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Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

ABSTRACT: Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1a (IL-1a) dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Rectum, Epithelial Cell

DISEASE(S): Colorectal Cancer

SUBMITTER: Adele Nicolas

LAB HEAD: Florian R. Greten

PROVIDER: PXD030422 | Pride | 2022-02-08

REPOSITORIES: Pride

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			Action	DRS
	Cohort_file_IDs.txt	Txt
	H_Bohnenberger_070316_150416_KRK_56.raw	Raw
	H_Bohnenberger_070316_150416_KRK_57.raw	Raw
	H_Bohnenberger_070316_150416_KRK_58.raw	Raw
	H_Bohnenberger_070316_150416_KRK_59.raw	Raw

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Similar Datasets

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells without considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that interleukin-1 (IL-1 dependent inflammatory cancer-associated fibroblast (iCAF) polarization triggers oxidative DNA damage in iCAFs leading to p53-mediated therapy-induced senescence associated with changes in matrisome composition, chemoradiotherapy resistance and disease progression. IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. In rectal cancer patients a dominant iCAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels correlate with poor prognosis. Moreover, conditioned supernatant from patient tumor organoids renders fibroblasts susceptible to radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for iCAFs in therapy resistance and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-02-08 | PXD020871 | Pride

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

Project description:Standard cancer therapy targets tumor cells while not considering the possible collateral damage on the tumor microenvironment that could impair therapy response. Employing patient-derived tumor organoids and primary stroma cells or a novel murine rectal cancer model, we show that tumor cell-derived IL-1a polarizes cancer-associated fibroblasts (CAFs) towards a pro-inflammatory phenotype causing an elevated oxidative DNA damage mediated by reactive nitrogen species (NOS) and subsequently sensitizing iCAFs to a p53-mediated therapy-induced senescence, which triggers changes in matrisome composition culminating in chemoradiotherapy resistance and disease progression. Consequently, IL-1 inhibition, prevention of iCAF senescence or senolytic therapy sensitizes mice to irradiation. Importantly, rectal cancer patients with poor response to radiotherapy are characterized by an increased number of CAFs, a dominant inflammatory CAF gene signature as well as lower IL-1 receptor antagonist (IL-1RA) serum levels. Low baseline IL1RA gene expression predicts poor outcome while IL-1RA serum levels are associated with a single nucleotide polymorphism (SNP) in IL1RA (rs4251961 T/C). Moreover, conditioned supernatant from patient tumor organoids sensitizes fibroblasts to undergo radiation-induced senescence in an IL-1-dependent manner. Collectively, we unravel a critical role for inflammatory CAFs in cancer therapy and identify IL-1 signaling as an attractive target for stroma-repolarization and prevention of CAF senescence.

2022-01-12 | GSE190826 | GEO

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer [II]

2022-01-14 | GSE190005 | GEO

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer [I]

2022-01-14 | GSE190003 | GEO

Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer

2021-12-18 | GSE191093 | GEO

Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer

Project description:Standard therapy of rectal cancer comprises a combination of local radio- and systemic chemotherapy prior to surgery. Despite comparable tumor morphology and stage the outcome of such neoadjuvant therapy is heterogeneous and the underlying factors that define therapy response are unknown. Here we demonstrate that cancer-associated fibroblasts (CAFs) rather than tumor cells themselves have major impact on therapy response and survival in a novel pre-clinical in vivo model of rectal cancer as well as in patients. We show that irradiation of tumors increases DNA damage further in inflammatory CAFs causing them to undergo a p53-dependent senescence program, which is associated with the secretion of various extracellular matrix components that strongly promote therapy resistance and progression. Administration of venetoclax (senolytics) renders therapy-resistant mice sensitive to irradiation. Collectively, we demonstrate how inflammatory polarization of CAFs affects cancer therapy and identify IL-1 signaling as an attractive target to repolarize CAFs in neoadjuvant therapy of rectal cancer.

