Refining colorectal cancer classification and clinical stratification through a single-cell atlas.

Autor: Khaliq AM; Indiana University School of Medicine, Indianapolis, IN, USA., Erdogan C; Isparta University of Applied Sciences, Isparta, Turkey., Kurt Z; Northumbria University, Newcastle Upon Tyne, UK., Turgut SS; Yildiz Technical University, Istanbul, Turkey., Grunvald MW; Rush University Medical Center, Chicago, IL, USA., Rand T; Tempus Labs, Inc., Chicago, IL, USA., Khare S; Tempus Labs, Inc., Chicago, IL, USA., Borgia JA; Rush University Medical Center, Chicago, IL, USA., Hayden DM; Rush University Medical Center, Chicago, IL, USA., Pappas SG; Rush University Medical Center, Chicago, IL, USA., Govekar HR; Rush University Medical Center, Chicago, IL, USA., Kam AE; Rush University Medical Center, Chicago, IL, USA., Reiser J; Rush University Medical Center, Chicago, IL, USA., Turaga K; The University of Chicago, Chicago, IL, USA., Radovich M; Indiana University School of Medicine, Indianapolis, IN, USA., Zang Y; Indiana University School of Medicine, Indianapolis, IN, USA., Qiu Y; Indiana University School of Medicine, Indianapolis, IN, USA., Liu Y; Indiana University School of Medicine, Indianapolis, IN, USA., Fishel ML; Indiana University School of Medicine, Indianapolis, IN, USA., Turk A; Indiana University School of Medicine, Indianapolis, IN, USA., Gupta V; Rush University Medical Center, Chicago, IL, USA., Al-Sabti R; Rush University Medical Center, Chicago, IL, USA., Subramanian J; Inova Schar Cancer Institute, Fairfax, VA, USA., Kuzel TM; Rush University Medical Center, Chicago, IL, USA., Sadanandam A; Institute of Cancer Research, London, UK., Waldron L; CUNY Graduate School of Public Health and Health Policy, New York, NY, USA., Hussain A; University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, Baltimore, MD, USA., Saleem M; Rush University Medical Center, Chicago, IL, USA., El-Rayes B; University of Alabama, O'Neil Comprehensive Cancer Institute, Birmingham, AL, USA., Salahudeen AA; Tempus Labs, Inc., Chicago, IL, USA., Masood A; Indiana University School of Medicine, Indianapolis, IN, USA. asmasood@iu.edu.
Jazyk: angličtina
Zdroj: Genome biology [Genome Biol] 2022 May 11; Vol. 23 (1), pp. 113. Date of Electronic Publication: 2022 May 11.
DOI: 10.1186/s13059-022-02677-z
Abstrakt: Background: Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells.
Results: Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance.
Conclusions: Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients.
(© 2022. The Author(s).)
Databáze: MEDLINE
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