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

Khaliq, Ateeq M., Erdogan, Cihat, Kurt, Zeyneb, Turgut, Sultan Sevgi, Grunvald, Miles W., Rand, Tim, Khare, Sonal, Borgia, Jeffrey A., Hayden, Dana M., Pappas, Sam G., Govekar, Henry R., Kam, Audrey E., Reiser, Jochen, Turaga, Kiran, Radovich, Milan, Zang, Yong, Qiu, Yingjie, Liu, Yunlong, Fishel, Melissa L., Turk, Anita, Gupta, Vineet, Al-Sabti, Ram, Subramanian, Janakiraman, Kuzel, Timothy M., Sadanandam, Anguraj, Waldron, Levi, Hussain, Arif, Saleem, Mohammad, El-Rayes, Bassel, Salahudeen, Ameen A. and Masood, Ashiq (2022) Refining colorectal cancer classification and clinical stratification through a single-cell atlas. Genome Biology, 23 (1). p. 113. ISSN 1474-760X

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Official URL: https://doi.org/10.1186/s13059-022-02677-z

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

Item Type: Article
Additional Information: Funding information: This study was supported by the startup fund provided to Ashiq Masood by the Rush University Medical Center; the OCM grant to Ashiq Masood by Rush University Cancer Center. Part of this study was supported by startup funds from Indiana University. Part of Arif Hussain time was supported by a Merit Review Award (I01 BX000545) from the Medical Research Service, Department of Veterans Affairs. We would also like to thank Dr. Kristian Pietras for providing a differential gene expression list of CAFs from his paper titled “Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing”. Bassel El-Rayes is supported by the National Institutes of Health (1R01CA228406). Mohammad Saleem is supported by the National Institutes of Health grant (R01CA193739).
Uncontrolled Keywords: Cancer-associated fibroblast, CMS classification, Colorectal cancer, Single-cell analysis, Immunotherapy, Stromal signatures
Subjects: A300 Clinical Medicine
Department: Faculties > Engineering and Environment > Computer and Information Sciences
Depositing User: Rachel Branson
Date Deposited: 13 May 2022 13:54
Last Modified: 13 May 2022 14:00
URI: http://nrl.northumbria.ac.uk/id/eprint/49126

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