Spatially resolved transcriptomics deconvolutes prognostic histological subgroups in patients with colorectal cancer and synchronous liver metastases

Wood, C. S. et al. (2023) Spatially resolved transcriptomics deconvolutes prognostic histological subgroups in patients with colorectal cancer and synchronous liver metastases. Cancer Research, 83(8), pp. 1329-1344. (doi: 10.1158/0008-5472.CAN-22-2794) (PMID:37057593) (PMCID:PMC10102851)

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Strong immune responses in primary colorectal cancer correspond with better patient survival following surgery compared with tumors with predominantly stromal microenvironments. However, biomarkers to identify patients with colorectal cancer liver metastases (CRLM) with good prognosis following surgery for oligometastatic disease remain elusive. The aim of this study was to determine the practical application of a simple histological assessment of immune cell infiltration and stromal content in predicting outcome following synchronous resection of primary colorectal cancer and CRLM and to interrogate the underlying functional biology that drives disease progression. Samples from patients undergoing synchronous resection of primary colorectal cancer and CRLM were evaluated in detail through histological assessment, panel genomic and bulk transcriptomic assessment, IHC, and GeoMx spatial transcriptomics (ST) analysis. High immune infiltration of metastases was associated with improved cancer-specific survival. Bulk transcriptomic analysis was confounded by stromal content, but ST demonstrated that the invasive edge of the metastases of long-term survivors was characterized by adaptive immune cell populations enriched for type II IFN signaling and MHC-class II antigen presentation. In contrast, patients with poor prognosis demonstrated increased abundance of regulatory T cells and neutrophils with enrichment of Notch and TGFβ signaling pathways at the metastatic tumor center. In summary, histological assessment can stratify outcomes in patients undergoing synchronous resection of CRLM, suggesting that it has potential as a prognostic biomarker. Furthermore, ST analysis has revealed significant intratumoral and interlesional heterogeneity and identified the underlying transcriptomic programs driving each phenotype. Significance: Spatial transcriptomics uncovers heterogeneity between patients, between matched lesions in the same patient, and within individual lesions and identifies drivers of metastatic progression in colorectal cancer with reactive and suppressed immune microenvironments.

Item Type:Articles
Additional Information:K.A.F. Pennel was supported by the MRC Fellowship (MR/R502327/1). A.J. Cameron was supported by an MRC Clinical Research Training Fellowship (MR/V029711/1). C.W. Steele was funded by the Chief Scientist Office of Scotland, Cancer Research UK, and the Academy of Medical Sciences. C.S.D. Roxburgh is funded by Chief Scientist Office. O.J. Sansom was funded by Cancer Research UK (core funding to the CRUK Beatson Institute A17196 and A31287 and core funding to O.J. Sansom's laboratory A21139). N.B. Jamieson was funded by Cancer Research UK (C55370/A25813).
Glasgow Author(s) Enlighten ID:Jamieson, Professor Nigel and Horgan, Professor Paul and Pennel, Miss Kathryn and Leslie, Ms Holly and Quinn, Dr Jean and Biankin, Professor Andrew and Wood, Dr Colin and McMillan, Professor Donald and Van Wyk, Dr Hester and Cameron, Mr Andrew and Nixon, Mr Colin and Roseweir, Dr Antonia and legrini, assya and Steele, Dr Colin and Melissourgou-Syka, Lydia and Hay, Dr Jennifer and Roxburgh, Professor Campbell and Edwards, Professor Joanne and Sansom, Professor Owen
Authors: Wood, C. S., Pennel, K. A.F., Leslie, H., Legrini, A., Cameron, A. J., Melissourgou-Syka, L., Quinn, J. A., van Wyk, H. C., Hay, J., Roseweir, A. K., Nixon, C., Roxburgh, C. S.D., McMillan, D. C., Biankin, A. V., Sansom, O. J., Horgan, P. G., Edwards, J., Steele, C. W., and Jamieson, N. B.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Cancer Research
Publisher:American Association for Cancer Research
ISSN (Online):1538-7445
Published Online:14 April 2023
Copyright Holders:Copyright © 2023 The Authors
First Published:First published in Cancer Research
Publisher Policy:Reproduced under a Creative Commons license
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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
301364COMBINATION THERAPIES TARGETING IMMUNE EVASION IN PANCREATIC CANCERNigel JamiesonCancer Research UK (CRUK)C55370/A25813CS -Translational Research Centre
313949National Productivity Investment Fund StudentshipsGeorge BaillieMedical Research Council (MRC)MR/R502327/1MVLS - Graduate School
312409Pancreatic Cystic Lesions: Spatial TranscriptomicsNigel JamiesonMedical Research Council (MRC)MR/V029711/1Institute of Cancer Sciences