Cancer-associated fibroblast-derived gene signatures determine prognosis in colon cancer patients

Herrera, Mercedes; Berral-González, Alberto; López-Cade, Igor; Galindo-Pumariño, Cristina; Bueno-Fortes, Santiago; Martín-Merino, Manuel; Carrato, Alfredo; Ocaña, Alberto; Pinta, Carolina de la; López-Alfonso, Ana; Peña, Cristina; García-Barberán, Vanesa; Rivas, Javier De Las

doi:10.1186/s12943-021-01367-x

Cited by 66 publications

(55 citation statements)

References 13 publications

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“…Several gene signatures related to cancer invasion, including invasiveness signature, epithelial-mesenchymal transition (EMT), pan-fibroblast TGFb response signature (Pan-F-TBRS) and two key immune cells in tumor microenvironment (effector CD8+ T and cancer associated fibroblasts (CAFs)) were chosen to further investigation of the role of LMRG score in tumorigenesis and metastasis [ 49 , 50 ]. The enrichment score of each gene signature was calculated using sample gene set enrichment analysis (ssGSEA) algorithm.…”

Section: Resultsmentioning

confidence: 99%

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma

et al. 2021

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Background and aim Lipid metabolic reprogramming is considered to be a new hallmark of malignant tumors. The purpose of this study was to explore the expression profiles of lipid metabolism-related genes (LMRG) in colorectal cancer (CRC). Methods The lipid metabolism statuses of 500 CRC patients from the Cancer Genome Atlas (TCGA) and 523 from the Gene Expression Omnibus (GEO GSE39582) database were analyzed. The risk signature was constructed by univariate Cox regression and least absolute shrinkage and selection operator (LASSO) Cox regression. Results A novel four-LMRG signature (PROCA1, CCKBR, CPT2, and FDFT1) was constructed to predict clinical outcomes in CRC patients. The risk signature was shown to be an independent prognostic factor for CRC and was associated with tumour malignancy. Principal components analysis demonstrated that the risk signature could distinguish between low- and high-risk patients. There were significantly differences in abundances of tumor-infiltrating immune cells and mutational landscape between the two risk groups. Patients in the low-risk group were more likely to have higher tumor mutational burden, stem cell characteristics, and higher PD-L1 expression levels. Furthermore, a genomic-clinicopathologic nomogram was established and shown to be a more effective risk stratification tool than any clinical parameter alone. Conclusions This study demonstrated the prognostic value of LMRG and showed that they may be partially involved in the suppressive immune microenvironment formation.

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Section: Resultsmentioning

confidence: 99%

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma

et al. 2021

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“…However, having been developed using bulk transcriptomic data, there is now increasing recognition that there are distinct contributions to bulk CMS from both tumor and non-tumor cells and that CMS may not be adequate to capture intra-tumor heterogeneity [24,[61][62][63]. Specifically, the classification of CMS4 tumors has been identified as primarily influenced by genes expressed in cancer-associated fibroblasts (CAFs) and other stromal cell subtypes [64][65][66][67]. Recognizing this stromal influence, newer CMS classification algorithms have been developed to minimizing the effect of CAF expressed genes, which is of particular importance in cell line and organoid CRC models [40,[68][69][70][71].…”

Section: Discussionmentioning

confidence: 99%

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

Chowdhury

Hofree

Lin

et al. 2021

Cancers

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The implications of intratumor heterogeneity on the four consensus molecular subtypes (CMS) of colorectal cancer (CRC) are not well known. Here, we use single-cell RNA sequencing (scRNASeq) to build an algorithm to assign CMS classification to individual cells, which we use to explore the distributions of CMSs in tumor and non-tumor cells. A dataset of colorectal tumors with bulk RNAseq (n = 3232) was used to identify CMS specific-marker gene sets. These gene sets were then applied to a discovery dataset of scRNASeq profiles (n = 10) to develop an algorithm for single-cell CMS (scCMS) assignment, which recapitulated the intrinsic biology of all four CMSs. The single-cell CMS assignment algorithm was used to explore the scRNASeq profiles of two prospective CRC tumors with mixed CMS via bulk sequencing. We find that every CRC tumor contains individual cells of each scCMS, as well as many individual cells that have enrichment for features of more than one scCMS (called mixed cells). scCMS4 and scCMS1 cells dominate stroma and immune cell clusters, respectively, but account for less than 3% epithelial cells. These data imply that CMS1 and CMS4 are driven by the transcriptomic contribution of immune and stromal cells, respectively, not tumor cells.

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“…The samples corresponded in all cases to primary tumors, without pre-operative chemotherapy and/or radiotherapy. Details about the phenotypic data of this CRC cohort are available since they have also been published in Herrera et al, 2021 [ 41 ].…”

Section: Methodsmentioning

confidence: 99%

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

Bueno-Fortes

Muenzner

Berral-González

et al. 2021

Cancers

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The epithelial–mesenchymal transition (EMT) is associated with tumor aggressiveness and increased invasion, migration, metastasis, angiogenesis, and drug resistance. Although the HCT116 p21-/- cell line is well known for its EMT-associated phenotype, with high Vimentin and low E-cadherin protein levels, the gene signature of this rather intermediate EMT-like cell line has not been determined so far. In this work, we present a robust molecular and bioinformatics analysis, to reveal the associated gene expression profile and its correlation with different types of colorectal cancer tumors. We compared the quantitative signature obtained with the NanoString platform with the expression profiles of colorectal cancer (CRC) Consensus Molecular Subtypes (CMS) as identified, and validated the results in a large independent cohort of human tumor samples. The expression signature derived from the p21-/- cells showed consistent and reliable numbers of upregulated and downregulated genes, as evaluated with two machine learning methods against the four CRC subtypes (i.e., CMS1, 2, 3, and 4). High concordance was found between the upregulated gene signature of HCT116 p21-/- cells and the signature of the CMS4 mesenchymal subtype. At the same time, the upregulated gene signature of the native HCT116 cells was similar to that of CMS1. Using a multivariate Cox regression model to analyze the survival data in the CRC tumor cohort, we selected genes that have a predictive risk power (with a significant gene risk incidence score). A set of genes of the mesenchymal signature was proven to be significantly associated with poor survival, specifically in the CMS4 CRC human cohort. We suggest that the gene signature of HCT116 p21-/- cells could be a suitable metric for mechanistic studies regarding the CMS4 signature and its functional consequences in CRC. Moreover, this model could help to discover the molecular mechanisms of intermediate EMT, which is known to be associated with extraordinarily high stemness and drug resistance.

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Cancer-associated fibroblast-derived gene signatures determine prognosis in colon cancer patients

Cited by 66 publications

References 13 publications

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma

A lipid metabolism-related genes prognosis biomarker associated with the tumor immune microenvironment in colorectal carcinoma

Implications of Intratumor Heterogeneity on Consensus Molecular Subtype (CMS) in Colorectal Cancer

A Gene Signature Derived from the Loss of CDKN1A (p21) Is Associated with CMS4 Colorectal Cancer

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