@article{be0b5a2f10ee45f49169ede24bc62e90,
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 = "Funding Information: This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at https://humantumoratlas.org/htan-authors/ . The authors wish to thank the study participants and other contributing investigators, including Jumpei Kondo, Emily Poulin, Eunyoung Choi, Reid Ness, Yu Shyr, Harvey Murff, David Pocalyko, Jeffrey Rathmell, Mary Philip, Nancy Zhang, Joke Reumers, Harrison Kiang, and Eric Eisenberg. We apologize in advance to those we have failed to acknowledge due to space constraints. This study was supported by the Human Tumor Atlas Network grant U2CCA233291 (to R.J.C., K.S.L., and M.J.S.), R01CA97386 (to W.Z.), R35CA197570 and P50CA236733 (to R.J.C.), R01DK103831 (to K.S.L.), K07CA122451 (to M.J.S.), T32LM012412 (in support of B.C.), DK123489 (to J.A.G.), U01CA215798 (in support of C.R.S.), F31DK127687 (to P.N.V.), NCI task order HHSN261100039 under contract HHSN261201500003I (to A. Regev), VA IBX000930 , DOD CA160479 and DK101332 , and Cancer UK 29075 (to J.R.G.) and P30CA068485 (to Vanderbilt-Ingram Cancer Center). Polyp RNA-seq funding was provided by Janssen (to M.J.S.). Cores used by this study included Survey and Biospecimen Shared Resource, TPSR ( U24DK059637 ), DHSR , the CHTN ( UM1CA183727 ), VANTAGE , and REDCap ( UL1TR000445 ). R.J.C. acknowledges the generous support of the Nicholas Tierney GI Cancer Memorial Fund . A portion of the participants were studied as the result of resources and the use of facilities at the Veterans Affairs Tennessee Valley Healthcare System. Funding Information: This publication is part of the HTAN (Human Tumor Atlas Network) Consortium paper package. A list of HTAN members is available at https://humantumoratlas.org/htan-authors/. The authors wish to thank the study participants and other contributing investigators, including Jumpei Kondo, Emily Poulin, Eunyoung Choi, Reid Ness, Yu Shyr, Harvey Murff, David Pocalyko, Jeffrey Rathmell, Mary Philip, Nancy Zhang, Joke Reumers, Harrison Kiang, and Eric Eisenberg. We apologize in advance to those we have failed to acknowledge due to space constraints. This study was supported by the Human Tumor Atlas Network grant U2CCA233291 (to R.J.C. K.S.L. and M.J.S.), R01CA97386 (to W.Z.), R35CA197570 and P50CA236733 (to R.J.C.), R01DK103831 (to K.S.L.), K07CA122451 (to M.J.S.), T32LM012412 (in support of B.C.), DK123489 (to J.A.G.), U01CA215798 (in support of C.R.S.), F31DK127687 (to P.N.V.), NCI task order HHSN261100039 under contract HHSN261201500003I (to A. Regev), VA IBX000930, DOD CA160479 and DK101332, and Cancer UK 29075 (to J.R.G.) and P30CA068485 (to Vanderbilt-Ingram Cancer Center). Polyp RNA-seq funding was provided by Janssen (to M.J.S.). Cores used by this study included Survey and Biospecimen Shared Resource, TPSR (U24DK059637), DHSR, the CHTN (UM1CA183727), VANTAGE, and REDCap (UL1TR000445). R.J.C. acknowledges the generous support of the Nicholas Tierney GI Cancer Memorial Fund. A portion of the participants were studied as the result of resources and the use of facilities at the Veterans Affairs Tennessee Valley Healthcare System. Conceptualization, B.C. M.K.W. W.Z. C.L.S. R.J.C. M.J.S. and K.S.L.; data curation, B.C. C.R.S. X.Z. C.N.H. L.D.B. M.J.S. K.S.L. P.N.V. H.K. A. Rolong, J.R. K.K. K.P. M.H. J.H.C. S.S. K.N. M.G. G.M.B. A.J.A. and A.C.A.; formal analysis, B.C. E.T.M. M.A.R.-S. C.N.H. S.V. Q.L. and K.S.L.; investigation, B.C. E.T.M. A.J.S. X.Z. Y.X. A.N.S.-S. N.O.M. Q.S. J.L.D. C.N.H. Y.Z. F.R. L.D.B. Q.C. J.L.F. J.T.R. T.S. W.J.H. R.J.C. M.J.S. K.S.L. M.I. and H.N.; methodology, B.C. E.T.M. A.J.S. X.Z. A.N.S.-S. J.L.F. R.J.C. M.J.S. K.S.L. A.L.J. J.A.G. M.I. and H.N.; project administration, E.T.M. A.J.S. X.Z. Q.L. R.J.C. M.JS. and K.S.L.; Resources, M.K.W. W.Z. J.R.G. J.T.R. W.J.H. Q.L. R.J.C. M.J.S. and K.S.L.; software, B.C. C.N.H. Q.L. K.S.L. T.S. and W.M.G.; supervision, R.J.C. M.J.S. K.S.L. O.R.-R. A. Regev, and N.H.; validation, B.C. and C.N.H.; visualization, B.C. M.A.R.-S. Q.S. C.N.H. S.V. W.J.H. Q.L. R.J.C. M.J.S. and K.S.L.; writing – original draft, B.C. W.J.H. R.J.C. M.J.S. and K.S.L.; writing – reviewing & editing, B.C. E.T.M. A.J.S. M.A.R.-S. X.A. A.N.S.-S. N.O.M. Q.S. J.L.D. Y.X. C.N.H. Y.Z. M.K.W. F.R. L.D.B. W.Z. Q.C. C.L.S. J.R.G. J.L.F. S.V. J.T.R. T.S. W.J.H. J.A.G. Q.L. R.J.C. M.J.S. and K.S.L. M.J.S. C.L.S. W.M.G. and K.N. receive funding from Janssen. C.L.S. M.G. and K.N. receive funding from Bristol Myers Squibb. W.M.G. receives funding from Tempus and Pavmed technologies; is a board member for Freenome, Guardant Health, and SEngine; and consults for DiaCarta. A.J.A. receives funding from Mirati Therapeutics, Deerfield, and Novo Ventures and consults for Oncorus, Arrakis Therapeutics, and Merck. G.M.B. receives funding from Palleon Pharmaceuticals, Olink Proteomics, and Takeda Oncology and is a board member for Novartis and Nektar Therapeutics. A.C.A. is a board member for Tizona Therapeutics, Compass Therapeutics, Zumutor Biologics, and ImmuneOncia and consults for iTeos Therapeutics. M.G. and K.N. receive funding from Merck and Servier. K.N. receives funding from Revolution Medicines, Evergrande Group, Pharmavite, and Merck; is a board member for Seattle Genetics and BiomX; and consults for X-Biotix Therapeutics. A. Regev is a founder of and equity holder in Celsius Therapeutics and holds equity in Immunitas Therapeutics. O.R.-R. and A. Regev are employees of Genentech. N.H. holds equity in BioNTech and consults for Related Sciences/Danger Bio. All other authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure ethnic or other types of diversity in the recruitment of human subjects. We worked to ensure that the study questionnaires were prepared in an inclusive way. We worked to ensure sex balance in the selection of non-human subjects. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in science. One or more of the authors of this paper received support from a program designed to increase minority representation in science. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = dec,
day = "22",
doi = "10.1016/j.cell.2021.11.031",
language = "English",
volume = "184",
pages = "6262--6280.e26",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "26",
}
