Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Extracellular matrix targeted mRNA profiles of PKN2 KO/WT mouse pancreatic stellate cell lines (PSCs) treated with TGF-b or vehicle control

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) promotes fibrotic, therapy-resistant tumours. Conversely, suppression of CAFs can result in aggressive metastatic tumours. Here we show that the Rho-effector kinase protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 was associated with reduced PSC proliferation and contractility, retention of lipid droplets and decreased a-SMA stress fibres. PKN2 loss was also associated with a myofibroblast CAF to -like inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. In spheroid co-cultures with PDAC cells, loss of PKN2 prevented PSC invasion but, counter-intuitively, promoted invasive cancer cell outgrowth. Further, deletion of PKN2 in the pancreatic stroma induced more locally invasive, orthotopic pancreatic tumours. Finally, we demonstrated that a PKN2KO PKN2 KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast differentiation function can limit important stromal tumour suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

ORGANISM(S): Mus musculus

PROVIDER: GSE189245 | GEO | 2021/11/22

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumour invasion.

Project description:In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) promotes fibrotic, therapy-resistant tumours. Conversely, suppression of CAFs can result in aggressive metastatic tumours. Here we show that the Rho-effector kinase protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 was associated with reduced PSC proliferation and contractility, retention of lipid droplets and decreased a-SMA stress fibres. PKN2 loss was also associated with a myofibroblast CAF to -like inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. In spheroid co-cultures with PDAC cells, loss of PKN2 prevented PSC invasion but, counter-intuitively, promoted invasive cancer cell outgrowth. Further, deletion of PKN2 in the pancreatic stroma induced more locally invasive, orthotopic pancreatic tumours. Finally, we demonstrated that a PKN2KO PKN2 KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast differentiation function can limit important stromal tumour suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

2021-11-19 | GSE189027 | GEO

Single-Cell Analysis of Human Pancreatic Ductal Adenocarcinoma

Project description:<p>Cancer-associated fibroblasts (CAFs) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we employ single-cell RNA-sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human PDAC tumors. Six human PDAC tumor specimens from six patients were collected, and processed for single-cell RNA-sequencing analysis. Adjacent-normal pancreas tissue was also collected from two of the patients. Tumor samples were digested, and fluorescence-activated cell sorting was used to isolate viable cells. For one tumor sample, viable, CD45-negative, CD31-negative, and EpCAM-negative cells were also isolated to enrich for CAFs. The 10X Chromium platform was then used to isolate single cells for RNA-sequencing analysis. This work has demonstrated the differences in immune cell populations between adjacent-normal and tumor tissues, and identified subpopulations of epithelial cells and CAFs present in PDAC tumors. This high-throughput analysis is a resource to better understand the cell populations present in PDAC, and may ultimately aid in the development of more effective therapies for this deadly malignancy.</p>

| phs001840 | dbGaP

RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors (IOA-289 and PF-8380) against DMSO treated controls

Project description:Autotaxin (ATX), encoded by ENPP2, catalyzes the production of lysophosphatidic acid (LPA), an important regulator within the tumor microenvironment (TME). ATX is a clinical target in pancreatic ductal adenocarcinoma (PDAC), yet the pro-tumorigenic action of the ATX/LPA axis in PDAC remains unclear. PDAC is characterized by a highly fibrotic tumor microenvironment (TME) due to an abundance of cancer associated fibroblasts (CAFs), acting as a barrier to therapy and contributing to the poor survival of PDAC patients. The mechanism by which ATX inhibition influences CAFs and their secretome is still not fully characterized. To identified potential downstream mediators of ATX signaling, we performed RNA-seq of pancreatic CAF-derived cell line 0082T treated with Autotaxin inhibitors, IOA-289 and PF-8380. PF-8380 treatment resulted in a higher number of differentially expressed genes compared to IOA-289 treatment. IOA-289 treatment resulted in only four significantly differentially expressed genes (CTGF, PLIN2, HHIP, and AHNAK). However, only PLIN2, which was upregulated and CTGF, which was downregulated, overlapped between the two ATX inhibitors. As CTGF (connective tissue growth factor) is a pro-fibrotic and pro-tumorigenic factor, it suggests a key role for CAF-derived ATX in promoting autocrine and paracrine pro-tumorigenic signaling in PDAC.

