Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis

Hank, Thomas; Liss, Andrew S.

doi:10.3390/epigenomes2020011

Cited by 2 publications

(1 citation statement)

References 81 publications

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“…The role of epigenetic regulation in the initiation steps of PDAC is now demonstrated. 50 Transient expression of reprogramming factors (i.e., OCT3/4, SOX2, KLF4, c-MYC) 51 has been demonstrated to induce ADM. 17 The repression of acinar cell enhancers that reduces the expression of acinar cell transcription factors and increases expression of ductal genes is now recognized as an ADM inducer. Coherently, deletion of acinar-cell transcription factors leads to ADM. 27, 28, 52–54 Inversely, a forced expression of these factors prevents the ADM formation.…”

Section: Discussionmentioning

confidence: 99%

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Brunet

Vargas

Fanjul

et al. 2023

Preprint

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Background & Aims: Although specialized and dedicated to the production of digestive enzymes, pancreatic acinar cells harbor a high plasticity and are able to modify their identity. They undergo reversible acinar-to-ductal cell metaplasia (ADM) through epigenetic silencing of the acinar lineage gene program mainly controlled by PTF1a (Pancreas Transcription Factor 1a). ADM becomes irreversible in the presence of oncogenic Kras mutations and leads to the formation of preneoplastic lesions. We investigated the role of the E3 ubiquitin ligase Thyroid hormone Receptor Interacting Protein 12 (TRIP12), involved in PTF1a degradation, in pancreatic carcinogenesis. Methods: We used genetically engineered mouse models of pancreas-selective Trip12 deletion, mutant Kras (G12D) and mutant Trp53 (R172H). We performed RNA sequencing analysis from acinar cells and cell lines derived from mice models tumors. We investigated the impact of TRIP12 deficiency on acute pancreatitis, tumor formation and metastasis development. Results: TRIP12 is overexpressed in human pancreatic preneoplastic lesions and tumors. We show that a conditional deletion of TRIP12 in the pancreas during murine embryogenesis alters pancreas homeostasis and acinar cell genes expression patterns in adults. EGF induced-ADM is suppressed in TRIP12-depleted pancreatic acini. In vivo, a loss of TRIP12 prevents acini to develop ADM in response to pancreatic injury, the formation of Kras-induced pancreatic preneoplastic lesions, and impairs tumors and metastasis formation in the presence of mutated Trp53. TRIP12 is required for Claudin18.2 isoform expression in pancreatic tumors cells. Conclusions: Our study identifies TRIP12 as a novel regulator of acinar fate in the adult pancreas with an important dual role in pancreatic carcinogenesis, in initiation steps and in metastatic behavior of tumor cells.

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Section: Discussionmentioning

confidence: 99%

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Brunet

Vargas

Fanjul

et al. 2023

Preprint

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Clinicopathologic and Molecular Features of Pancreatic Ductal Adenocarcinomas Harboring Alterations in COMPASS-like Complex Genes

Hissong

Zhao

Shi

2022

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Recent genome-wide sequencing studies have identified a subset of pancreatic ductal adenocarcinomas (PDACs) harboring significant alterations in epigenetic regulation genes, including the COMPASS-like complex genes. Whether this subset of PDACs has specific histologic characteristics or carries prognostic or therapeutic implications is unknown. Objective.— To determine the specific clinicopathologic and molecular features of PDACs carrying mutations in COMPASS-like complex genes. Design.— We analyzed a series of 103 primary and metastatic PDACs with comprehensive molecular profiling, including 13 PDACs carrying loss-of-function COMPASS-like complex gene alterations (study cohort). Another 45 patients carrying PDACs with wild-type COMPASS-like complex genes were used as the control group. Results.— PDACs within the study cohort were smaller, harboring frequent areas of poor differentiation and concurrent alterations in KRAS, TP53, SMAD4, and CDKN2A. A subset of metastatic PDACs from the study cohort showed squamous differentiation. There was a trend toward decreased survival in the study group. We further interrogated 2 public data sets and found that PDACs with COMPASS-like complex gene alterations have increased rates of TP53 mutation, body-tail location, poor differentiation or undifferentiated histology, and a higher death rate. Conclusions.— COMPASS-like complex gene alterations likely represent a subset of more aggressive PDACs with poor or squamous differentiation histologically and increased concurrent TP53 mutations. These findings may have potential prognostic and therapeutic implications.

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Recent Advances in Chromatin Mechanisms Controlling Pancreatic Carcinogenesis

Cited by 2 publications

References 81 publications

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

The Loss of the E3 ubiquitin ligase TRIP12 inhibits Pancreatic Acinar Cell Plasticity and Tumor Cell Metastatic Capacity

Clinicopathologic and Molecular Features of Pancreatic Ductal Adenocarcinomas Harboring Alterations in COMPASS-like Complex Genes

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