Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Ester Gil Vasquez; Nadia Nasreddin; Gabriel N. Valbuena; Eoghan J. Mulholland; Hayley L. Belnoue-Davis; Holly R. Eggington; Ryan O. Schenck; Valérie M. Wouters; Pratyaksha Wirapati; Kathryn Gilroy; Tamsin R. M. Lannagan; Dustin J. Flanagan; Arafath K. Najumudeen; Sulochana Omwenga; Amy M. B. McCorry; Alistair Easton; Viktor H. Koelzer; James E. East; Dion Morton; Livio Trusolino; Timothy Maughan; Andrew D. Campbell; Maurice B. Loughrey; Philip D. Dunne; Petros Tsantoulis; David J. Huels; Sabine Tejpar; Owen J. Sansom; Simon J. Leedham

doi:https://doi.org/10.1016/j.stem.2022.07.008

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

Ester Gil Vasquez, Nadia Nasreddin, Gabriel N. Valbuena, Eoghan J. Mulholland, Hayley L. Belnoue-Davis, Holly R. Eggington, Ryan O. Schenck, Valérie M. Wouters, Pratyaksha Wirapati, Kathryn Gilroy, Tamsin R. M. Lannagan, Dustin J. Flanagan, Arafath K. Najumudeen, Sulochana Omwenga, Amy M. B. McCorry, Alistair Easton, Viktor H. Koelzer, James E. East, Dion Morton, Livio TrusolinoTimothy Maughan, Andrew D. Campbell, Maurice B. Loughrey, Philip D. Dunne, Petros Tsantoulis, David J. Huels, Sabine Tejpar, Owen J. Sansom, Simon J. Leedham

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

26 Citations (Scopus)

Abstract

Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.

Original language	English
Pages (from-to)	1213-1228.e8
Journal	Cell Stem Cell
Volume	29
Issue number	8
DOIs	https://doi.org/10.1016/j.stem.2022.07.008
Publication status	Published - 4 Aug 2022

Keywords

cell plasticity
colorectal cancer
colorectal neoplasia
intestinal polyps
intestinal stem cells
molecular phenotyping
stem cells

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https://doi.org/10.1016/j.stem.2022.07.008

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Vasquez, E. G., Nasreddin, N., Valbuena, G. N., Mulholland, E. J., Belnoue-Davis, H. L., Eggington, H. R., Schenck, R. O., Wouters, V. M., Wirapati, P., Gilroy, K., Lannagan, T. R. M., Flanagan, D. J., Najumudeen, A. K., Omwenga, S., McCorry, A. M. B., Easton, A., Koelzer, V. H., East, J. E., Morton, D., ... Leedham, S. J. (2022). Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia. Cell Stem Cell, 29(8), 1213-1228.e8. https://doi.org/10.1016/j.stem.2022.07.008

@article{47d9c2e1296c4ec9ac5b32b499bbd2c8,

title = "Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia",

abstract = "Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.",

keywords = "cell plasticity, colorectal cancer, colorectal neoplasia, intestinal polyps, intestinal stem cells, molecular phenotyping, stem cells",

author = "Vasquez, {Ester Gil} and Nadia Nasreddin and Valbuena, {Gabriel N.} and Mulholland, {Eoghan J.} and Belnoue-Davis, {Hayley L.} and Eggington, {Holly R.} and Schenck, {Ryan O.} and Wouters, {Val{\'e}rie M.} and Pratyaksha Wirapati and Kathryn Gilroy and Lannagan, {Tamsin R. M.} and Flanagan, {Dustin J.} and Najumudeen, {Arafath K.} and Sulochana Omwenga and McCorry, {Amy M. B.} and Alistair Easton and Koelzer, {Viktor H.} and East, {James E.} and Dion Morton and Livio Trusolino and Timothy Maughan and Campbell, {Andrew D.} and Loughrey, {Maurice B.} and Dunne, {Philip D.} and Petros Tsantoulis and Huels, {David J.} and Sabine Tejpar and Sansom, {Owen J.} and Leedham, {Simon J.}",

