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Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE224567 | GEO | 2023/02/06

REPOSITORIES: GEO

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Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas.

Project description:Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Here, by employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.

| S-EPMC10017707 | biostudies-literature

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

Project description:Lineage plasticity has been proposed as a major source of intratumoral heterogeneity and therapeutic resistance. Employing an inducible genetic engineered mouse model, we illustrate that lineage plasticity enables advanced Pancreatic Ductal Adenocarcinoma (PDAC) tumors to develop spontaneous relapse following elimination of the central oncogenic driver - Yap. Transcriptomic and immunohistochemistry analysis of a large panel of PDAC tumors reveals that within high-grade tumors, small niches of PDAC cells gradually evolve to re-activate pluripotent transcription factors (PTFs), which lessen their dependency on Yap. Comprehensive Cut&Tag analysis demonstrate that although acquisition of PTF expression is coupled with the process of epithelial-to-mesenchymal transition (EMT), PTFs form a core transcriptional regulatory circuitry (CRC) with Jun to overcome Yap dependency, which is distinct from the classic TGFb-induced EMT-TF network. A chemical-genetic screen and follow-up functional studies establish Brd4 as an epigenetic gatekeeper for the PTF-Jun CRC, and strong synergy between BET and Yap inhibitors in blocking PDAC growth.

2023-03-02 | GSE224566 | GEO

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

2023-01-11 | GSE210412 | GEO

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas

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Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [RNA-Seq]

| PRJNA934450 | ENA

Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

Project description:Spontaneously Evolved Progenitor Niches Escape Yap Oncogene Addiction in Advanced Pancreatic Ductal Adenocarcinomas [Cut&Tag]

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Oncogene addiction and immune escape: friends or foes?

Project description: Not available

| S-EPMC7576068 | biostudies-literature

Kras oncogene ablation prevents resistance in advanced lung adenocarcinomas.

Project description:KRASG12C inhibitors have revolutionized the clinical management of patients with KRASG12C-mutant lung adenocarcinoma. However, patient exposure to these inhibitors leads to the rapid onset of resistance. In this study, we have used genetically engineered mice to compare the therapeutic efficacy and the emergence of tumor resistance between genetic ablation of mutant Kras expression and pharmacological inhibition of oncogenic KRAS activity. Whereas Kras ablation induces massive tumor regression and prevents the appearance of resistant cells in vivo, treatment of KrasG12C/Trp53-driven lung adenocarcinomas with sotorasib, a selective KRASG12C inhibitor, caused a limited antitumor response similar to that observed in the clinic, including the rapid onset of resistance. Unlike in human tumors, we did not observe mutations in components of the RAS-signaling pathways. Instead, sotorasib-resistant tumors displayed amplification of the mutant Kras allele and activation of xenobiotic metabolism pathways, suggesting that reduction of the on-target activity of KRASG12C inhibitors is the main mechanism responsible for the onset of resistance. In sum, our results suggest that resistance to KRAS inhibitors could be prevented by achieving a more robust inhibition of KRAS signaling mimicking the results obtained upon Kras ablation.

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Ras oncogene-independent activation of RALB signaling is a targetable mechanism of escape from NRAS(V12) oncogene addiction in acute myeloid leukemia.

Project description:Somatic mutations that lead to constitutive activation of NRAS and KRAS proto-oncogenes are among the most common in human cancer and frequently occur in acute myeloid leukemia (AML). An inducible NRAS(V12)-driven AML mouse model has established a critical role for continued NRAS(V12) expression in leukemia maintenance. In this model genetic suppression of NRAS(V12) expression results in rapid leukemia remission, but some mice undergo spontaneous relapse with NRAS(V12)-independent (NRI) AMLs providing an opportunity to identify mechanisms that bypass the requirement for Ras oncogene activity and drive leukemia relapse. We found that relapsed NRI AMLs are devoid of NRAS(V12) expression and signaling through the major oncogenic Ras effector pathways, phosphatidylinositol-3-kinase and mitogen-activated protein kinase, but express higher levels of an alternate Ras effector, Ralb, and exhibit NRI phosphorylation of the RALB effector TBK1, implicating RALB signaling in AML relapse. Functional studies confirmed that inhibiting CDK5-mediated RALB activation with a clinically relevant experimental drug, dinaciclib, led to potent RALB-dependent antileukemic effects in human AML cell lines, induced apoptosis in patient-derived AML samples in vitro and led to a 2-log reduction in the leukemic burden in patient-derived xenograft mice. Furthermore, dinaciclib potently suppressed the clonogenic potential of relapsed NRI AMLs in vitro and prevented the development of relapsed AML in vivo. Our findings demonstrate that Ras oncogene-independent activation of RALB signaling is a therapeutically targetable mechanism of escape from NRAS oncogene addiction in AML.

| S-EPMC5464975 | biostudies-literature

A Yap-Myc-Sox2-p53 Regulatory Network Dictates Metabolic Homeostasis and Differentiation in Kras-Driven Pancreatic Ductal Adenocarcinomas.

Project description:Employing inducible genetically engineered and orthotopic mouse models, we demonstrate a key role for transcriptional regulator Yap in maintenance of Kras-mutant pancreatic tumors. Integrated transcriptional and metabolomics analysis reveals that Yap transcribes Myc and cooperates with Myc to maintain global transcription of metabolic genes. Yap loss triggers acute metabolic stress, which causes tumor regression while inducing epigenetic reprogramming and Sox2 upregulation in a subset of pancreatic neoplastic cells. Sox2 restores Myc expression and metabolic homeostasis in Yap-deficient neoplastic ductal cells, which gradually re-differentiate into acinar-like cells, partially restoring pancreatic parenchyma in vivo. Both the short-term and long-term effects of Yap loss in inducing cell death and re-differentiation, respectively, are blunted in advanced, poorly differentiated p53-mutant pancreatic tumors. Collectively, these findings reveal a highly dynamic and interdependent metabolic, transcriptional, and epigenetic regulatory network governed by Yap, Myc, Sox2, and p53 that dictates pancreatic tumor metabolism, growth, survival, and differentiation.

| S-EPMC6783361 | biostudies-literature

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