. is supported by the Klarman Cell Observatory . J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207 ). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063 . P.P.M. is supported by NCI- CA196405 . L.M. is supported by The Alan and Sandra Gerry Foundation . We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748 , Cycle for Survival, and the Marie-Jos{\'e}e and Henry R. Kravis Center for Molecular Oncology at MSKCC ; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute ; and the MIT Bio-Micro Center . A.R., T.J., and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. Funding Information: We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals, the Howard Hughes Medical Institute, and, in part, by P01-CA42063 and the NIH/NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society, Rita Allen, Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI-CA187317. A.R. is supported by the Klarman Cell Observatory. J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063. P.P.M. is supported by NCI-CA196405. L.M. is supported by The Alan and Sandra Gerry Foundation. We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748, Cycle for Survival, and the Marie-Jos?e and Henry R. Kravis Center for Molecular Oncology at MSKCC; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute; and the MIT Bio-Micro Center. A.R. T.J. and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. conceived, designed, and directed the study. T.T. N.D.M. J.E.C. D.C. K.W. M.T. G.G.H. O.S. J.K. K.P. A.H. Y.Y. T.D. D.R.P. N.S. O.C. and T.H. performed the experiments. K.V.E. and J.-H.L. developed human tumor organoid culture methodology. M.H. O.A. C.B.M.P. A.S. A.T. and J.E.C. conducted bioinformatic analyses. P.P.M. J.T.P. N.R. and C.M.R. provided human tissues and clinical annotation. C.M.R. A.A. T.H. and L.M. provided conceptual advice. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. wrote the manuscript with comments from all authors. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. also received funding from Calico and currently receives funding from Johnson & Johnson, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder in Celsius Therapeutics and a SAB member for Thermo Fisher, Asimov, Neogene Therapeutics, and Syros Pharmaceuticals, and an equity holder of Immunitas Therapeutics. C.M.R. serves on the SAB of Bridge Medicines and Harpoon Therapeutics, and has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech, Ipsen, Loxo, Pharmamar, and Vavotek. None of the affiliations listed above represent a conflict of interest with the design or execution of this study or interpretation of data presented in this manuscript. Other authors have nothing to disclose. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = aug,

day = "10",

doi = "10.1016/j.ccell.2020.06.012",

language = "American English",

volume = "38",

pages = "229--246.e13",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "2",

}

Marjanovic, ND, Hofree, M, Chan, JE, Canner, D, Wu, K, Trakala, M, Hartmann, GG, Smith, OC, Kim, JY, Evans, KV, Hudson, A, Ashenberg, O, Porter, CBM, Bejnood, A, Subramanian, A, Pitter, K, Yan, Y, Delorey, T, Phillips, DR, Shah, N, Chaudhary, O, Tsankov, A, Hollmann, T, Rekhtman, N, Massion, PP, Poirier, JT, Mazutis, L, Li, R, Lee, JH, Amon, A, Rudin, CM, Jacks, T, Regev, A & Tammela, T 2020, 'Emergence of a High-Plasticity Cell State during Lung Cancer Evolution', Cancer Cell, vol. 38, no. 2, pp. 229-246.e13. https://doi.org/10.1016/j.ccell.2020.06.012

TY - JOUR

T1 - Emergence of a High-Plasticity Cell State during Lung Cancer Evolution

AU - Marjanovic, Nemanja Despot

AU - Hofree, Matan

AU - Chan, Jason E.

AU - Canner, David

AU - Wu, Katherine

AU - Trakala, Marianna

AU - Hartmann, Griffin G.

AU - Smith, Olivia C.

AU - Kim, Jonathan Y.

AU - Evans, Kelly Victoria

AU - Hudson, Anna

AU - Ashenberg, Orr

AU - Porter, Caroline B.M.

AU - Bejnood, Alborz

AU - Subramanian, Ayshwarya

AU - Pitter, Kenneth

AU - Yan, Yan

AU - Delorey, Toni

AU - Phillips, Devan R.

AU - Shah, Nisargbhai

AU - Chaudhary, Ojasvi

AU - Tsankov, Alexander

AU - Hollmann, Travis

AU - Rekhtman, Natasha

AU - Massion, Pierre P.

AU - Poirier, John T.

AU - Mazutis, Linas

AU - Li, Ruifang

AU - Lee, Joo Hyeon

AU - Amon, Angelika

AU - Rudin, Charles M.