note = "Funding Information: The authors thank Genentech (California, USA) for the supply of the Lgr5 DTR mouse. S.J.L. is supported by a Wellcome Trust Senior Clinical Research Fellowship ( 206314/Z/17/Z ), Worldwide Cancer Research grant ( 16-0042 ), and Rosetrees Trust and Stoneygate Trust research grant ( M493 ). N.N. and J.E.E. are supported by National Institute for Health Research ( NIHR ) Oxford Biomedical Research Centre . P.T. is supported by the “Ligue Genevoise contre le cancer.” V.H.K. is funded by the Swiss National Science Foundation ( P2SKP3_168322/1 and P2SKP3_168322/2 ) and Werner and Hedy Berger-Janser Foundation for Cancer Research ( 08/2017 ). E.J.M. is funded by the Lee Placito Medical Research Fund ( University of Oxford ). D.J.H. is supported by the KWF Young Investigator program (13544). This research was also supported by an International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK ( A26825 and A28223 ), FC AECC ( GEACC18004TAB ), and AIRC ( 22795 ). Core funding to the Wellcome Centre for Human Genetics was provided by the Wellcome Trust ( 090532/Z/09/Z ). This research was funded, in part, by the Wellcome Trust . For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this work are those of the author/s and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: The authors thank Genentech (California, USA) for the supply of the Lgr5DTR mouse. S.J.L. is supported by a Wellcome Trust Senior Clinical Research Fellowship (206314/Z/17/Z), Worldwide Cancer Research grant (16-0042), and Rosetrees Trust and Stoneygate Trust research grant (M493). N.N. and J.E.E. are supported by National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. P.T. is supported by the “Ligue Genevoise contre le cancer.” V.H.K. is funded by the Swiss National Science Foundation (P2SKP3_168322/1 and P2SKP3_168322/2) and Werner and Hedy Berger-Janser Foundation for Cancer Research (08/2017). E.J.M. is funded by the Lee Placito Medical Research Fund (University of Oxford). D.J.H. is supported by the KWF Young Investigator program (13544). This research was also supported by an International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB), and AIRC (22795). Core funding to the Wellcome Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). This research was funded, in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this work are those of the author/s and not necessarily those of the NHS, the NIHR, or the Department of Health. E.G.V. N.N. and S.J.L. conceived and designed the project. Funding was obtained by S.J.L. and O.S. Experiments were conducted by E.G.V. N.N. H.B.-D. E.M. T.R.M.L. D.F. A.K.N. S.O. A.M. K.S. A.C. V.W. and D.H. Bioinformatic analysis was carried out by G.V. K.G. P.W. P.T. E.D. N.N. and E.G.V. Pathology support, image analysis, and intellectual input was provided by V.H.K. and A.E. Tissue and data provision were provided by J.E.E. S.T. T.M. D.M. D.C. and L.T. Conceptual input and data interpretation was provided by O.S. P.D. and S.T. The manuscript was written by E.G.V. N.N. G.V. and S.J.L. S.J.L. has received grant income from UCB Pharma. V.H.K. has served as an invited speaker on behalf of Indica Labs. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2022 The Authors",

year = "2022",

month = aug,

day = "4",

doi = "https://doi.org/10.1016/j.stem.2022.07.008",

language = "English",

volume = "29",

pages = "1213--1228.e8",

journal = "Cell Stem Cell",

issn = "1934-5909",

publisher = "Cell Press",

number = "8",

}

Vasquez, EG, Nasreddin, N, Valbuena, GN, Mulholland, EJ, Belnoue-Davis, HL, Eggington, HR, Schenck, RO, Wouters, VM, Wirapati, P, Gilroy, K, Lannagan, TRM, Flanagan, DJ, Najumudeen, AK, Omwenga, S, McCorry, AMB, Easton, A, Koelzer, VH, East, JE, Morton, D, Trusolino, L, Maughan, T, Campbell, AD, Loughrey, MB, Dunne, PD, Tsantoulis, P, Huels, DJ, Tejpar, S, Sansom, OJ & Leedham, SJ 2022, 'Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia', Cell Stem Cell, vol. 29, no. 8, pp. 1213-1228.e8. https://doi.org/10.1016/j.stem.2022.07.008

TY - JOUR

T1 - Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

AU - Vasquez, Ester Gil

AU - Nasreddin, Nadia

AU - Valbuena, Gabriel N.

AU - Mulholland, Eoghan J.

AU - Belnoue-Davis, Hayley L.

AU - Eggington, Holly R.

AU - Schenck, Ryan O.

AU - Wouters, Valérie M.

AU - Wirapati, Pratyaksha

AU - Gilroy, Kathryn

AU - Lannagan, Tamsin R. M.

AU - Flanagan, Dustin J.

AU - Najumudeen, Arafath K.

AU - Omwenga, Sulochana

AU - McCorry, Amy M. B.

AU - Easton, Alistair

AU - Koelzer, Viktor H.

AU - East, James E.

AU - Morton, Dion

AU - Trusolino, Livio

AU - Maughan, Timothy

AU - Campbell, Andrew D.

AU - Loughrey, Maurice B.

AU - Dunne, Philip D.

AU - Tsantoulis, Petros

AU - Huels, David J.

AU - Tejpar, Sabine

AU - Sansom, Owen J.

AU - Leedham, Simon J.

