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

Ateeq M Khaliq; Cihat Erdoğan; Zeyneb Kurt; Sultan Sevgi Turgut; Miles W Grunvald; Tim Rand; Sonal Khare; Jeffrey A Borgia; Dana M Hayden; Sam G Pappas; Henry R Govekar; Audrey E. Kam; Jochen Reiser; Kiran Turaga; Milan Radovich; Yong Zang; Yingjie Qiu; Yunlong Liu; Melissa L. Fishel; Anita Turk; Vineet Gupta; Ram Al-Sabti; Janakiraman Subramanian; Timothy M Kuzel; Anguraj Sadanandam; Levi Waldron; Arif Hussain; Mohammad Saleem; Bassel El-Rayes; Ameen Salahudeen; Ashiq Masood

doi:10.1186/s13059-022-02677-z

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

Ateeq M Khaliq, Cihat Erdoğan, Zeyneb Kurt, Sultan Sevgi Turgut, Miles W Grunvald, Tim Rand, Sonal Khare, Jeffrey A Borgia, Dana M Hayden, Sam G Pappas, Henry R Govekar, Audrey E. Kam, Jochen Reiser, Kiran Turaga, Milan Radovich, Yong Zang, Yingjie Qiu, Yunlong Liu, Melissa L. Fishel, Anita TurkVineet Gupta, Ram Al-Sabti, Janakiraman Subramanian, Timothy M Kuzel, Anguraj Sadanandam, Levi Waldron, Arif Hussain, Mohammad Saleem, Bassel El-Rayes, Ameen Salahudeen, Ashiq Masood^*

^*Corresponding author for this work

Computer Information Sciences Department

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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

Original language	English
Article number	113
Number of pages	30
Journal	Genome Biology
Volume	23
Issue number	1
DOIs	https://doi.org/10.1186/s13059-022-02677-z
Publication status	Published - 11 May 2022

Keywords

Cancer-associated fibroblast
CMS classification
Colorectal cancer
Single-cell analysis
Immunotherapy
Stromal signatures

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Khaliq, A. M., Erdoğan, C., Kurt, Z., Turgut, S. S., Grunvald, M. W., Rand, T., Khare, S., Borgia, J. A., Hayden, D. M., Pappas, S. G., Govekar, H. R., Kam, A. E., Reiser, J., Turaga, K., Radovich, M., Zang, Y., Qiu, Y., Liu, Y., Fishel, M. L., ... Masood, A. (2022). Refining colorectal cancer classification and clinical stratification through a single-cell atlas. Genome Biology, 23(1), Article 113. https://doi.org/10.1186/s13059-022-02677-z

@article{72819dfdb96143c2ad9563071ed118c0,

title = "Refining colorectal cancer classification and clinical stratification through a single-cell atlas",

abstract = "BackgroundColorectal 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.ResultsTumor 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.ConclusionsDistinct 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",

keywords = "Cancer-associated fibroblast, CMS classification, Colorectal cancer, Single-cell analysis, Immunotherapy, Stromal signatures",

author = "Khaliq, {Ateeq M} and Cihat Erdoğan and Zeyneb Kurt and Turgut, {Sultan Sevgi} and Grunvald, {Miles W} and Tim Rand and Sonal Khare and Borgia, {Jeffrey A} and Hayden, {Dana M} and Pappas, {Sam G} and Govekar, {Henry R} and Kam, {Audrey E.} and Jochen Reiser and Kiran Turaga and Milan Radovich and Yong Zang and Yingjie Qiu and Yunlong Liu and Fishel, {Melissa L.} and Anita Turk and Vineet Gupta and Ram Al-Sabti and Janakiraman Subramanian and Kuzel, {Timothy M} and Anguraj Sadanandam and Levi Waldron and Arif Hussain and Mohammad Saleem and Bassel El-Rayes and Ameen Salahudeen and Ashiq Masood",

note = "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). ",

year = "2022",

month = may,

day = "11",

doi = "10.1186/s13059-022-02677-z",

language = "English",

volume = "23",

journal = "Genome Biology",

issn = "1474-7596",

publisher = "BioMed Central",

number = "1",

}

Khaliq, AM, Erdoğan, C, Kurt, Z, Turgut, SS, Grunvald, MW, Rand, T, Khare, S, Borgia, JA, Hayden, DM, Pappas, SG, Govekar, HR, Kam, AE, Reiser, J, Turaga, K, Radovich, M, Zang, Y, Qiu, Y, Liu, Y, Fishel, ML, Turk, A, Gupta, V, Al-Sabti, R, Subramanian, J, Kuzel, TM, Sadanandam, A, Waldron, L, Hussain, A, Saleem, M, El-Rayes, B, Salahudeen, A & Masood, A 2022, 'Refining colorectal cancer classification and clinical stratification through a single-cell atlas', Genome Biology, vol. 23, no. 1, 113. https://doi.org/10.1186/s13059-022-02677-z

TY - JOUR

T1 - Refining colorectal cancer classification and clinical stratification through a single-cell atlas

AU - Khaliq, Ateeq M

AU - Erdoğan, Cihat

AU - Kurt, Zeyneb

AU - Turgut, Sultan Sevgi

AU - Grunvald, Miles W

AU - Rand, Tim

AU - Khare, Sonal

AU - Borgia, Jeffrey A

AU - Hayden, Dana M

AU - Pappas, Sam G

AU - Govekar, Henry R

AU - Kam, Audrey E.

AU - Reiser, Jochen

AU - Turaga, Kiran

AU - Radovich, Milan

AU - Zang, Yong

AU - Qiu, Yingjie

AU - Liu, Yunlong

AU - Fishel, Melissa L.

AU - Turk, Anita

AU - Gupta, Vineet

AU - Al-Sabti, Ram

AU - Subramanian, Janakiraman

AU - Kuzel, Timothy M

AU - Sadanandam, Anguraj

AU - Waldron, Levi

AU - Hussain, Arif

AU - Saleem, Mohammad

AU - El-Rayes, Bassel

AU - Salahudeen, Ameen

AU - Masood, Ashiq

N1 - 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).

PY - 2022/5/11

Y1 - 2022/5/11

N2 - BackgroundColorectal 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.ResultsTumor 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.ConclusionsDistinct 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

AB - BackgroundColorectal 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.ResultsTumor 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.ConclusionsDistinct 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

KW - Cancer-associated fibroblast

KW - CMS classification

KW - Colorectal cancer

KW - Single-cell analysis

KW - Immunotherapy

KW - Stromal signatures

UR - http://www.scopus.com/inward/record.url?scp=85129725852&partnerID=8YFLogxK

U2 - 10.1186/s13059-022-02677-z

DO - 10.1186/s13059-022-02677-z

M3 - Article

C2 - 35538548

SN - 1474-7596

VL - 23

JO - Genome Biology

JF - Genome Biology

IS - 1

M1 - 113

ER -

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

Abstract

Keywords

UN SDGs

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