Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Bob Chen; Cherie’ R. Scurrah; Eliot T. McKinley; Alan J. Simmons; Marisol A. Ramirez-Solano; Xiangzhu Zhu; Nicholas O. Markham; Cody N. Heiser; Paige N. Vega; Andrea Rolong; Hyeyon Kim; Quanhu Sheng; Julia L. Drewes; Yuan Zhou; Austin N. Southard-Smith; Yanwen Xu; James Ro; Angela L. Jones; Frank Revetta; Lynne D. Berry; Hiroaki Niitsu; Mirazul Islam; Karin Pelka; Matan Hofree; Jonathan H. Chen; Siranush Sarkizova; Kimmie Ng; Marios Giannakis; Genevieve M. Boland; Andrew J. Aguirre; Ana C. Anderson; Orit Rozenblatt-Rosen; Aviv Regev; Nir Hacohen; Kenta Kawasaki; Toshiro Sato; Jeremy A. Goettel; William M. Grady; Wei Zheng; M. Kay Washington; Qiuyin Cai; Cynthia L. Sears; James R. Goldenring; Jeffrey L. Franklin; Timothy Su; Won Jae Huh; Simon Vandekar; Joseph T. Roland; Qi Liu; Robert J. Coffey; Martha J. Shrubsole; Ken S. Lau

doi:10.1016/j.cell.2021.11.031

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Bob Chen, Cherie’ R. Scurrah, Eliot T. McKinley, Alan J. Simmons, Marisol A. Ramirez-Solano, Xiangzhu Zhu, Nicholas O. Markham, Cody N. Heiser, Paige N. Vega, Andrea Rolong, Hyeyon Kim, Quanhu Sheng, Julia L. Drewes, Yuan Zhou, Austin N. Southard-Smith, Yanwen Xu, James Ro, Angela L. Jones, Frank Revetta, Lynne D. BerryHiroaki Niitsu, Mirazul Islam, Karin Pelka, Matan Hofree, Jonathan H. Chen, Siranush Sarkizova, Kimmie Ng, Marios Giannakis, Genevieve M. Boland, Andrew J. Aguirre, Ana C. Anderson, Orit Rozenblatt-Rosen, Aviv Regev, Nir Hacohen, Kenta Kawasaki, Toshiro Sato, Jeremy A. Goettel, William M. Grady, Wei Zheng, M. Kay Washington, Qiuyin Cai, Cynthia L. Sears, James R. Goldenring, Jeffrey L. Franklin, Timothy Su, Won Jae Huh, Simon Vandekar, Joseph T. Roland, Qi Liu, Robert J. Coffey^*, Martha J. Shrubsole^*, Ken S. Lau^*

^*Corresponding author for this work

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

139 Scopus citations

Abstract

Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

Original language	English
Pages (from-to)	6262-6280.e26
Journal	Cell
Volume	184
Issue number	26
DOIs	https://doi.org/10.1016/j.cell.2021.11.031
State	Published - 22 Dec 2021
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2021 The Authors

Keywords

adenoma
colorectal cancer
cytotoxic
differentiation
metaplasia
multiplex
polyp
serrated
single-cell RNA-seq
stem cells

UN SDGs

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

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10.1016/j.cell.2021.11.031

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Chen, B., Scurrah, C. R., McKinley, E. T., Simmons, A. J., Ramirez-Solano, M. A., Zhu, X., Markham, N. O., Heiser, C. N., Vega, P. N., Rolong, A., Kim, H., Sheng, Q., Drewes, J. L., Zhou, Y., Southard-Smith, A. N., Xu, Y., Ro, J., Jones, A. L., Revetta, F., ... Lau, K. S. (2021). Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps. Cell, 184(26), 6262-6280.e26. https://doi.org/10.1016/j.cell.2021.11.031

@article{b8c4ec219de04fc0afcc027fe0bdc87f,

title = "Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps",

abstract = "Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.",

keywords = "adenoma, colorectal cancer, cytotoxic, differentiation, metaplasia, multiplex, polyp, serrated, single-cell RNA-seq, stem cells",

author = "Bob Chen and Scurrah, {Cherie{\textquoteright} R.} and McKinley, {Eliot T.} and Simmons, {Alan J.} and Ramirez-Solano, {Marisol A.} and Xiangzhu Zhu and Markham, {Nicholas O.} and Heiser, {Cody N.} and Vega, {Paige N.} and Andrea Rolong and Hyeyon Kim and Quanhu Sheng and Drewes, {Julia L.} and Yuan Zhou and Southard-Smith, {Austin N.} and Yanwen Xu and James Ro and Jones, {Angela L.} and Frank Revetta and Berry, {Lynne D.} and Hiroaki Niitsu and Mirazul Islam and Karin Pelka and Matan Hofree and Chen, {Jonathan H.} and Siranush Sarkizova and Kimmie Ng and Marios Giannakis and Boland, {Genevieve M.} and Aguirre, {Andrew J.} and Anderson, {Ana C.} and Orit Rozenblatt-Rosen and Aviv Regev and Nir Hacohen and Kenta Kawasaki and Toshiro Sato and Goettel, {Jeremy A.} and Grady, {William M.} and Wei Zheng and Washington, {M. Kay} and Qiuyin Cai and Sears, {Cynthia L.} and Goldenring, {James R.} and Franklin, {Jeffrey L.} and Timothy Su and Huh, {Won Jae} and Simon Vandekar and Roland, {Joseph T.} and Qi Liu and Coffey, {Robert J.} and Shrubsole, {Martha J.} and Lau, {Ken S.}",

