Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

A patient-derived ccRCC model that retains native stromal features to assess fibrosis-driven personalized therapeutic response

ABSTRACT: Clear cell renal cell carcinoma (ccRCC) is characterized by a complex tumor microenvironment, in which stromal components such as collagen and cancer- associated fibroblasts (CAF) play a pivotal role in therapeutic resistance. To investigate the contribution of fibrosis to interpatient variability in treatment response, we developed a patient-derived xenograft (PDX) model using the chick chorioallantoic membrane (CAM) assay. This model preserves key stromal features of the original tumors, including collagen types I, III and VII, fibronectin, lysyl oxidases (LOX), and CAF markers such as fibroblast activation protein (FAP) and α-smooth muscle actin (α-SMA). Transcriptomic analyses confirm the conservation of gene expression profiles related to stromal architecture, extracellular matrix composition, and cellular metabolism within the xenografts. In vivo assays across multiple PDXs reveal heterogeneous responses to antifibrotic agents, which correlate with the collagen content of the original tumors. Notably, antifibrotic pretreatment enhances therapeutic efficacy in xenografts derived from tumors with collagen levels ranging from 5 to 25%. This model provides a physiologically relevant platform to assess fibrosis- driven therapeutic responses in ccRCC and supports the integration of stromal profiling into personalized treatment strategies.

ORGANISM(S): Gallus gallus Homo sapiens

PROVIDER: GSE315653 | GEO | 2026/01/05

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Perturb-seq experiment on patient-derived cancer-associated fibroblast in vitro cell line models from pancreatic ductal adenocarcinoma

Project description:Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their plethora of pro- and antitumorigenic functions. Recent findings attributed this functional heterogeneity to specializations in CAF subtypes. A precise targeting of specific subtypes would thus be required to design therapies that effectively modulate CAF phenotypes, but our knowledge of CAF heterogeneity in solid tumors, particularly pancreatic ductal adenocarcinoma (PDAC), is still lacking. Here, we use single-cell transcriptomics to characterize CAF subtype heterogeneity in in vitro CAF cell lines isolated from pancreatic tumor patients and investigate subtype-resolution modulations arising from perturbing potential stromal genes. We use the immortalized CAF cell lines to perform single-cell CRISPR perturbations of candidate stromal targets, revealing not only the subtype-specific effects of the perturbations, but also the impact of model-type selection on the translatability of insights.

2025-09-12 | GSE306853 | GEO

Single-cell RNA-seq of patient-derived cancer-associated fibroblast in vitro cell line models from pancreatic ductal adenocarcinoma

Project description:Cancer-associated fibroblasts (CAFs) are sought after as potential therapeutic targets due to their plethora of pro- and antitumorigenic functions. Recent findings attributed this functional heterogeneity to specializations in CAF subtypes. A precise targeting of specific subtypes would thus be required to design therapies that effectively modulate CAF phenotypes, but our knowledge of CAF heterogeneity in solid tumors, particularly pancreatic ductal adenocarcinoma (PDAC), is still lacking. Here, we use single-cell transcriptomics to characterize CAF subtype heterogeneity in in vitro CAF cell lines isolated from PDAC patients and investigate subtype-resolution modulations arising from perturbing potential stromal genes. We demonstrate that co-culturing CAFs with tumor cells can produce primary cell line models that can reliably represent CAF phenotypes observed in tumors, with correlations to immuno-resistant and immuno-modulatory phenotypes. With trajectory analysis, we infer the continuum of state changes that underlie the interconvertibility of CAF subtypes. Finally, we use the immortalized CAF cell lines to perform single-cell CRISPR perturbations of candidate stromal targets, revealing not only the subtype-specific effects of the perturbations, but also the impact of model-type selection on the translatability of insights.

2025-11-01 | GSE301398 | GEO

Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [ChIP-seq]

Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-J? in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Examination of genome-wide CSL binding sites in primary human dermal fibroblasts usinf two different antibodies against CSL

2015-08-24 | E-GEOD-59942 | biostudies-arrayexpress

Physical and functional CSL-p53 interactions underlie control of cancer stromal cell evolution [RNA-seq]

Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Human Dermal Fibroblasts were transfected with two different siRNA against CSL in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis.

2015-08-24 | E-GEOD-65473 | biostudies-arrayexpress

Cytokine Priming Enhances the Antifibrotic Effects of Mesenchymal Stromal Cells Conditioned Medium Via Fibrogenic Myofibroblasts Elimination and Extracellular Matrix Degradation.