2024-10-06 | E-MTAB-14494 | biostudies-arrayexpress

Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma impair CD8+ T cell activation and limit responsiveness to immunotherapy in mice

Project description:Senescent cells within tumors and their stroma exert complex pro- and anti-tumorigenic functions, yet the potential for targeting such senescent cells for improved therapy remains largely unknown. Here, we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic ductal adenocarcinomas (PDAC) and in premalignant lesions in mice and humans. Senescent CAFs represented different previously-defined CAF subtypes. Senescent CAFs isolated from mouse and humans expressed elevated levels of immunoregulatory genes. Depletion of senescent CAFs, either genetically or using the Bcl-2 inhibitor ABT-199 (venetoclax), increased the proportion of activated CD8+ T cells in mouse pancreatic carcinomas, whereas induction of CAF senescence had the opposite effect. Combining ABT-199 with an immune checkpoint therapy regimen significantly reduced mouse tumor burden. These results indicate that senescent CAFs in PDAC stroma limit the numbers of activated cytotoxic CD8+ T cells, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

2024-06-24 | PXD053144 | Pride

Serum levels of iCAF-derived Osteoglycin predict favorable outcome in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma, the main cellular constituents of which are cancer-associated fibroblasts (CAFs). Heterogeneity in the PDAC CAF population was recently delineated demonstrating that both tumor-promoting and -suppressive activities co-exist in the stroma. Here, we aimed to identify biomarkers for the CAF population that contribute to a favorable outcome. Osteoglycin (OGN) was identified as a candidate serum prognostic marker. Single-cell analysis in KPC mice indicated that OGN is derived from a subgroup of inflammatory CAFs. OGN-expressing fibroblasts are distinct from resident healthy pancreatic stellate cells and arise during pancreatitis. Serum OGN levels were prognostic for favorable overall survival in two independent PDAC cohorts.

2022-08-23 | GSE197908 | GEO

Cancer Associated Fibroblast-FAK regulates malignant cell metabolism

Project description:Breast and pancreatic cancers are characterised by profound metabolic changes1,2. Until recently, these changes have been ascribed to their intrinsic genetic profiles2-4. However, the contribution of cancer-associated fibroblasts (CAFs) to cell metabolism has not been fully investigated5. Here, we provide clinical evidence that reduction in stromal Focal Adhesion Kinase (FAK) correlates with reduced overall survival in human breast and pancreatic cancer patients. To model this, we developed FSP-Cre+;FAKfl/fl mice where FAK was deleted in a subpopulation of CAFs. We establish that loss of CAF-FAK is sufficient to enhance tumour growth without affecting desmoplasia in orthotopically injected breast and pancreatic carcinomas. Additionally, deletion of CAF-FAK enhances disease progression in the MMTV-PyMT spontaneous model of breast cancer. Furthermore, despite this pro-tumourigenic effect, a significant reduction in tumour angiogenesis was observed in late-stage tumours, but not early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice. This indicates that loss of CAF-FAK is sufficient to reduce malignant cell dependency on blood vessel support suggesting acquired metabolic alterations in cancer cells. Indeed, 18F-FDG-PET imaging and glucose flux analysis revealed enhanced glucose catabolism in early-stage, size-matched tumours in FSP-Cre+;FAKfl/fl mice in vivo. Mechanistically, we demonstrate that conditioned medium from FAK-null CAFs enhances glycolysis and glycolytic capacity in malignant cells. Proteomics and phosphoproteomics analysis reveal enriched cytokine-mediated signalling pathways in FAK-null CAFs and subsequent enrichment of associated phosphopeptides in malignant cells, respectively. Overall, our data uncover a novel mechanism by which cytokines, regulated by CAF-FAK, can promote cancer growth and progression, and identify a new set of CAF-derived targets to interfere with cancer metabolism.