2023-08-12 | GSE156281 | GEO

Proteomic mapping of atrial and ventricular protein expression in patients with aortic valve stenosis

Project description:Objectives: The primary objective of this high-resolution proteomic study was to investigate patients with severe aortic valve stenosis (AVS) to detect novel biomarkers for diagnostic and/or therapeutic purposes. Background: Among patients with severe AVS, some are likely to rapidly progress with a higher mortality and benefit from prompt surgical or interventional care. To select these patients, novel disease-related biomarkers are needed. Methods: We used induced pluripotent stem cell derived cardiomyocytes as a relative quantification standard to profile the proteomes of formalin-fixed paraffin-embedded (FFPE) atria and left ventricles from 30 patients with AVS. Results: In total, 3370 proteins were quantified using high-resolution mass spectrometry. Statistical analysis revealed significant upregulation of 64 proteins in the atria and 27 proteins in the ventricles including several known chamber specific marker-proteins. Atrial upregulation of proteins that belong to the interstitial compartment or contribute to endocrine function was observed. To uncover disease related proteins, we compared our data to similar published datasets from healthy and diseased hearts. We performed gene set enrichment analyses to pinpoint global proteomic characteristics of a decompensated state of AVS with hypertrophy, like the downregulation of ventricular mitochondrial proteins and the development of ventricular fibrosis. Finally, we propose a set of high abundant proteins like LGALS3BP, TUBA4A, TINAGL1 and LAMA2 as well as SRL, FHL1 and ATP2A2 playing a crucial role in AVS-related heart disease. Conclusions: We established a reproducible workflow for high-resolution quantitative proteomics of FFPE myocardial samples and provide interesting candidate proteins with biomarker potential for AVS.

2023-01-09 | PXD014297 | Pride

High-throughput proteomic analysis of rectal cancer for prediction of non-complete response after concurrent chemoradiation therapy

Project description:Colorectal cancer (CRC) is the third most common lethal malignancy in Korea and worldwide. Rectal cancer patients occupy about 30% of CRC patients, and the majority of rectal cancer patients had locally advanced disease at diagnosis. The standard treatment of locally advanced rectal cancer (LARC) is neoadjuvant radiation therapy with concurrent chemotherapy (CCRT) followed by total mesorectal excision (TME). This multidisciplinary team approach improved local tumor control and overall survival of rectal cancer patients. High throughput proteomic analysis and machine learning algorithm identify DUOX2 (dual oxidase 2) as a novel biomarker for prediction of non-complete response after concurrent chemoradiation therapy for rectal cancer.High throughput proteomic analysis and machine learning algorithm identify DUOX2 (dual oxidase 2) as a novel biomarker for prediction of non-complete response after concurrent chemoradiation therapy for rectal cancer.

2023-03-11 | PXD023302 | Pride

Transcription profiling of SKGT4 and HET-1A cell lines exposed to deoxycholic acid (DCA)

Project description:This SuperSeries is composed of the following subset Series: GSE13376: Exposure of Barrett's associated adenocarcinoma cell lines SKGT4 to deoxycholic acid (DCA) GSE13378: Exposure of squamous esophageal cell line HET-1A to deoxycholic acid (DCA) Refer to individual Series

2010-03-02 | E-GEOD-13400 | biostudies-arrayexpress

Macrodissection versus Microdissection of Rectal Carcinoma: Minor Influence of Stroma to Tumor Gene Profiles

Project description:Background: The molecular determinants of carcinogenesis, tumor progression and patient prognosis can be deduced from simultaneous comparison of thousands of genes by microarray analysis. However, the presence of stroma cells in surgically excised carcinoma tissues might obscure the tumor cell-specific gene expression profiles of these samples. To circumvent this complication, laser microdissection can be performed to separate tumor epithelium from the surrounding stroma and healthy tissue. In this report, we compared RNAs isolated from macrodissected, of which only surrounding healthy tissue had been removed, and microdissected rectal carcinoma samples by microarray analysis in order to determine the most reliable approach to detect the expression of tumor cell-derived genes by microarray analysis. Results: As microdissection yielded low tissue and RNA quantities, extra rounds of mRNA amplification were necessary to obtain sufficient RNA for microarray experiments. These second rounds of amplification influenced the gene expression profiles. Moreover, the presence of stroma cells in macrodissected samples had a minor contribution to the tumor cell gene expression profiles, which can be explained by the observation that more RNA is extracted from tumor epithelial cells than from stroma. Conclusion: These data demonstrate that the more convenient procedure of macrodissection can be adequately used and yields reliable data regarding the identification of tumor cell-specific gene expression profiles. Keywords: macrodissection, microdissection, RNA amplification, stroma, rectal carcinoma

2005-06-07 | GSE2738 | GEO

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