Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors.

Autor:	Heiser CN; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Simmons AJ; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Revetta F; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., McKinley ET; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Ramirez-Solano MA; Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Wang J; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Kaur H; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Shao J; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Computer Science, Vanderbilt University, Nashville, TN 37235, USA., Ayers GD; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Wang Y; Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Glass SE; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Tasneem N; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Chen Z; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Qin Y; Incendia Therapeutics, Inc., Boston, MA 02135, USA., Kim W; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Rolong A; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Chen B; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Vega PN; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Drewes JL; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Markham NO; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Saleh N; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA., Nikolos F; Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA., Vandekar S; Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Jones AL; Vanderbilt Technologies for Advanced Genomics, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Washington MK; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Roland JT; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Chan KS; Department of Urology, Neal Cancer Center, Houston Methodist Research Institute, Houston, TX 77030, USA., Schürpf T; Incendia Therapeutics, Inc., Boston, MA 02135, USA., Sears CL; Department of Medicine, Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA., Liu Q; Department of Biostatistics and Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 37235, USA., Shrubsole MJ; Department of Medicine, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Coffey RJ; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: robert.coffey@vumc.org., Lau KS; Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA; Department of Surgery, Vanderbilt University Medical Center, Nashville, TN 37232, USA; Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA. Electronic address: ken.s.lau@vanderbilt.edu.
Jazyk:	angličtina
Zdroj:	Cell [Cell] 2023 Dec 07; Vol. 186 (25), pp. 5620-5637.e16.
DOI:	10.1016/j.cell.2023.11.006
Abstrakt:	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. Competing Interests: Declaration of interests 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. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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