دورية أكاديمية
Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.
| العنوان: | Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data. |
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| المؤلفون: | Fisher NC; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Byrne RM; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Leslie H; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Wood C; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Legrini A; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Cameron AJ; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Ahmaderaghi B; School of Electronics, Electrical Engineering and Computer Science, Queen's University Belfast, Belfast, United Kingdom., Corry SM; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Malla SB; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Amirkhah R; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., McCooey AJ; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Rogan E; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Redmond KL; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Sakhnevych S; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Domingo E; University of Oxford, Oxford, United Kingdom., Jackson J; Information Services, Queen's University Belfast, Belfast, United Kingdom., Loughrey MB; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom.; Department of Cellular Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom., Leedham S; University of Oxford, Oxford, United Kingdom., Maughan T; University of Oxford, Oxford, United Kingdom., Lawler M; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom., Sansom OJ; Cancer Research UK Beatson Institute, Glasgow, United Kingdom.; Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Lamrock F; School of Mathematics and Physics, Queen's University Belfast, Belfast, United Kingdom., Koelzer VH; Department of Pathology and Molecular Pathology, University and University Hospital of Zürich, Zürich, Switzerland., Jamieson NB; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom., Dunne PD; The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, Belfast, United Kingdom.; Cancer Research UK Beatson Institute, Glasgow, United Kingdom. |
| المصدر: | Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2022 Sep 15; Vol. 28 (18), pp. 4056-4069. |
| نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: The Association Country of Publication: United States NLM ID: 9502500 Publication Model: Print Cited Medium: Internet ISSN: 1557-3265 (Electronic) Linking ISSN: 10780432 NLM ISO Abbreviation: Clin Cancer Res Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Denville, NJ : The Association, c1995- |
| مواضيع طبية MeSH: | Ovarian Neoplasms*/pathology , Prostatic Neoplasms*/pathology, Female ; Gene Expression Profiling/methods ; Gene Expression Regulation, Neoplastic ; Humans ; Male ; Stromal Cells/metabolism ; Transcriptome ; Tumor Microenvironment/genetics |
| مستخلص: | Purpose: Precise mechanism-based gene expression signatures (GES) have been developed in appropriate in vitro and in vivo model systems, to identify important cancer-related signaling processes. However, some GESs originally developed to represent specific disease processes, primarily with an epithelial cell focus, are being applied to heterogeneous tumor samples where the expression of the genes in the signature may no longer be epithelial-specific. Therefore, unknowingly, even small changes in tumor stroma percentage can directly influence GESs, undermining the intended mechanistic signaling. Experimental Design: Using colorectal cancer as an exemplar, we deployed numerous orthogonal profiling methodologies, including laser capture microdissection, flow cytometry, bulk and multiregional biopsy clinical samples, single-cell RNA sequencing and finally spatial transcriptomics, to perform a comprehensive assessment of the potential for the most widely used GESs to be influenced, or confounded, by stromal content in tumor tissue. To complement this work, we generated a freely-available resource, ConfoundR; https://confoundr.qub.ac.uk/, that enables users to test the extent of stromal influence on an unlimited number of the genes/signatures simultaneously across colorectal, breast, pancreatic, ovarian and prostate cancer datasets. Results: Findings presented here demonstrate the clear potential for misinterpretation of the meaning of GESs, due to widespread stromal influences, which in-turn can undermine faithful alignment between clinical samples and preclinical data/models, particularly cell lines and organoids, or tumor models not fully recapitulating the stromal and immune microenvironment. Conclusions: Efforts to faithfully align preclinical models of disease using phenotypically-designed GESs must ensure that the signatures themselves remain representative of the same biology when applied to clinical samples. (©2022 The Authors; Published by the American Association for Cancer Research.) |
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| معلومات مُعتمدة: | 29834 United Kingdom CRUK_ Cancer Research UK; 168322 Switzerland SNSF_ Swiss National Science Foundation; MR/V029711/1 United Kingdom MRC_ Medical Research Council; A28223 United Kingdom CRUK_ Cancer Research UK; 206314/Z/17/Z United Kingdom WT_ Wellcome Trust; A29834 United Kingdom CRUK_ Cancer Research UK; A25142 United Kingdom CRUK_ Cancer Research UK; C55370/A25813 United Kingdom CRUK_ Cancer Research UK; MR/M016587/1 United Kingdom MRC_ Medical Research Council; MC_PC_21042 United Kingdom MRC_ Medical Research Council; A26825 United Kingdom CRUK_ Cancer Research UK |
| تواريخ الأحداث: | Date Created: 20220706 Date Completed: 20220916 Latest Revision: 20240210 |
| رمز التحديث: | 20240210 |
| مُعرف محوري في PubMed: | PMC9475248 |
| DOI: | 10.1158/1078-0432.CCR-22-1102 |
| PMID: | 35792866 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1557-3265 |
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| DOI: | 10.1158/1078-0432.CCR-22-1102 |