@article{0f76bbaac15849babf2f239bc82f8ad7,
title = "Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors",
abstract = "Colorectal cancer exhibits dynamic cellular and genetic heterogeneity during progression from precursor lesions toward malignancy. Analysis of spatial multi-omic data from 31 human colorectal specimens enabled phylogeographic mapping of tumor evolution that revealed individualized progression trajectories and accompanying microenvironmental and clonal alterations. Phylogeographic mapping ordered genetic events, classified tumors by their evolutionary dynamics, and placed clonal regions along global pseudotemporal progression trajectories encompassing the chromosomal instability (CIN+) and hypermutated (HM) pathways. Integrated single-cell and spatial transcriptomic data revealed recurring epithelial programs and infiltrating immune states along progression pseudotime. We discovered an immune exclusion signature (IEX), consisting of extracellular matrix regulators DDR1, TGFBI, PAK4, and DPEP1, that charts with CIN+ tumor progression, is associated with reduced cytotoxic cell infiltration, and shows prognostic value in independent cohorts. This spatial multi-omic atlas provides insights into colorectal tumor-microenvironment co-evolution, serving as a resource for stratification and targeted treatments.",
keywords = "colorectal cancer, immune exclusion, tumor evolution, spatial transcriptomics, multiplex imaging, tumor progression, microsatellite instability, stem cells, mutations, Microsatellite Instability, Prognosis, Colorectal Neoplasms/pathology, Humans, Tumor Microenvironment, Gene Expression Profiling, Phylogeny, Disease Progression, Chromosomal Instability/genetics, Mutation, p21-Activated Kinases/genetics",
author = "Heiser, {Cody N.} and Simmons, {Alan J.} and Frank Revetta and McKinley, {Eliot T.} and Ramirez-Solano, {Marisol A.} and Jiawei Wang and Harsimran Kaur and Justin Shao and Ayers, {Gregory D.} and Yu Wang and Glass, {Sarah E.} and Naila Tasneem and Zhengyi Chen and Yan Qin and William Kim and Andrea Rolong and Bob Chen and Vega, {Paige N.} and Drewes, {Julia L.} and Markham, {Nicholas O.} and Nabil Saleh and Fotis Nikolo and Simon Vandekar and Jones, {Angela L.} and Washington, {M. Kay} and Roland, {Joseph T.} and Chan, {Keith S.} and Thomas Sch{\"u}rpf and Sears, {Cynthia L.} and Qi Liu and Shrubsole, {Martha J.} and Coffey, {Robert J.} and Lau, {Ken S.}",
note = "Funding Information: This publication is part of the Human Tumor Atlas Network (HTAN) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors. The authors wish to thank the study participants and other contributing investigators including Vito Quaranta, Jake Hughey, Sarah Groves, and Taerang (Dennis) Kim. 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 U2CCA233291 and Translational and Basic Science Research in Early Lesions U54CA274367 (to R.J.C. K.S.L. M.J.S. and C.L.S.), R35CA197570 and P50CA236733 (to R.J.C.), R01DK103831 (to K.S.L.), K07CA122451 (to M.J.S.), F31DK127687 (to P.N.V.), 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 TPSR (P30DK058404), DHSR, the CHTN (UM1CA183727), and VANTAGE. 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. R.J.C. acknowledges the generous support of the Nicholas Tierney GI Cancer Memorial Fund. Diagrams were created with BioRender.com. Conceptualization, C.N.H. M.J.S. R.J.C. and K.S.L.; data curation, C.N.H. A.J.S. F.R. J.W. H.K. N.T. W.K. B.C. M.A.R.-S. E.T.M. P.N.V. J.T.R. M.K.W. M.J.S. and K.S.L.; formal analysis, C.N.H. E.T.M. M.A.R.-S. D.A. Y.W. S.E.G. B.C. N.S. J.L.D. N.O.M. A.R. Q.L. Z.C. and K.S.L.; investigation, C.N.H. A.J.S. M.K.W. C.L.S. M.J.S. R.J.C. and K.S.L.; methodology, C.N.H. A.J.S. E.T.M. Y.W. D.A. S.V. H.K. and K.S.L.; project administration, C.N.H. A.J.S. E.T.M. J.T.R. Q.L. M.K.W. M.J.S. R.J.C. and K.S.L.; resources, M.K.W. J.T.R. Q.L. M.J.S. R.J.C. and K.S.L.; software, C.N.H. H.K. B.C. J.S. E.T.M. Q.L. and K.S.L.; supervision, M.K.W. R.J.C. M.J.S. and K.S.L.; validation, C.N.H. H.K. N.T. Y.Q. T.S. F.N. and K.S.C.; visualization, C.N.H. Y.W. D.A. B.C. R.J.C. M.J.S. and K.S.L.; writing – original draft, C.N.H. R.J.C. and K.S.L.; writing – reviewing and editing, C.N.H. A.J.S. F.R. E.T.M. M.A.R.-S. J.W. J.S. Y.W. D.A. S.E.G. B.C. H.K. P.N.V. J.L.D. A.R. N.S. S.V. M.K.W. J.T.R. C.L.S. Q.L. M.J.S. R.J.C. and K.S.L. C.N.H. is an employee of Regeneron Pharmaceuticals. M.J.S. receives funding from Janssen. B.C. is an employee of Genentech. E.T.M. is an employee of GlaxoSmithKline. Y.Q. and T.S. are stockholders and employees of Incendia Therapeutics. 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. One or more of the authors of this paper self-identifies as an underrepresented ethnic minority in their field of research or within their geographical location. One or more of the authors of this paper self-identifies as a member of the LGBTQIA+ community. One or more of the authors of this paper received support from a program designed to increase minority representation in their field of research. Funding Information: This publication is part of the Human Tumor Atlas Network (HTAN) Consortium paper package. A list of HTAN members is available at humantumoratlas.org/htan-authors . The authors wish to thank the study participants and other contributing investigators including Vito Quaranta, Jake Hughey, Sarah Groves, and Taerang (Dennis) Kim. 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 U2CCA233291 and Translational and Basic Science Research in Early Lesions U54CA274367 (to R.J.C., K.S.L., M.J.S., and C.L.S.), R35CA197570 and P50CA236733 (to R.J.C.), R01DK103831 (to K.S.L.), K07CA122451 (to M.J.S.), F31DK127687 (to P.N.V.), 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 TPSR (P30DK058404) , DHSR, the CHTN (UM1CA183727), and VANTAGE. 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. R.J.C. acknowledges the generous support of the Nicholas Tierney GI Cancer Memorial Fund . Diagrams were created with BioRender.com . Funding Information: C.N.H. is an employee of Regeneron Pharmaceuticals. M.J.S. receives funding from Janssen. B.C. is an employee of Genentech. E.T.M. is an employee of GlaxoSmithKline. Y.Q. and T.S. are stockholders and employees of Incendia Therapeutics. All other authors declare no competing interests. Publisher Copyright: {\textcopyright} 2023 The Author(s)",
year = "2023",
month = dec,
day = "7",
doi = "10.1016/j.cell.2023.11.006",
language = "English (US)",
volume = "186",
pages = "5620--5637.e16",
journal = "Cell",
issn = "0092-8674",
publisher = "Cell Press",
number = "25",
}