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Radiation induced extracellular matrix changes muscle-invasive bladder cancer

ABSTRACT: Muscle-invasive bladder cancer (MIBC) is a prevalent disease that can be treated with radiotherapy, but has a poor prognosis. Radiation-induced extracellular matrix (ECM) remodelling and fibrosis can induce tumour resistance and recurrence, but have not been studied in MIBC. Here, we aimed to characterise the impact of radiation on the ECM composition of MIBC. Three MIBC cell lines (T24, UMUC3, J82) were treated with fractionated radiation. We used proteomics to analyse the ECM composition produced by surviving cancer cells and immunofluorescence to investigate changes in the morphology and number of ECM fibres. We evaluated the RNA expression of identified ECM proteins (FN1, COL5A1, COL1A1, TNF6AIP6, FLG) in one cystectomy (TCGA-BLCA, n=397) and two radiotherapy (BC2001, n=313; BCON, n=151) cohorts. There were 613 proteins affected by radiation (padj<0.05, fold change >2 or <-2), 68 of which were ECM-associated proteins. There was a general increase in proteases and protease regulators but heterogeneity across cell lines. Enrichment analysis showed ECM organisation was the primary pathway affected. Immunofluorescence confirmed radiation affected ECM structure, generally, reducing the number, length and width of fibres. Five ECM genes of interest were identified (COL1A1, COL5A2, FN1, FLG, TNFAIP6), constituting an ECM signature. High FN1, COL1A1, TNF6AIP6 mRNA levels and ECM signature scores were independent poor prognostic markers, while FLG mRNA expression independently predicted radiotherapy benefit in a meta-analysis (n=861). We found high COL1A1 expression levels predicted hypoxia-modifying treatment benefit. Prognostic significance of COL5A2, FN1 and the ECM signature was dependent on patients harbouring TP53-mutations. Radiation alters the composition and structure of the ECM produced by MIBC. As a proof-of-concept, we showed that radiation-affected ECM genes are independent prognostic and predictive markers of radiotherapy benefit in MIBC. Future studies should validate these radiation-induced ECM changes in clinical samples, and explore the role of FLG in radioresistance.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Permanent Cell Line Cell, Cell Culture

DISEASE(S): Urinary Bladder Cancer

SUBMITTER: Conrado Guerrero Quiles

LAB HEAD: Ananya Choudhury

PROVIDER: PXD066069 | Pride | 2025-07-23

REPOSITORIES: pride

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			Action	DRS
	20230323_HumphriesM_GuerreroC.cellLines_dependant_high_confidence.xlsx	Xlsx
	20230323_HumphriesM_GuerreroC_J1.raw	Raw
	20230323_HumphriesM_GuerreroC_J2.raw	Raw
	20230323_HumphriesM_GuerreroC_J3.raw	Raw
	20230323_HumphriesM_GuerreroC_J4.raw	Raw

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Project description:We present the proteome biology of bladder cancer based on a cohort comprising treatment-naÃƒÂ¯ve non-muscle invasive (NMIBC, N=17) and treatment-naÃƒÂ¯ve muscle-invasive bladder cancer (MIBC, N=51), as well as neoadjuvant-treated MIBC (N=11); using formalin-fixed, paraffin-embedded samples and data-independent acquisition yielding >8,000 protein identifications. The NMIBC proteome reveals two subgroups that represent cell adhesion or lipid metabolism biology. MIBC, compared to NMIBC, shows an altered metabolic proteome together with enrichment of extracellular matrix (ECM), immune response, and complement proteins; in line with three proteomic MIBC subgroups that represent ECM, metabolic, or immune signatures. The ECM and immune subgroups are enriched for markers of M2-like tumor-associated macrophages and dendritic cells, while markers for natural killer cells are exclusive for the ECM subgroup, and markers for cytotoxic T-cells are a hallmark of the immune subgroup. Infiltration of CD8+ PD1+ positive cytotoxic T cells correlated with PD-L1 expression of MIBC, as demonstrated by multiplex immunofluorescence analysis. The metabolic subgroup presents a comparably immune-depleted microenvironment. YAP1 signaling is particularly prominent in the ECM subgroup. The protein BSCL2 emerges as a prognostic marker for MIBC. We highlight increased endogenous proteolysis in MIBC alongside the upregulation of matrix metalloproteases exceeding the upregulation of their endogenous inhibitors. Genomic panel sequencing underlines prevalent FGFR3 mutations in NMIBC and prevalent TP53 mutations in MIBC, but a genomic underpinning of the MIBC subgroups remains elusive. Proteogenomic analysis yields protein-level evidence for more than 1,300 single amino acid variants. The proteomes of neoadjuvant-treated MIBC resembled treatment-naÃƒÂ¯ve MIBC. Tumor-stroma interaction of MIBC was further investigated by proteomic analysis of patient-derived xenografts of MIBC. Our study adds to the proteome-level understanding of bladder cancer.

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Radiation induced extracellular matrix changes muscle-invasive bladder cancer

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