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Desmoplasia is associated with carcinoma associated fibroblasts’ heterogeneity in non-small cell lung cancer patients

ABSTRACT: Cancer associated fibroblasts (CAFs) are well known to strongly influence tumor development, progression, and metastasis. Their characteristics and prognostic gene signature in non-small cell lung cancer (NSCLC) patients have been recognized. Heterogeneity of CAFs has long been observed, however, the functional heterogeneity of CAFs between patients and their genetic basis are far less known. Here, we report the distinction of two CAF subtypes obtained from primary cultures of CAFs and matched normal fibroblasts (NFs) from 28 resected NSCLC. These 28 pathological NSCLC (82 % adenocarcinoma) were categorized into two types according to the histological properties of the peritumoral stroma: High desmoplasia (HD; n=14), and low desmoplasia (LD; n=14), and the prognostic significance evaluated. This classification seems to align with functional CAFs, as those with HD have higher rate of gel contraction, higher rate of tumor growth and poor prognosis. To demonstrate a gene expression profile specific to CAF activity we used Illumina DASAL Microarray gene expression analysis on extracted RNA from 24 CAF cell lines (12 CAFs-HD and 12 CAFs-LD) that were embedded in collagen gel for 24 hours. From the CAF cohort, the most significant genes that are correlated with the desmoplasia are identified to be enriched in the clinical cohort of 181 NSCLC patients. Overall, our studies showed that in NSCLC, desmoplasia is significantly associated with poor prognosis and is able to significantly subgroup CAF between NSCLC patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE116679 | GEO | 2019/04/17

REPOSITORIES: GEO

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Project description:The tumor microenvironment strongly influences cancer development, progression and metastasis. The role of carcinoma-associated fibroblasts (CAFs) in these processes and their clinical impact has not been studied systematically in non-small cell lung carcinoma (NSCLC). We established primary cultures of CAFs and matched normal fibroblasts (NFs) from 15 resected NSCLC. We demonstrate that CAFs have greater ability than NFs to enhance the tumorigenicity of lung cancer cell lines. Microarray gene expression analysis of the 15 matched CAF and NF cell lines identified 46 differentially expressed genes, encoding for proteins that are significantly enriched for extracellular proteins regulated by the TGF-beta signaling pathway. We have identified a subset of 11 genes that formed a prognostic gene expression signature, which was validated in multiple independent NSCLC microarray datasets. Functional annotation using protein-protein interaction analyses of these and published cancer stroma-associated gene expression changes revealed prominent involvement of the focal adhesion and MAPK signalling pathways. Fourteen (30%) of the 46 genes also were differentially expressed in laser-capture micro-dissected corresponding primary tumor stroma compared to the matched normal lung. Six of these 14 genes could be induced by TGF-beta1 in NF. The results establish the prognostic impact of CAF-associated gene expression changes in NSCLC patients. This SuperSeries is composed of the following subset Series: GSE22862: Prognostic Gene Expression Signature of Carcinoma Associated Fibroblasts in Non-Small Cell Lung Cancer [expression profiling_CAFs] GSE22863: Prognostic Gene Expression Signature of Carcinoma Associated Fibroblasts in Non-Small Cell Lung Cancer [expression profiling_NSCLC stroma] GSE27284: Prognostic Gene Expression Signature of Carcinoma Associated Fibroblasts in Non-Small Cell Lung Cancer [methylation profiling] GSE27289: Prognostic Gene Expression Signature of Carcinoma Associated Fibroblasts in Non-Small Cell Lung Cancer [genome variation profiling]

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Desmoplasia is associated with carcinoma associated fibroblasts’ heterogeneity in non-small cell lung cancer patients

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