Biological Misinterpretation of Transcriptional Signatures in Tumor Samples Can Unknowingly Undermine Mechanistic Understanding and Faithful Alignment with Preclinical Data.
Journal
Clinical cancer research : an official journal of the American Association for Cancer Research
ISSN: 1557-3265
Titre abrégé: Clin Cancer Res
Pays: United States
ID NLM: 9502500
Informations de publication
Date de publication:
15 09 2022
15 09 2022
Historique:
received:
07
04
2022
revised:
08
06
2022
accepted:
29
06
2022
pubmed:
7
7
2022
medline:
17
9
2022
entrez:
6
7
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 35792866
pii: 706888
doi: 10.1158/1078-0432.CCR-22-1102
pmc: PMC9475248
mid: EMS147802
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4056-4069Subventions
Organisme : Swiss National Science Foundation
ID : 168322
Pays : Switzerland
Organisme : Medical Research Council
ID : MR/V029711/1
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A28223
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 206314/Z/17/Z
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A29834
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A25142
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C55370/A25813
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M016587/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_21042
Pays : United Kingdom
Organisme : Cancer Research UK
ID : A26825
Pays : United Kingdom
Informations de copyright
©2022 The Authors; Published by the American Association for Cancer Research.
Références
Nat Cancer. 2022 Feb;3(2):219-231
pubmed: 35145327
Nat Commun. 2017 May 31;8:15657
pubmed: 28561046
Cancer Res. 2018 Feb 1;78(3):769-780
pubmed: 29229604
Sci Rep. 2017 Nov 30;7(1):16618
pubmed: 29192179
Nat Genet. 2015 Apr;47(4):320-9
pubmed: 25706628
Nat Commun. 2017 May 31;8:15107
pubmed: 28561063
Br J Cancer. 2021 Mar;124(6):1175-1176
pubmed: 33311590
Cell Commun Signal. 2020 Apr 7;18(1):59
pubmed: 32264958
Clin Cancer Res. 2016 Aug 15;22(16):4095-104
pubmed: 27151745
J Pathol Clin Res. 2020 Oct;6(4):283-296
pubmed: 32401426
Transl Cancer Res. 2015 Jun;4(3):256-269
pubmed: 26213686
Nat Cancer. 2022 Feb;3(2):135
pubmed: 35228748
Nat Rev Cancer. 2016 Aug;16(8):525-37
pubmed: 27388699
Histopathology. 2017 Jul;71(1):12-26
pubmed: 28165633
Nat Rev Genet. 2021 Oct;22(10):627-644
pubmed: 34145435
Cancer Cell. 2014 Jun 16;25(6):719-34
pubmed: 24856586
Clin Cancer Res. 2021 Jan 1;27(1):288-300
pubmed: 33028592
Nature. 2012 Mar 28;483(7391):603-7
pubmed: 22460905
Nat Med. 2015 Nov;21(11):1350-6
pubmed: 26457759
Commun Biol. 2020 Oct 9;3(1):565
pubmed: 33037292
Clin Cancer Res. 2016 Aug 15;22(16):3989-91
pubmed: 27334836
Malawi Med J. 2012 Sep;24(3):69-71
pubmed: 23638278
Nat Rev Cancer. 2017 Dec;17(12):751-765
pubmed: 29077691
Cell. 2015 Sep 24;163(1):39-53
pubmed: 26406370
Cell Syst. 2015 Dec 23;1(6):417-425
pubmed: 26771021
Cancer Discov. 2012 May;2(5):401-4
pubmed: 22588877
Nat Cancer. 2022 Feb;3(2):232-250
pubmed: 35221336
Genome Biol. 2016 Oct 20;17(1):218
pubmed: 27765066
Cancer Cell. 2020 Apr 13;37(4):456-470
pubmed: 32289270
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
J Pathol. 2018 Dec;246(4):422-426
pubmed: 30105762
Nat Genet. 2015 Apr;47(4):312-9
pubmed: 25706627
J Natl Cancer Inst. 2017 Aug 1;109(8):
pubmed: 28376187
Nat Methods. 2021 Jan;18(1):9-14
pubmed: 33408395
Nat Commun. 2013;4:2612
pubmed: 24113773