note = "Publisher Copyright: {\textcopyright} 2021 The Authors",

year = "2021",

month = dec,

day = "22",

doi = "10.1016/j.cell.2021.11.031",

language = "אנגלית",

volume = "184",

pages = "6262--6280.e26",

journal = "Cell",

issn = "0092-8674",

publisher = "Elsevier B.V.",

number = "26",

}

Chen, B, Scurrah, CR, McKinley, ET, Simmons, AJ, Ramirez-Solano, MA, Zhu, X, Markham, NO, Heiser, CN, Vega, PN, Rolong, A, Kim, H, Sheng, Q, Drewes, JL, Zhou, Y, Southard-Smith, AN, Xu, Y, Ro, J, Jones, AL, Revetta, F, Berry, LD, Niitsu, H, Islam, M, Pelka, K, Hofree, M, Chen, JH, Sarkizova, S, Ng, K, Giannakis, M, Boland, GM, Aguirre, AJ, Anderson, AC, Rozenblatt-Rosen, O, Regev, A, Hacohen, N, Kawasaki, K, Sato, T, Goettel, JA, Grady, WM, Zheng, W, Washington, MK, Cai, Q, Sears, CL, Goldenring, JR, Franklin, JL, Su, T, Huh, WJ, Vandekar, S, Roland, JT, Liu, Q, Coffey, RJ, Shrubsole, MJ & Lau, KS 2021, 'Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps', Cell, vol. 184, no. 26, pp. 6262-6280.e26. https://doi.org/10.1016/j.cell.2021.11.031

TY - JOUR

T1 - Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

AU - Chen, Bob

AU - Scurrah, Cherie’ R.

AU - McKinley, Eliot T.

AU - Simmons, Alan J.

AU - Ramirez-Solano, Marisol A.

AU - Zhu, Xiangzhu

AU - Markham, Nicholas O.

AU - Heiser, Cody N.

AU - Vega, Paige N.

AU - Rolong, Andrea

AU - Kim, Hyeyon

AU - Sheng, Quanhu

AU - Drewes, Julia L.

AU - Zhou, Yuan

AU - Southard-Smith, Austin N.

AU - Xu, Yanwen

AU - Ro, James

AU - Jones, Angela L.

AU - Revetta, Frank

AU - Berry, Lynne D.

AU - Niitsu, Hiroaki

AU - Islam, Mirazul

AU - Pelka, Karin

AU - Hofree, Matan

AU - Chen, Jonathan H.

AU - Sarkizova, Siranush

AU - Ng, Kimmie

AU - Giannakis, Marios

AU - Boland, Genevieve M.

AU - Aguirre, Andrew J.

AU - Anderson, Ana C.

AU - Rozenblatt-Rosen, Orit

AU - Regev, Aviv

AU - Hacohen, Nir

AU - Kawasaki, Kenta

AU - Sato, Toshiro

AU - Goettel, Jeremy A.

AU - Grady, William M.

AU - Zheng, Wei

AU - Washington, M. Kay

AU - Cai, Qiuyin

AU - Sears, Cynthia L.

AU - Goldenring, James R.

AU - Franklin, Jeffrey L.

AU - Su, Timothy

AU - Huh, Won Jae

AU - Vandekar, Simon

AU - Roland, Joseph T.

AU - Liu, Qi

AU - Coffey, Robert J.

AU - Shrubsole, Martha J.

AU - Lau, Ken S.

PY - 2021/12/22

Y1 - 2021/12/22

N2 - Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

AB - Colorectal cancers (CRCs) arise from precursor polyps whose cellular origins, molecular heterogeneity, and immunogenic potential may reveal diagnostic and therapeutic insights when analyzed at high resolution. We present a single-cell transcriptomic and imaging atlas of the two most common human colorectal polyps, conventional adenomas and serrated polyps, and their resulting CRC counterparts. Integrative analysis of 128 datasets from 62 participants reveals adenomas arise from WNT-driven expansion of stem cells, while serrated polyps derive from differentiated cells through gastric metaplasia. Metaplasia-associated damage is coupled to a cytotoxic immune microenvironment preceding hypermutation, driven partly by antigen-presentation differences associated with tumor cell-differentiation status. Microsatellite unstable CRCs contain distinct non-metaplastic regions where tumor cells acquire stem cell properties and cytotoxic immune cells are depleted. Our multi-omic atlas provides insights into malignant progression of colorectal polyps and their microenvironment, serving as a framework for precision surveillance and prevention of CRC.

KW - adenoma

KW - colorectal cancer

KW - cytotoxic

KW - differentiation

KW - metaplasia

KW - multiplex

KW - polyp

KW - serrated

KW - single-cell RNA-seq

KW - stem cells

UR - http://www.scopus.com/inward/record.url?scp=85121323228&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.11.031

DO - 10.1016/j.cell.2021.11.031

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34910928

AN - SCOPUS:85121323228

SN - 0092-8674

VL - 184

SP - 6262-6280.e26

JO - Cell

JF - Cell

IS - 26

ER -

Differential pre-malignant programs and microenvironment chart distinct paths to malignancy in human colorectal polyps

Abstract

Bibliographical note

Keywords

UN SDGs

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