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Modulation of the tumor promoting functions of cancer associated fibroblasts by PDE5 inhibition

ABSTRACT: Modulation of the tumor promoting functions of cancer associated fibroblasts by PDE5 inhibition increases the efficacy of chemotherapy in human preclinical models of edophageal adenocarcinoma

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Antigoni Manousopoulou

LAB HEAD: Spiros D. Garbis

PROVIDER: PXD031148 | Pride | 2022-08-12

REPOSITORIES: Pride

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			Action	DRS
	11may15_vardenefil_1.raw	Raw
	11may15_vardenefil_10.raw	Raw
	11may15_vardenefil_2.raw	Raw
	11may15_vardenefil_21.raw	Raw
	11may15_vardenefil_22.raw	Raw

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Publications

Phosphodiesterase type 5 inhibitors enhance chemotherapy in preclinical models of esophageal adenocarcinoma by targeting cancer-associated fibroblasts.

Sharpe Benjamin P BP Hayden Annette A Manousopoulou Antigoni A Cowie Andrew A Walker Robert C RC Harrington Jack J Izadi Fereshteh F Breininger Stella P SP Gibson Jane J Pickering Oliver O Jaynes Eleanor E Kyle Ewan E Saunders John H JH Parsons Simon L SL Ritchie Alison A AA Clarke Philip A PA Collier Pamela P Mongan Nigel P NP Bates David O DO Yacqub-Usman Kiren K Garbis Spiros D SD Walters Zoë Z Rose-Zerilli Matthew M Grabowska Anna M AM Underwood Timothy J TJ

Cell reports. Medicine 20220601 6

The chemotherapy resistance of esophageal adenocarcinomas (EACs) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that, by targeting the tumor-promoting functions of the predominant TME cell type, cancer-associated fibroblasts (CAFs) with phosphodiesterase type 5 inhibitors (PDE5i), we can enhance the efficacy of standard-of-care chemotherapy. In ex vivo conditions, PDE5i prevent the transdifferentiation of normal fibroblasts to CAF and aboli ...[more]

PMID: 35732148

Similar Datasets

Modulation of the tumor promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

Project description:Modulation of the tumor promoting functions of cancer associated fibroblasts by phosphodiesterase type 5 inhibition increases the efficacy of chemotherapy in human preclinical models of esophageal adenocarcinoma

| PRJNA800044 | ENA

Project description:The chemotherapy resistance of esophageal adenocarcinomas (EAC) is underpinned by cancer cell extrinsic mechanisms of the tumor microenvironment (TME). We demonstrate that by targeting the tumor-promoting functions of the predominant TME cell type, cancer associated fibroblasts (CAF) with phosphodiesterase type 5 inhibitors (PDE5i) we can enhance the efficacy of standard-of-care chemotherapy. These findings demonstrate that CAF drive chemotherapy resistance in EAC and can be targeted by repurposing PDE5i, a safe and well tolerated class of drug administered to millions of patients world-wide to treat erectile dysfunction.

2022-01-29 | GSE194277 | GEO

Targeting of metastasis-promoting tumor-associated fibroblasts and modulation of pancreatic tumor-associated stroma with a carboxymethylcellulose-docetaxel nanoparticle.

Project description:Pancreatic ductal adenocarcinomas are characterized by the desmoplastic reaction, a dense fibrous stroma that has been shown to be supportive of tumor cell growth, invasion, and metastasis, and has been associated with resistance to chemotherapy and reduced patient survival. Here, we investigated targeted depletion of stroma for pancreatic cancer therapy via taxane nanoparticles. Cellax-DTX polymer is a conjugate of docetaxel (DTX), polyethylene glycol (PEG), and acetylated carboxymethylcellulose, a construct which condenses into well-defined 120nm particles in an aqueous solution, and is suitable for intravenous injection. We examined Cellax-DTX treatment effects in highly stromal primary patient-derived pancreatic cancer xenografts and in a metastatic PAN02 mouse model of pancreatic cancer, focusing on specific cellular interactions in the stroma, pancreatic tumor growth and metastasis. Greater than 90% of Cellax-DTX particles accumulate in smooth muscle actin (SMA) positive cancer-associated fibroblasts which results in long-term depletion of this stromal cell population, an effect not observed with Nab-paclitaxel (Nab-PTX). The reduction in stromal density leads to a >10-fold increase in tumor perfusion, reduced tumor weight and a reduction in metastasis. Consentingly, Cellax-DTX treatment increased survival when compared to treatment with gemcitabine or Nab-PTX in a metastatic PAN02 mouse model. Cellax-DTX nanoparticles interact with the tumor-associated stroma, selectively interacting with and depleting SMA positive cells and macrophage, effects of which are associated with significant changes in tumor progression and metastasis.

