Abstract
Original language | English |
---|---|
Pages (from-to) | 1213-1228.e8 |
Journal | Cell Stem Cell |
Volume | 29 |
Issue number | 8 |
DOIs | |
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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In: Cell Stem Cell, Vol. 29, No. 8, 04.08.2022, p. 1213-1228.e8.
Research output: Contribution to journal › Article › Academic › peer-review
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 -