2020-02-18 | PXD008276 | Pride

RNA Expression Profile of normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) derived from human Pancreatic Ductal Adenocarcinoma.

Project description:Although how CAFs impact the tumor epithelium is being progressively unveiled, transcriptional processes of lineage plasticity in fibroblasts govern the acquisition and transition of the CAF phenotype are much less understood. Here, to explore the potential involvement of the circular RNAs (circRNAs) in fibroblast activation and phenotype acquisition, we isolated CAFs and NFs from human pancreatic cancer and paired normal pancreatic tissue. Next, we conducted circRNA profiling five CAFs and three paired NFs by high throughput sequencing. Our results showed that clusters of circRNAs were aberrantly expressed in CAFs compared with NFs, and provided potential targets for future treatment of PDAC and novel insights into PDAC microenvironment.

2021-04-15 | GSE172096 | GEO

Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.

2023-09-18 | GSE223205 | GEO

Cancer-associated fibroblast driven paracrine IL-6/STAT3 signalling promotes migration and dissemination in invasive lobular carcinoma

Project description:Invasive Lobular Carcinoma (ILC) is an under-studied yet common subtype of breast cancer. A key feature of ILC tumours, due to their single-file invasive growth pattern, is a high stromal content and in particular, an abundance of cancer-associated fibroblasts (CAFs). We identified that IL-6 secreted from primary ILC patient-derived CAFs drives STAT3 activation in ILC cell lines and found that IL6, STAT3, pSTAT3 and subsequent downstream gene expression induced by IL-6 within CAF conditioned media is upregulated in ILC tumours compared to Invasive Ductal Carcinoma tumours, the most common subtype of breast cancer. This dataset contains 3`-mRNAseq data from ILC cell lines (SUM44PE and MDA-MB-134VI) and patient-derived organoids (HCI-013 and HCI-018) stimulated with either recombinant human IL-6 (10 ng/ml) for 24 hours or 1 week or SUM44PE cells stimulated with CAF conditioned media (CAF CM)collected from ED26 primary ILC CAFs (characterised here: doi.org/10.3390/cancers14040904) +/- an IL-6 neutralising antibody. RNA was extracted using Qiagen RNeasy mini-kit and libraries were prepared using QuantSeq 3’ mRNA-Seq Library Prep Kit (FWD) for Illumina (Lexogen Inc, #015).

2024-10-11 | GSE276108 | GEO

Senescent cancer-associated fibroblasts in pancreatic adenocarcinoma suppress CD8+ T cell activation and inhibit response to immune checkpoint therapy [Kras_p53]

Project description:Senescent cells appear within tumors and their stroma, exerting complex pro- and anti-tumorigenic functions. The effects of senescent tumor stromal cells are mostly unknown, as is the potential for targeting such senescent cells for improved therapy. Here we uncover the presence of a senescent subset of cancer-associated fibroblasts (CAFs) within pancreatic adenocarcinomas and in premalignant pancreatic lesions. Senescent CAFs show reduced proliferation, and are often associated with the inflammatory CAF (iCAF) subtype. We isolated and characterized senescent CAFs from mouse models and directly from human patients, and found that they express elevated levels of immune-regulatory genes. In a panel of mouse PDACs, high levels of senescent CAFs correlated with low T cell infiltration. Removal of senescent CAFs from PDAC stroma, either genetically or through treatment with the senolytic drug ABT-199 (venetoclax), a Bcl2 inhibitor, increased rates of activated cytotoxic CD8+ T cells within tumors. Conversely, activation of CAF senescence within PDACs led to reduced CD8+ T cell numbers. Media from senescent PDAC CAFs inhibited T cell proliferation and activation. We show that implanted PDAC tumors show improved response to immune checkpoint therapy when co-treated with the senolytic drug. These results reveal that the presence of senescent CAFs in PDAC stroma acts to repress cytotoxic T cell activity, and suggest that their targeted elimination through senolytic treatment may enhance immunotherapy.

2024-06-06 | GSE235242 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data