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

Genome Biology

Levi Waldron¹  Milan Radovich²  Yunlong Liu²  Melissa L. Fishel²  Yong Zang²  Yingjie Qiu²  Ashiq Masood²  Anita Turk²  Ateeq M. Khaliq²  Janakiraman Subramanian³  Anguraj Sadanandam⁴  Cihat Erdogan⁵  Zeyneb Kurt⁶  Miles W. Grunvald⁷  Audrey E. Kam⁷  Ram Al-Sabti⁷  Sam G. Pappas⁷  Timothy M. Kuzel⁷  Jeffrey A. Borgia⁷  Dana M. Hayden⁷  Vineet Gupta⁷  Jochen Reiser⁷  Henry R. Govekar⁷  Mohammad Saleem⁷  Ameen A. Salahudeen⁸  Sonal Khare⁸  Tim Rand⁸  Kiran Turaga⁹  Bassel El-Rayes^1,10  Arif Hussain^1,11  Sultan Sevgi Turgut^1,12 

[1] CUNY Graduate School of Public Health and Health Policy;Indiana University School of Medicine;Inova Schar Cancer Institute;Institute of Cancer Research;Isparta University of Applied Sciences;Northumbria University;Rush University Medical Center;Tempus Labs, Inc.;The University of Chicago;University of Alabama, O’Neil Comprehensive Cancer Institute;University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center;Yildiz Technical University;

关键词: Cancer-associated fibroblast;    CMS classification;    Colorectal cancer;    Single-cell analysis;    Immunotherapy;    Stromal signatures;   

DOI  :  10.1186/s13059-022-02677-z

来源: DOAJ

【 摘 要 】

Abstract 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.

【 授权许可】

Unknown