Molecular cartography uncovers evolutionary and microenvironmental dynamics in sporadic colorectal tumors

Date:	7 December 2023
PMID:	38065082
Category:	N/A
Authors:	Cody N Heiser, Alan J Simmons, Frank Revetta, Eliot T McKinley, Marisol A Ramirez-Solano, Jiawei Wang, Harsimran Kaur, Justin Shao, Gregory D Ayers, Yu Wang, Sarah E Glass, Naila Tasneem, Zhengyi Chen, Yan Qin, William Kim, Andrea Rolong, Bob Chen, Paige N Vega, Julia L Drewes, Nicholas O Markham, Nabil Saleh, Fotis Nikolos, Simon Vandekar, Angela L Jones, M Kay Washington, Joseph T Roland, Keith S Chan, Thomas Schürpf, Cynthia L Sears, Qi Liu, Martha J Shrubsole, Robert J Coffey, Ken S Lau
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..

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Acknowledgements:

The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.

The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:

Project Number:	Awardee Organization
U54CA274374	Fred Hutchinson Cancer Center
U54CA274375	Houston Methodist Research Institute
U54CA274370	Johns Hopkins University
U54CA274371	UT MD Anderson Cancer Center
U54CA274367	Vanderbilt University Medical Center