| S-EPMC4409566 | biostudies-literature

TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

Project description:TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

| PRJNA1297167 | ENA

The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy

Project description:The single cell transcriptional landscape of esophageal adenocarcinoma and its modulation by neoadjuvant chemotherapy

| PRJNA917632 | ENA

TET1 Functions as a Tumor Suppressor in Lung Adenocarcinoma Through Epigenetic Remodeling and Immune Modulation

Project description:Ten-Eleven Translocation (TET1-3) dioxygenases oxidize 5-methylcytosine (5mC) in DNA to generate 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), initiating DNA demethylation. Since their discovery in 2009, there have been contradictory reports regarding the roles of TET proteins in cancer. TET genes have been characterized as tumor suppressors because their expression levels are reduced in many human cancers including lymphoma, prostate, and pancreas, and TET2 gene mutations are common in hematological cancers. In contrast, TET1 was recently reported to be overexpressed in triple negative breast cancer and to act as a protooncogene in lung cancer. In the present study, we employed genetic approaches to directly address the function of TET1 protein in lung adenocarcinoma. We found that overexpression of TET1 in human lung adenocarcinoma (H441, H1975) cells decreased their proliferation and inhibited colony formation, cell migration, and 3D spheroid tumorigenesis. In contrast, TET1 knockout accelerated lung adenocarcinoma cell growth and promoted colony formation, cell migration, and 3D spheroid tumorigenesis. Transcriptomics and proteomics analyses revealed that TET1 overexpression was associated with increased prevalence of immune markers, primarily via activation of the TNF and NF-kB signaling pathways. Conversely, TET1 knockout in lung adenocarcinoma cells induced the expression of genes involved in cellular metabolism and cell growth. Our results are consistent with tumor suppressor role of TET1 gene in lung adenocarcinoma cells (H441, H1975) and reveal its possible role in activating antitumor immunity.

2025-08-20 | GSE303729 | GEO

Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite

Project description:Chemotherapy Modulation by a Cancer-Associated Microbiota Metabolite

| PRJNA1098747 | ENA

Neutrophil modulation by IL-1β-induced fibroblasts

Project description:Neutrophil modulation by IL-1β-induced fibroblasts

| PRJNA1104365 | ENA

Identifying tumor promoting genomic alterations in tumor-associated fibroblasts via retrovirus-insertional mutagenesis.

Project description:Tumor-associated fibroblasts (TAFs) are often essential for solid tumor growth. However, few genetic or epigenetic alterations have been found in TAFs during the progression of solid tumors. Employing a tumor-stromal cell co-injection model, we adapted here retroviral-insertional mutagenesis to stromal cells to identify novel tumor-associated genes in TAFs. We successfully identified 20 gene candidates that might modulate tumor growth if altered in TAFs at genomic level. To validate our finding, the function of one of the candidate genes, tubulin tyrosine ligase (Ttl), was further studied in TAFs from fibrosarcoma, colon, breast and hepatocarcinoma. We demonstrated that down-regulated TTL expression in TAFs indeed promoted tumor growth in mice. Interestingly, decreased expression of TTL in tumor stromal cells also correlated with poor outcome in human colon carcinoma. Thus, the co-injection model of tumor cells with retrovirus-modified fibroblasts proved a valid method to identify tumor-modulating genes in TAFs, allowing for a deeper insight into the role of the stroma for tumor development.

| S-EPMC5722558 | biostudies-literature

Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions.

Project description:Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8+ T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM.Significance: Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg Cancer Res; 78(19); 5600-17. ©2018 AACR.

| S-EPMC6168405 | biostudies-literature

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