Project description:Fibrosis is a pathological scarring process characterized by persistent myofibroblasts activation with excessive accumulation of extracellular matrix (ECM). Fibrotic disorders represent an increasing burden of disease-associated morbidity and mortality worldwide for which there are limited therapeutic options. Reversing fibrosis requires the elimination of myofibroblasts, remodeling of the ECM, and regeneration of functional tissue. Multipotent mesenchymal stromal cells (MSC) have antifibrotic properties mediated by secreted factors present in their conditioned medium (MSC-CM). However, there are no standardized in vitro assays to predict the antifibrotic effects of human MSC, and, as a consequence, we lack evidence on the effect of cytokine priming on MSC’s antifibrotic effects. We hypothesize that the MSC-CM promotes fibrosis resolution in vitro and that this effect is enhanced following MSC cytokine priming.

2025-05-06 | PXD051586 | Pride

Macropinocytosis maintains CAF subtype identity under metabolic stress in pancreatic cancer [nanoString nCounter]

Project description:Pancreatic ductal adenocarcinoma (PDAC) tumors are glutamine-deficient, and both tumor cells and cancer-associated fibroblasts (CAFs) rely on this amino acid to maintain fitness and induce macropinocytosis as an adaptive response. CAFs play a critical role in sculpting the tumor microenvironment, yet how adaptations to metabolic stress impact the stromal architecture remains elusive. In this study, we find that macropinocytosis sustains the myCAF phenotype under glutamine limitation by preventing inflammatory reprogramming. Our data demonstrate that metabolic stress induces an intrinsic inflammatory CAF (iCAF) program through MEK-ERK signaling. We find that blocking macropinocytosis in vivo promotes myCAF-to-iCAF transitions, remodeling the tumor stroma. Importantly, stromal remodeling driven by macropinocytosis inhibition—including iCAF enrichment, collagen reduction, immune cell infiltration, and vascular expansion—sensitizes PDAC tumors to immunotherapy and chemotherapy. Our findings reveal that inhibiting macropinocytosis promotes an inflammatory, less fibrotic tumor microenvironment that can be leveraged to improve therapeutic responses in PDAC.

2025-06-27 | GSE301021 | GEO

A novel 3-D organotypic culture model by co-culturing alpha-SMA positive CAF and cholangiocarcinoma cells in a collagen matrix

Project description:The increased M-NM-1-smooth muscle-actin positive cancer-associated fibroblastic cells (CAF) in the desmoplastic stroma may relate to a more aggressive cancer and worse survival outcomes for intrahepatic cholangiocarcinoma (ICC) patients We developed a novel 3-D organotypic culture model by co-culturing M-NM-1-SMA positive CAF and cholangiocarcinoma cells in a collagen matrix. Cholangiocarcinoma cell lines were established by isolating M-NM-1-SMA positive cancer-associated fibroblastic cells (CAF) (BDEsp-TDFE4) and cholangiocarcinoma cells (BDEsp-TDEH10) from tumors arising from bile duct inoculation of spontaneously-transformed low grade malignant rat BDE1 cholangiocytes (BDEsp cells). These tumor-derived cells lines were then grown in a rat tail type I collagen gel matrix, alone or in co-culture, and their gene expression profile were compared.

2012-06-22 | E-GEOD-38889 | biostudies-arrayexpress

BMAL1-HIF2α heterodimers contribute to ccRCC

Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived A498 cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

2025-03-17 | GSE290669 | GEO

BMAL1-HIF2α heterodimers contribute to ccRCC [RNA-seq_Fig2]

Project description:Circadian disruption enhances cancer risk, and many tumors exhibit disordered circadian gene expression. We show rhythmic gene expression is unexpectedly robust in clear cell renal cell carcinoma (ccRCC). Furthermore, the clock gene BMAL1 is higher in ccRCC than in healthy kidneys, unlike in other tumor types. BMAL1 is closely related to ARNT and we show that BMAL1-HIF2α regulates a subset of HIF2α target genes in ccRCC cells. Depletion of BMAL1 reprograms HIF2α chromatin association and target gene expression and reduces ccRCC growth in culture and in xenografts. Analysis of pre-existing data reveals higher BMAL1 in patient-derived xenografts that are sensitive to growth suppression by HIF2α antagonists. We show that increasing BMAL1 sensitizes ccRCC-derived 786O cells to growth inhibition by PT2399. Together, these findings indicate that an alternate HIF2α heterodimer containing the circadian partner BMAL1 contributes to HIF2α activity, growth, and sensitivity to HIF2α antagonist drugs in ccRCC cells.

2025-05-08 | GSE269336 | GEO

BMAL1-HIF2α heterodimers contribute to ccRCC [RNA-seq]

2025-05-08 | GSE290779 | GEO