Refining colorectal cancer classification and clinical stratification through a single-cell atlas.
AuthorKhaliq, Ateeq M
Turgut, Sultan Sevgi
Grunvald, Miles W
Borgia, Jeffrey A
Hayden, Dana M
Pappas, Sam G
Govekar, Henry R
Kam, Audrey E
Fishel, Melissa L
Kuzel, Timothy M
Salahudeen, Ameen A
MetadataShow full item record
AbstractBackground: 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.
Data AvailibilityProcessed scRNA-seq and metadata are available in the NCBI Gene Expression Omnibus (GEO) database under the accession code GSE200997 . Additionally, Seurat objects, matrix files are available on GitHub . It is also been deposited to Zenodo (https://zenodo.org/) with assigned DOI: 10.5281/zenodo.6466249 . Public datasets used in our analysis were downloaded from GEO under accession numbers GSE39582 , GSE17536 , GSE132465 , GSE144735 , and GSE178341 ; raw counts were directly obtained from the author , and scRNA-seq data from Kieffer et al.  was downloaded from Bioturing platform . Due to privacy concerns for human patients, the raw FASTQ data used in this study will be made available upon request for scientific research.
Rights/Terms© 2022. The Author(s).
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/18879
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