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Tumorigenicity of KRAS-ablated pancreatic cancer cells requires STAT3 function

ABSTRACT: Tumorigenicity of KRAS-ablated pancreatic cancer cells requires STAT3 function

PROVIDER: PRJNA1153379 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30427846_1.fastq.gz	Fastqsanger.gz
	SRR30427846_2.fastq.gz	Fastqsanger.gz
	SRR30427847_1.fastq.gz	Fastqsanger.gz
	SRR30427847_2.fastq.gz	Fastqsanger.gz
	SRR30427848_1.fastq.gz	Fastqsanger.gz

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Tumorigenicity of KRAS-ablated pancreatic cancer cells requires STAT3 function

Project description:Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes, ranging from complete regression to frequent relapse. Mechanisms underpinning the resistance of cancer cells to KRAS inactivation remain to be understood. Here we investigate a conceptual framework of pancreatic ductal adenocarcinoma showing that CRISPR-mediated KRAS ablation impedes tumor growth contingent on the concomitant inactivation of the STAT3 transcription factor. Mechanistically, the incurred losses of KRAS and STAT3 disrupt a temporal balance between tumor cell differentiation, proliferation, and self-renewal. This in turn impairs tumor growth in mice and enhances their immune rejection, resulting in tumor clearance. Our findings identify a specific role for STAT3 in supporting cancer cell fitness with a particular focus on KRAS-inhibited tumors and provide a rationale for developing therapies targeting mutant KRAS and STAT3.

2025-02-05 | GSE275858 | GEO

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFÎºB-induced IL-8-expression by sequestering NFÎºB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFÎºB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance WT: Control lung; KRAS: Lung tumors expressing KRAS G12D; KRAS STAT3 KO: Lung tumors expressing KRAS G12D- STAT3 deficient; tumors of four mice pooled per sample

2015-02-05 | E-GEOD-52798 | biostudies-arrayexpress

Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

Project description:Oncogenic STAT3 functions are known in various malignancies. We found that STAT3 plays an unexpected tumor suppressive role in KRAS-mutant non-small-cell-lung cancer (NSCLC). In mice, tissue-specific inactivation of Stat3 resulted in increased Kras (G12D)-driven NSCLC initiation and malignant progression leading to markedly reduced survival. Clinically, low STAT3 expression levels correlate with poor survival in human lung adenocarcinoma patients with smoking history. Consistently, KRAS-mutant lung tumors showed reduced STAT3 levels. Mechanistically, we show that STAT3 controls NFκB-induced IL-8-expression by sequestering NFκB in the cytoplasm while IL-8 in turn regulates myeloid tumor infiltration and tumor vascularization thereby promoting tumor progression. These results identify a novel STAT3-NFκB-IL-8 axis in KRAS-mutant NSCLC with therapeutic and prognostic relevance

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RNA-sequencing of whole lungs from mice with activating Kras mutations and epithelial Stat3 deletion

Project description:We have previously shown that Kras mutant-induced lung tumors in CCSPCre/LSL-K-rasG12D mice (CC-LR) exhibited Stat3 activation. Here we sought to study the role of epithelial Stat3 in Kras-mutant lung tumor oncogenesis through derivation of a lung epithelial specific CC-LR/Stat3 conditional knockout (LR/Stat3D/D or LRDD) model. Analysis of tumor burdens revealed marked gender disparity following epithelial Stat3 deletion, LRDD males exhibited increased tumor burdens compared to male CC-LR animals whereas female LRDD mice displayed attenuated tumor development when compared to female CC-LR littermates. We then performed RNA-sequencing of whole lungs from the mice in order to understand global expression programs that may underlie this gender-specific effect of epithelial Stat3 deletion.

