Therapy-induced senescence of cancer-associated fibroblasts determines survival in rectal cancer
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ABSTRACT:
PROVIDER: PRJNA657259 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12455000_1.fastq.gz | Fastqsanger.gz | |||
| SRR12455000_2.fastq.gz | Fastqsanger.gz | |||
| SRR12455001_1.fastq.gz | Fastqsanger.gz | |||
| SRR12455001_2.fastq.gz | Fastqsanger.gz | |||
| SRR12455002_1.fastq.gz | Fastqsanger.gz |
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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
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
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-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.
2022-02-08 | PXD030422 | Pride
Project description:Purpose: MicroRNAs play a prominent role in a variety of physiological and pathological biological processes, including cancer. For rectal cancers, only limited data are available on microRNA expression profiles, while the underlying genomic and transcriptomic aberrations have been firmly established. We therefore aimed to comprehensively map the microRNA expression patterns of this disease. Experimental design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 72 patients (68 tumors and 70 normal mucosa) with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa microRNA expression profiles were subsequently established for all patients. The expression of selected microRNAs was validated using semi-quantitative real-time PCR. Results: Forty-nine microRNAs were significantly differentially expressed (log2-fold difference >0.5 and P<0.001) between rectal cancer and normal rectal mucosa. The predicted targets for the identified microRNAs were enriched for the following KEGG pathways: Wnt, TGF-beta, mTOR, insulin, MAPK, and ErbB signaling. Between rectal tumor and normal tissue, miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652*, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p were found to be differentially expressed. Of clinical impact, miR-135b expression correlated significantly with overall survival that could be validated in a larger multicenter patient set (n=94). Conclusion: The comprehensive analysis of the rectal cancer microRNAome uncovered novel microRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of rectal cancer. The identification and validation of miR-135b will help to identify novel molecular targets and pathways for therapeutic exploitation. Paired samples from rectal tumor and matched normal samples. Included are also 2 technical replicates.
2012-10-05 | E-GEOD-38389 | biostudies-arrayexpress
Project description:Purpose: MicroRNAs play a prominent role in a variety of physiological and pathological biological processes, including cancer. For rectal cancers, only limited data are available on microRNA expression profiles, while the underlying genomic and transcriptomic aberrations have been firmly established. We therefore aimed to comprehensively map the microRNA expression patterns of this disease. Experimental design: Tumor biopsies and corresponding matched mucosa samples were prospectively collected from 72 patients (68 tumors and 70 normal mucosa) with locally advanced rectal cancers. Total RNA was extracted, and tumor and mucosa microRNA expression profiles were subsequently established for all patients. The expression of selected microRNAs was validated using semi-quantitative real-time PCR. Results: Forty-nine microRNAs were significantly differentially expressed (log2-fold difference >0.5 and P<0.001) between rectal cancer and normal rectal mucosa. The predicted targets for the identified microRNAs were enriched for the following KEGG pathways: Wnt, TGF-beta, mTOR, insulin, MAPK, and ErbB signaling. Between rectal tumor and normal tissue, miR-492, miR-542-5p, miR-584, miR-483-5p, miR-144, miR-2110, miR-652*, miR-375, miR-147b, miR-148a, miR-190, miR-26a/b, and miR-338-3p were found to be differentially expressed. Of clinical impact, miR-135b expression correlated significantly with overall survival that could be validated in a larger multicenter patient set (n=94). Conclusion: The comprehensive analysis of the rectal cancer microRNAome uncovered novel microRNAs and pathways associated with rectal cancer. This information contributes to a detailed view of rectal cancer. The identification and validation of miR-135b will help to identify novel molecular targets and pathways for therapeutic exploitation.
2012-10-05 | GSE38389 | GEO
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
Project description:Importance: Neoadjuvant chemoradiotherapy (CRT) is the standard of care for advanced rectal cancer. Yet, predicting response to CRT remains an unmet clinical challenge. Objective: To investigate the transcriptomic determinants to predict response to neoadjuvant CRT and survival in patients with advanced rectal cancer. Design: A single-center, retrospective, cohort study. Setting: A comprehensive cancer center. Participants: Pre-treatment biopsies from 298 patients with rectal cancer, who were later treated with neoadjuvant CRT between 2004 and 2020, were analyzed by RNA sequencing. Main measures and outcomes: Transcriptional subtyping was performed by consensus molecular subtype (CMS) classification. Immune cell infiltration was assessed using MCP-counter scores and single-sample gene set enrichment analysis (ssGSEA). Patients with surgical specimens of tumor regression grade (TRG) 3-4 or who were managed by the watch-and-wait approach for more than 3 years were defined as good responders. Results: Patients classified as CMS1 (6.4%) had a significantly higher rate of good responders; albeit survival was comparable among the four subtypes. Good responders exhibited an enrichment in various immune-related pathways (IFNg and a responses, allograft rejection, IL6 STAT3 signaling during acute phase response, and inflammation), as determined by ssGSEA. MCP-counter scores for cytotoxic lymphocytes were significantly higher for good responders than non-responders (p = 0.0003), and significantly higher for responders than non-responders in GSE109057 (p = 0.0137), GSE87211 (p = 0.0092), and GSE45404 (p = 0.0327) datasets. Cytotoxic lymphocyte MCP-counter score was thus considered an independent predictor of response to CRT, as determined in the multivariable Cox analysis (OR 3.810 [95% CI 1.820-7.970]; p = 0.0004). Multivariable Cox analysis, including post-operative pathological factors, revealed cytotoxic lymphocyte MCP-counter score to be independently associated with recurrence-free survival (HR 0.382 [95% CI 0.158-0.923]; p = 0.0325) and overall survival (HR 0.157 [95% CI 0.030-0.827]; p = 0.0290). ssGSEA showed significantly higher levels of four subpopulations of cytotoxic cells (effector memory CD8 T, natural killer T, natural killer, and activated CD8 T cells) among good responders than non-responders. Conclusions and Relevance: Cytotoxic lymphocyte score, as computed by RNA sequencing, could be a useful marker for predicting response to CRT and survival among patients with rectal cancer.
2023-01-25 | GSE216616 | GEO
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.
2021-12-18 | GSE191093 | GEO
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
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
2022-01-14 | GSE190005 | GEO