Abstract
The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis. Here we report findings from one of the largest pan-cancer analyses of ECM gene dysregulation in cancer. We define a distinct set of ECM genes upregulated in cancer (C-ECM) and linked to worse prognosis. We found that the C-ECM transcriptional programme dysregulation is correlated with the activation of TGF-β signalling in cancer-associated fibroblasts and is linked to immunosuppression in otherwise immunologically active tumours. Cancers that activate this programme carry distinct genomic profiles, such as BRAF, SMAD4 and TP53 mutations and MYC amplification. Finally, we show that this signature is a predictor of the failure of PD-1 blockade and outperforms previously-proposed biomarkers. Thus, our findings identify a distinct transcriptional pattern of ECM genes in operation across cancers that may be potentially targeted, pending preclinical validation, using TGF-β blockade to enhance responses to immune-checkpoint blockade.
Highlights
The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis
Based on multiplatform analysis of The Cancer Genome Atlas (TCGA) data, we correlated these profiles to transforming growth factor (TGF)-β signalling in the tumour microenvironment and show that this transcriptional programme is enriched in immunologically active cancers, suggesting a possible role in immune evasion/adaptation
Using a range of approaches, we show that ECM dysregulation is associated with the presence of cancer-associated fibroblasts (CAFs) and the activity of TGF-β, among other regulators
Summary
The extracellular matrix (ECM) is a key determinant of cancer progression and prognosis. We found that the C-ECM transcriptional programme dysregulation is correlated with the activation of TGF-β signalling in cancer-associated fibroblasts and is linked to immunosuppression in otherwise immunologically active tumours. Cancers that activate this programme carry distinct genomic profiles, such as BRAF, SMAD4 and TP53 mutations and MYC amplification. Using deconvolution and analyses of transcriptional profiles from dissociated tumour fractions, we show that these genes are modulated in CAFs. Subsequently, based on multiplatform analysis of The Cancer Genome Atlas (TCGA) data, we correlated these profiles to transforming growth factor (TGF)-β signalling in the tumour microenvironment and show that this transcriptional programme is enriched in immunologically active cancers, suggesting a possible role in immune evasion/adaptation. We have identified a novel signature of immune evasion that is a potential target for pharmacological modulation and may facilitate effective patient stratification in precision immunotherapy, pending preclinical validation
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