AU - Jacks, Tyler

AU - Regev, Aviv

AU - Tammela, Tuomas

N1 - Funding Information: We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals , the Howard Hughes Medical Institute , and, in part, by P01-CA42063 and the NIH / NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society , Rita Allen , Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association ; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI - CA187317. A.R. is supported by the Klarman Cell Observatory . J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207 ). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063 . P.P.M. is supported by NCI- CA196405 . L.M. is supported by The Alan and Sandra Gerry Foundation . We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748 , Cycle for Survival, and the Marie-Josée and Henry R. Kravis Center for Molecular Oncology at MSKCC ; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute ; and the MIT Bio-Micro Center . A.R., T.J., and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. Funding Information: We thank E. Snyder for helpful suggestions; K. Daniels, R. Gardner, M. Griffin, M. Jennings, and G. Paradis for FACS support; K. Manova, M. Turkekul, and D. Yarilin for histology and microscopy support; S. Fujisawa and A. Santella for help with quantitative analysis of immunostained tissue sections; H. Mummey and X. Zhuang for help with experiments; A. Berns for development of the Ad5mSPC-Cre virus; and L. Gaffney and A. Hupalowska for help in preparing the figures. This work was supported by the Transcend Program and Janssen Pharmaceuticals, the Howard Hughes Medical Institute, and, in part, by P01-CA42063 and the NIH/NCI Cancer Center support grants P30-CA08748 (MSKCC) and P30-CA14051 (Koch Institute). T.T. is supported by American Cancer Society, Rita Allen, Josie Robertson, and V Foundation Scholarships and the American Association for Cancer Research Next Generation Transformative Research Award; the American Lung Association; the Stanley and Fiona Druckenmiller Center for Lung Cancer Research; and NCI-CA187317. A.R. is supported by the Klarman Cell Observatory. J.E.C. is supported by the MSK T32 Investigational Cancer Therapeutics Training Program Grant (NIH MSK ICTTP T32-CA009207). D.C. was supported by a graduate fellowship from the National Science Foundation and P01-CA42063. P.P.M. is supported by NCI-CA196405. L.M. is supported by The Alan and Sandra Gerry Foundation. We acknowledge the use of the Integrated Genomics Operation Core, funded by CCSG P30-CA08748, Cycle for Survival, and the Marie-Jos?e and Henry R. Kravis Center for Molecular Oncology at MSKCC; the Flow Cytometry and Histology Core Facilities at the Swanson Biotechnology Center at the Koch Institute; and the MIT Bio-Micro Center. A.R. T.J. and A.A. are Howard Hughes Medical Institute Investigators; T.J. is a David H. Koch Professor of Biology, and a Daniel K. Ludwig Scholar. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. conceived, designed, and directed the study. T.T. N.D.M. J.E.C. D.C. K.W. M.T. G.G.H. O.S. J.K. K.P. A.H. Y.Y. T.D. D.R.P. N.S. O.C. and T.H. performed the experiments. K.V.E. and J.-H.L. developed human tumor organoid culture methodology. M.H. O.A. C.B.M.P. A.S. A.T. and J.E.C. conducted bioinformatic analyses. P.P.M. J.T.P. N.R. and C.M.R. provided human tissues and clinical annotation. C.M.R. A.A. T.H. and L.M. provided conceptual advice. T.T. N.D.M. M.H. J.E.C. D.C. T.J. and A.R. wrote the manuscript with comments from all authors. T.J. is a member of the Board of Directors of Amgen and Thermo Fisher Scientific, and a co-Founder of Dragonfly Therapeutics and T2 Biosystems. T.J. serves on the Scientific Advisory Board of Dragonfly Therapeutics, SQZ Biotech, and Skyhawk Therapeutics. T.J. also received funding from Calico and currently receives funding from Johnson & Johnson, but this funding did not support the research described in this manuscript. A.R. is a co-founder and equity holder in Celsius Therapeutics and a SAB member for Thermo Fisher, Asimov, Neogene Therapeutics, and Syros Pharmaceuticals, and an equity holder of Immunitas Therapeutics. C.M.R. serves on the SAB of Bridge Medicines and Harpoon Therapeutics, and has consulted regarding oncology drug development with AbbVie, Amgen, Ascentage, Bicycle, Celgene, Daiichi Sankyo, Genentech, Ipsen, Loxo, Pharmamar, and Vavotek. None of the affiliations listed above represent a conflict of interest with the design or execution of this study or interpretation of data presented in this manuscript. Other authors have nothing to disclose. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/8/10

Y1 - 2020/8/10

N2 - Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS. Cellular states capable of promoting tumor progression and resisting therapies exist in heterogeneous tumors. Marjanovic et al. discover that a high-plasticity cell state common to mouse and human lung tumors drives cellular heterogeneity, is highly tumorigenic and drug resistant, and associates with poor patient prognosis.

AB - Tumor evolution from a single cell into a malignant, heterogeneous tissue remains poorly understood. Here, we profile single-cell transcriptomes of genetically engineered mouse lung tumors at seven stages, from pre-neoplastic hyperplasia to adenocarcinoma. The diversity of transcriptional states increases over time and is reproducible across tumors and mice. Cancer cells progressively adopt alternate lineage identities, computationally predicted to be mediated through a common transitional, high-plasticity cell state (HPCS). Accordingly, HPCS cells prospectively isolated from mouse tumors and human patient-derived xenografts display high capacity for differentiation and proliferation. The HPCS program is associated with poor survival across human cancers and demonstrates chemoresistance in mice. Our study reveals a central principle underpinning intra-tumoral heterogeneity and motivates therapeutic targeting of the HPCS. Cellular states capable of promoting tumor progression and resisting therapies exist in heterogeneous tumors. Marjanovic et al. discover that a high-plasticity cell state common to mouse and human lung tumors drives cellular heterogeneity, is highly tumorigenic and drug resistant, and associates with poor patient prognosis.

KW - cell state transition

KW - chromatin state

KW - differentiation

KW - drug resistance

KW - lung cancer

KW - plasticity

KW - single-cell transcriptomics

KW - tumor evolution

KW - tumor heterogeneity

KW - tumor progression

UR - http://www.scopus.com/inward/record.url?scp=85089003787&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.06.012

DO - 10.1016/j.ccell.2020.06.012

M3 - Article

C2 - 32707077

AN - SCOPUS:85089003787

SN - 1535-6108

VL - 38

SP - 229-246.e13

JO - Cancer Cell

JF - Cancer Cell

IS - 2

ER -

Emergence of a High-Plasticity Cell State during Lung Cancer Evolution

Abstract

Bibliographical note

Keywords

UN SDGs

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