N1 - Funding Information: The authors thank Genentech (California, USA) for the supply of the Lgr5 DTR mouse. S.J.L. is supported by a Wellcome Trust Senior Clinical Research Fellowship ( 206314/Z/17/Z ), Worldwide Cancer Research grant ( 16-0042 ), and Rosetrees Trust and Stoneygate Trust research grant ( M493 ). N.N. and J.E.E. are supported by National Institute for Health Research ( NIHR ) Oxford Biomedical Research Centre . P.T. is supported by the “Ligue Genevoise contre le cancer.” V.H.K. is funded by the Swiss National Science Foundation ( P2SKP3_168322/1 and P2SKP3_168322/2 ) and Werner and Hedy Berger-Janser Foundation for Cancer Research ( 08/2017 ). E.J.M. is funded by the Lee Placito Medical Research Fund ( University of Oxford ). D.J.H. is supported by the KWF Young Investigator program (13544). This research was also supported by an International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK ( A26825 and A28223 ), FC AECC ( GEACC18004TAB ), and AIRC ( 22795 ). Core funding to the Wellcome Centre for Human Genetics was provided by the Wellcome Trust ( 090532/Z/09/Z ). This research was funded, in part, by the Wellcome Trust . For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this work are those of the author/s and not necessarily those of the NHS, the NIHR, or the Department of Health. Funding Information: The authors thank Genentech (California, USA) for the supply of the Lgr5DTR mouse. S.J.L. is supported by a Wellcome Trust Senior Clinical Research Fellowship (206314/Z/17/Z), Worldwide Cancer Research grant (16-0042), and Rosetrees Trust and Stoneygate Trust research grant (M493). N.N. and J.E.E. are supported by National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. P.T. is supported by the “Ligue Genevoise contre le cancer.” V.H.K. is funded by the Swiss National Science Foundation (P2SKP3_168322/1 and P2SKP3_168322/2) and Werner and Hedy Berger-Janser Foundation for Cancer Research (08/2017). E.J.M. is funded by the Lee Placito Medical Research Fund (University of Oxford). D.J.H. is supported by the KWF Young Investigator program (13544). This research was also supported by an International Accelerator Award, ACRCelerate, jointly funded by Cancer Research UK (A26825 and A28223), FC AECC (GEACC18004TAB), and AIRC (22795). Core funding to the Wellcome Centre for Human Genetics was provided by the Wellcome Trust (090532/Z/09/Z). This research was funded, in part, by the Wellcome Trust. For the purpose of Open Access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. The views expressed in this work are those of the author/s and not necessarily those of the NHS, the NIHR, or the Department of Health. E.G.V. N.N. and S.J.L. conceived and designed the project. Funding was obtained by S.J.L. and O.S. Experiments were conducted by E.G.V. N.N. H.B.-D. E.M. T.R.M.L. D.F. A.K.N. S.O. A.M. K.S. A.C. V.W. and D.H. Bioinformatic analysis was carried out by G.V. K.G. P.W. P.T. E.D. N.N. and E.G.V. Pathology support, image analysis, and intellectual input was provided by V.H.K. and A.E. Tissue and data provision were provided by J.E.E. S.T. T.M. D.M. D.C. and L.T. Conceptual input and data interpretation was provided by O.S. P.D. and S.T. The manuscript was written by E.G.V. N.N. G.V. and S.J.L. S.J.L. has received grant income from UCB Pharma. V.H.K. has served as an invited speaker on behalf of Indica Labs. All other authors declare no competing interests. Publisher Copyright: © 2022 The Authors

PY - 2022/8/4

Y1 - 2022/8/4

N2 - Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.

AB - Intestinal homeostasis is underpinned by LGR5+ve crypt-base columnar stem cells (CBCs), but following injury, dedifferentiation results in the emergence of LGR5−ve regenerative stem cell populations (RSCs), characterized by fetal transcriptional profiles. Neoplasia hijacks regenerative signaling, so we assessed the distribution of CBCs and RSCs in mouse and human intestinal tumors. Using combined molecular-morphological analysis, we demonstrate variable expression of stem cell markers across a range of lesions. The degree of CBC-RSC admixture was associated with both epithelial mutation and microenvironmental signaling disruption and could be mapped across disease molecular subtypes. The CBC-RSC equilibrium was adaptive, with a dynamic response to acute selective pressure, and adaptability was associated with chemoresistance. We propose a fitness landscape model where individual tumors have equilibrated stem cell population distributions along a CBC-RSC phenotypic axis. Cellular plasticity is represented by position shift along this axis and is influenced by cell-intrinsic, extrinsic, and therapeutic selective pressures.

KW - cell plasticity

KW - colorectal cancer

KW - colorectal neoplasia

KW - intestinal polyps

KW - intestinal stem cells

KW - molecular phenotyping

KW - stem cells

UR - http://www.scopus.com/inward/record.url?scp=85135464912&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.stem.2022.07.008

DO - https://doi.org/10.1016/j.stem.2022.07.008

M3 - Article

C2 - 35931031

SN - 1934-5909

VL - 29

SP - 1213-1228.e8

JO - Cell Stem Cell

JF - Cell Stem Cell

IS - 8

ER -

Dynamic and adaptive cancer stem cell population admixture in colorectal neoplasia

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Keywords

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