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.
DescriptionFollowing publication of the original article , the authors noticed an error in Additional file 1. The incorrect Figure S5 was published. The corrected Additional file 1 is published in the correction and the original article  has been updated. See in https://doi.org/10.1186/s13059-022-02724-9.
Rights/Terms© 2022. The Author(s).
Identifier to cite or link to this itemhttp://hdl.handle.net/10713/18879
- Relative contribution of clinicopathological variables, genomic markers, transcriptomic subtyping and microenvironment features for outcome prediction in stage II/III colorectal cancer.
- Authors: Dienstmann R, Villacampa G, Sveen A, Mason MJ, Niedzwiecki D, Nesbakken A, Moreno V, Warren RS, Lothe RA, Guinney J
- Issue date: 2019 Oct 1
- Crosstalk Between the MSI Status and Tumor Microenvironment in Colorectal Cancer.
- Authors: Lin A, Zhang J, Luo P
- Issue date: 2020
- Genomic and transcriptomic characterization of heterogeneous immune subgroups of microsatellite instability-high colorectal cancers.
- Authors: Kim JH, Seo MK, Lee JA, Yoo SY, Oh HJ, Kang H, Cho NY, Bae JM, Kang GH, Kim S
- Issue date: 2021 Dec
- Consensus molecular subtype classification of colorectal adenomas.
- Authors: Komor MA, Bosch LJ, Bounova G, Bolijn AS, Delis-van Diemen PM, Rausch C, Hoogstrate Y, Stubbs AP, de Jong M, Jenster G, van Grieken NC, Carvalho B, Wessels LF, Jimenez CR, Fijneman RJ, Meijer GA, NGS-ProToCol Consortium:
- Issue date: 2018 Nov
- A next-generation sequencing-based strategy combining microsatellite instability and tumor mutation burden for comprehensive molecular diagnosis of advanced colorectal cancer.
- Authors: Xiao J, Li W, Huang Y, Huang M, Li S, Zhai X, Zhao J, Gao C, Xie W, Qin H, Cai S, Bai Y, Lan P, Zou Y
- Issue date: 2021 Mar 16