Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

ABSTRACT: Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

PROVIDER: PRJNA745330 | ENA |

REPOSITORIES: ENA

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	SRR15095819_1.fastq.gz	Fastqsanger.gz
	SRR15095819_2.fastq.gz	Fastqsanger.gz
	SRR15095820_1.fastq.gz	Fastqsanger.gz
	SRR15095820_2.fastq.gz	Fastqsanger.gz
	SRR15095821_1.fastq.gz	Fastqsanger.gz

Items per page:

1 - 5 of 32

Similar Datasets

Extrinsic KRAS signaling shapes the pancreatic microenvironment through fibroblast reprogramming

Project description:We utilized the inducible and reversible iKras* genetically engineered mouse model to intiate oncogenic Kras (Kras*) expression in the pancreatic epithelium by providing mice with doxycycline water, and then switched mice to regular water thereby turning expression of Kras* off for 3 days, 3 weeks post-induction of acute pancreatitis. Single cell RNA sequencing revealed that fibroblasts are reprogrammed by signals originating from epithelial Kras*-expressing cells to shape the immune microenvironment during pancreatic tumorigenesis.

2022-02-14 | GSE179846 | GEO

SHP2 Inhibition Abrogates Adaptive Resistance to KRAS-G12C-Inhibition and Remodels the Tumor Microenvironment of KRAS-Mutant Tumors

Project description:KRAS is the most frequently mutated oncogene in human cancer, and KRAS inhibition has been a longtime goal. Recently, inhibitors (G12C-Is) that bind KRAS-G12C-GDP and react with Cys-12 were developed. Using new affinity reagents to monitor KRAS-G12C activation and inhibitor engagement, we found that SHP2 inhibitors (SHP2-Is) increased KRAS-GDP occupancy, enhancing G12C-I efficacy. SHP2-Is abrogated feedback signaling by multiple RTKs and adaptive resistance to G12C-Is in vitro, in xenografts, and in syngeneic KRAS-G12C-mutant pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC) models. The combination of SHP2-I and G12C-I evoked favorable changes in the immune microenvironment, decreasing myeloid suppressor cells, increasing CD8+ T cells, and sensitizing tumors to PD-1 blockade. Experiments using an inhibitor-resistant SHP2 mutant showed that SHP2 inhibition in PDAC cells is required for tumor regression and remodeling of the immune microenvironment, but SHP2-Is also had direct effects on angiogenesis. Our results demonstrate that SHP2-I/G12C-I combinations confer a substantial survival benefit in PDAC and NSCLC and identify additional potential combination strategies. G12C-Is show significant, but limited, efficacy as single agents, in part because of “adaptive resistance”. We find that combining G12C-Is with SHP2-Is abrogates adaptive resistance and results in favorable changes in the immune microenvironment that potentiate PD-1 blockade in KRAS-mutant malignancies. SHP2-Is also can have direct, context-dependent, effects on tumor vasculature.

2020-10-01 | GSE149815 | GEO

Mutant KRAS-associated proteome is mainly controled by exogenous factors

Project description:KRAS signaling has been extensively studied, yet the clarification between KRAS-autonomous and non-autonomous mechanisms are still less explored. Understanding how KRAS signaling and effects are affected by exogenous stimuli can provide valuable insights not only to understand resistance mechanisms that justify pathway inhibition failure, but also to uncover novel therapeutic targets for mutant KRAS patients. Hence, aiming at understanding KRAS-autonomous versus non autonomous mechanisms, we studied the response of two mutant KRAS colorectal cancer cell lines (HCT116 and LS174T) - control and KRAS silenced- to TGFβ1-activated fibroblasts secretome. By performing a total proteome analysis, we observed that TGFβ1-activated fibroblast-secreted factors triggered cell-line specific proteome alterations and that mutant KRAS governs approximately 1/3 of those alterations. Moreover, the analysis of the impact of exogenous factors on the modulation of KRAS proteome revealed that more than 2/3 of the KRAS-associated proteome is controlled in a KRAS-non-autonomous manner, dependent on the exogeneous factors, in both cell lines. This work highlights the context-dependency of KRAS-associated signaling and reinforces the importance of establishing more integrative models resembling the complexity of the tumor microenvironment to study KRAS-associated signals.

2022-04-06 | PXD030551 | Pride

BRCA Mutation Status Shapes the Microenvironment of Pancreatic Adenocarcinoma

Project description:BRCA Mutation Status Shapes the Microenvironment of Pancreatic Adenocarcinoma

| PRJNA859234 | ENA

BRCA Mutation Status Shapes the Microenvironment of Pancreatic Adenocarcinoma

Project description:BRCA Mutation Status Shapes the Microenvironment of Pancreatic Adenocarcinoma

| PRJNA859233 | ENA

Determination of the tumor microenvironment remodeling by KRAS targeted therapy in pancreatic cancer

Project description:Oncogenic KRAS is now recognized as a viable target for drug intervention; nevertheless, the efficacy of KRAS-targeted therapy is impeded by various resistance mechanisms. The intricate interplay between cancer cells and the cells within the tumor microenvironment (TME) actively contributes to the mutual promotion of resistance to KRAS-targeted therapies. To discern specific cell populations orchestrating tumor responses in pancreatic ductal adenocarcinoma (PDAC), we conducted single-cell RNA sequencing (scRNA-seq) on spontaneous tumors obtained from genetically engineered mouse models. This analysis was performed both before and after the inhibition or genetic ablation of KRAS, shedding light on the dynamic changes occurring at the single-cell level.

2024-10-09 | GSE252834 | GEO

MTFR2 shapes a barrier of immune microenvironment in hepatocellular carcinoma

Project description:MTFR2 shapes a barrier of immune microenvironment in hepatocellular carcinoma

| PRJNA875910 | ENA

Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [CRISPR]

Project description:Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease for which new therapeutic interventions are needed. Here, we assessed the cellular response to pharmacological KRAS inhibition, targeting the central oncogenic factor in PDAC. In a panel of PDAC cell lines, pharmaceutical inhibition of the KRASG12D allele with MRTX1133 yields variable efficacy in the suppression of cell growth and downstream gene expression programs in 2D culture. CRISPR-Cas9 loss-of-function screens identified ITGB1 as a novel driver for enhanced therapeutic response that regulates mechanotransdcution signaling and YAP/TAZ expression, which is further confirmed by gene specific knockdowns and combinatorial drug synergy. Interestingly, MRTX1133 is considerably more efficacious in the context of 3D cell cultures. Moreover, MRTX1133 elicits a more pronounced cytostatic effect in controlling the in vivo tumor growth in PDAC patient-derived xenografts. In syngeneic models, KRASG12D inhibition leads to potent tumor regression that did not occur in immune-deficient hosts. Digital spatial profiling on tumor tissues indicates that MRTX1133-mediated KRAS inhibition enhances interferon-γ signaling and induces antigen presentation that modulates the tumor microenvironment. Further investigation on the immunological response using single-cell sequencing and multispectral imaging reveals that tumor regression is associated with suppression of neutrophils and influx of effector CD8+ T-cells. Thus, both tumor cell-intrinsic and extrinsic events contribute to response and credential KRASG12D inhibition as a promising strategy for a large percentage of PDAC tumors.

2024-01-24 | GSE249537 | GEO

Extracellular niche and tumor microenvironment enhance the impact of KRAS inhibitors in pancreatic cancer models [DSP]

2024-01-24 | GSE249538 | GEO

Tissue microenvironment shapes distinct sets of machineries to regulate ILC2 properties

Project description:Tissue microenvironment shapes distinct sets of machineries to regulate ILC2 properties

| PRJNA643921 | ENA