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Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

ABSTRACT: Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58547 | GEO | 2016/02/11

SECONDARY ACCESSION(S): PRJNA252855

REPOSITORIES: GEO

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Prox1 haploinsufficiency sensitizes the pancreas to KrasG12D-induced transformation

Project description:Oncogenic mutations in Kras initiate neoplastic transformation in the pancreas through a process that hijacks the activity of developmental regulators and induces an inflammatory microenvironment. We report that the homeodomain transcription factor Prox1 is a novel component of a progenitor signature that is activated in acinar cells undergoing dedifferentiation and ductal metaplasia conversion. Also, the conditional deletion of a single Prox1 allele markedly accelerates early transformation and significantly enhances features of inflammation in pancreatic tissues carrying a Kras oncogene. By using in vitro and in silico approaches, we demonstrate that Prox1 negatively regulates the expression of proinflammatory genes and genes implicated in malignant transformation in pancreatic cells. Microrrays were used to identify gene expression profiles and pathways that are differentially activated after enforced expression of PROX1 in the PROX1-negative human pancreatic ductal adenocarcinoma (PDAC) cell line Capan1. MSCV retroviral transduction was used to generate Capan1 cells that ectopically express PROX1 and selected for puromycin resistance. Three independent transductions with control virus (MSCV_puro) and 3 independent transductions with Prox1-cDNA virus (MSCV_PROX1_puro) were conducted for these experiments.

2016-02-11 | E-GEOD-58547 | biostudies-arrayexpress

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PROX1 Orchestrates Tumor Metabolic Plasticity by Integrating LKB1-AMPK Signaling with BCAA Catabolism (ATAC-Seq)

Project description:Tumor cell metabolic plasticity is essential for tumor progression and therapeutic response, but the mechanism for regulation of metabolic plasticity remain poorly explored. Here, we identify PROX1 as an essential determinant for tumor metabolic plasticity. Notably, PROX1 is significantly reduced in response to metabolic stress or AMPK activation and is elevated in LKB1-deficient tumors in mice and human. Furthermore, the Ser79 phosphorylation of PROX1 by AMPK significantly alters its protein activity and allows a rapid recruitment of CUL4-DDB1 E3 ubiquitin ligase to promote PROX1 degradation under glucose starvation, a critical event that drives BCAA metabolism rewiring to suppress mTOR signaling. Importantly, PROX1 loss or Ser79 phosphorylation in HCC shows therapeutic resistance to metformin. Consistently, genetic ablation of PROX1 renders LKB1‐deficient KRAS-driven lung cancer resistant to phenformin treatment. Conversely, mice harboring non-phosphorylated PROX1 mutant or LKB1 mutant exhibit high PROX1 stabilization, promoting liver and lung cancer progression. Clinically, AMPK-PROX1 axis in human cancers is important for patient clinical outcomes. Collectively, our results demonstrate that the deficiency in the LKB1-AMPK axis in cancers reactivates PROX1 to sustain intracellular BCAA pools, resulting in enhanced mTOR signaling, and facilitating tumorigenesis and aggressiveness.

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