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STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

Project description:KRASG12C inhibitors have demonstrated clinical efficacy in KRASG12C-mutant non-small cell lung cancer (NSCLC), yet adaptive resistance limits their sustained therapeutic benefit. Through high-throughput screening of a pharmacological library, we identified a potent synergistic interaction between the KRASG12C inhibitor sotorasib and the signal transducer and activator of transcription 3 (STAT3) inhibitor napabucasin in KRASG12C-mutant NSCLC models. This combination exhibited superior anti-neoplastic activity compared to monotherapy in vitro and across diverse in vivo models. Mechanistically, KRASG12C inhibitor induced compensatory STAT3 activation, leading to adaptive resistance to sotorasib, which was abrogated by napabucasin. Notably, we elucidated a novel function of STAT3 in regulating HLA-B expression, an inhibitory ligand for natural killer (NK) cells, upon KRASG12C inhibition. The combination therapy enhanced NK cell-mediated cytotoxicity by disrupting the direct binding of phosphorylated STAT3 to the HLA-B promoter to downregulate its expression on neoplastic cells. Our findings unveiled an unexpected immunomodulatory mechanism underlying the synergism between KRAS and STAT3 inhibition, highlighting the potential of concurrently targeting oncogenic signaling cascades and the tumor microenvironment. This study provides a compelling rationale for the clinical evaluation of combined KRASG12C and STAT3 interruption in KRASG12C-mutant NSCLC patients, potentially offering a novel therapeutic strategy to overcome resistance and improve clinical outcomes.

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Project description:Breast Cancer (BC) has been associated with alterations in signaling through a number of growth factor and hormone regulated pathways. Mouse models for metastatic BC have been developed using oncoproteins that activate PI3K, Stat3 and Ras signaling. To determine the role of each pathway, we analyzed mouse mammary tumor formation when they were activated singly or pairwise. We used microarrays to detect differentially expressed genes in the KRas(G12D/+);CreT and R26(H1047R/+);KRas(G12D/+);CreT tumors Total RNA was extracted from tumors developed by Qiagen RNAeasy kit and hybridized on Affymetrix microarrays.

2015-09-16 | E-GEOD-73073 | biostudies-arrayexpress

The Stat3-Fam3a axis promotes muscle stem cell myogenic lineage progression by inducing mitochondrial respiration

Project description:Metabolic reprogramming is an active regulator of stem cell fate choices, and successful stem cell differentiation in different compartments requires the induction of oxidative phosphorylation. However, the mechanisms that promote mitochondrial respiration during stem cell differentiation are poorly understood. Here we demonstrate that Stat3 promotes muscle stem cell myogenic lineage progression by stimulating mitochondrial respiration. We identify Fam3a, a cytokine-like protein, as a major Stat3 downstream effector in muscle stem cells. We demonstrate that Fam3a is required for muscle stem cell commitment and skeletal muscle development. We show that myogenic cells secrete Fam3a, and exposure of Stat3-ablated muscle stem cells to recombinant Fam3a in vitro and in vivo rescues their defects in mitochondrial respiration and myogenic commitment. Together, these findings indicate that Fam3a is a Stat3-regulated secreted factor that promotes muscle stem cell oxidative metabolism and differentiation, and suggests that Fam3a is a potential tool to modulate cell fate choices.

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RIP4 inhibits STAT3 Signaling to sustain Lung Adencarcinoma Differentiation

Project description:Evaluation of the role of RIP4 in lung adenocarcinoma revealed that RIP4 inhibits STAT3 signaling in vitro and in vivo. Repression of RIP4 enhanced STAT3 signaling activation in KRAS LSL/G12D/wt; p53flox/flox murine tumors. This promoted cancer dedifferentiation through ECM remodeling

2016-06-30 | GSE81154 | GEO

STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

Project description:STAT3 inhibitors synergize with KRAS G12C inhibitors in NSCLC by restricting adaptive resistance of STAT3 signaling and augmenting NK cell cytotoxicity

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Expression data comparing KRas(G12D/+);CreT, R26(H1047R/+);KRas(G12D/+);CreT, and MMTV-Neu mouse mammary tumors

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