Key transcriptional effectors of the pancreatic acinar phenotype and oncogenic transformation
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ABSTRACT:
SUBMITTER: Azevedo-Pouly A
PROVIDER: S-EPMC10553828 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:Background and aimsAberrant acinar to ductal metaplasia (ADM), one of the earliest events involved in exocrine pancreatic cancer development, is typically studied using pancreata from genetically engineered mouse models.MethodsWe used primary, human pancreatic acinar cells from organ donors to evaluate the transcriptional and pathway profiles during the course of ADM.ResultsFollowing 6 days of three-dimensional culture on Matrigel, acinar cells underwent morphological and molecular changes indicative of ADM. mRNA from 14 donors' paired cells (day 0, acinar phenotype and day 6, ductal phenotype) was subjected to whole transcriptome sequencing. Acinar cell specific genes were significantly downregulated in the samples from the day 6 cultures while ductal cell-specific genes were upregulated. Several regulons of ADM were identified including transcription factors with reduced activity (PTF1A, RBPJL, and BHLHA15) and those ductal and progenitor transcription factors with increased activity (HNF1B, SOX11, and SOX4). Cells with the ductal phenotype contained higher expression of genes increased in pancreatic cancer while cells with an acinar phenotype had lower expression of cancer-associated genes.ConclusionOur findings support the relevancy of human in vitro models to study pancreas cancer pathogenesis and exocrine cell plasticity.
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Project description:The role of the ataxia-telangiectasia-mutated (ATM) gene in human malignancies, especially in solid tumors, remains poorly understood. In the present study, we explored the involvement of ATM in transforming primary human cells into cancer stem cells. We show that ATM plays an unexpected role in facilitating oncogene-induced malignant transformation through transcriptional reprogramming. Exogenous expression of an oncogene cocktail induced a significant amount of DNA double-strand breaks in human fibroblasts that caused persistent activation of ATM, which in turn enabled global transcriptional reprogramming through chromatin relaxation, allowing oncogenic transcription factors to access chromatin. Consistently, deficiencies in ATM significantly attenuated oncogene-induced transformation of human cells. In addition, ATM inhibition significantly reduced tumorigenesis in a mouse model of mammary cancer. ATM and cellular DNA damage response therefore play a previously unknown role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells. SIGNIFICANCE: These findings uncover a novel pro-oncogenic role for ATM and show that contrary to established theory, ATM does not always function as a tumor suppressor; its function is however dependent on cell type.
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Project description:The Snail1 transcriptional factor is required for correct embryonic development, yet its expression in adult animals is very limited and its functional roles are not evident. We have now conditionally inactivated Snail1 in adult mice and analyzed the phenotype of these animals. Snail1 ablation rapidly altered pancreas structure: one month after Snail1 depletion, acinar cells were markedly depleted, and pancreas accumulated adipose tissue. Snail1 expression was not detected in the epithelium but was in pancreatic mesenchymal cells (PMCs). Snail1 ablation in cultured PMCs downregulated the expression of several β-catenin/Tcf-4 target genes, modified the secretome of these cells and decreased their ability to maintain acinar markers in cultured pancreas cells. Finally, Snail1 deficiency modified the phenotype of pancreatic tumors generated in transgenic mice expressing c-myc under the control of the elastase promoter. Specifically, Snail1 depletion did not significantly alter the size of the tumors but accelerated acinar-ductal metaplasia. These results demonstrate that Snail1 is expressed in PMCs and plays a pivotal role in maintaining acinar cells within the pancreas in normal and pathological conditions.
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Project description:ObjectivesEmerging evidence from mouse models suggests that mutant Kras can drive the development of pancreatic ductal adenocarcinoma (PDA) precursors from acinar cells by enforcing ductal de-differentiation at the expense of acinar identity. Recently, human genome-wide association studies have identified NR5A2, a key regulator of acinar function, as a susceptibility locus for human PDA. We investigated the role of Nr5a2 in exocrine maintenance, regeneration and Kras driven neoplasia.DesignTo investigate the function of Nr5a2 in the pancreas, we generated mice with conditional pancreatic Nr5a2 deletion (PdxCre(late); Nr5a2(c/c)). Using this model, we evaluated acinar differentiation, regeneration after caerulein pancreatitis and Kras driven pancreatic neoplasia in the setting of Nr5a2 deletion.ResultsWe show that Nr5a2 is not required for the development of the pancreatic acinar lineage but is important for maintenance of acinar identity. Nr5a2 deletion leads to destabilisation of the mature acinar differentiation state, acinar to ductal metaplasia and loss of regenerative capacity following acute caerulein pancreatitis. Loss of Nr5a2 also dramatically accelerates the development of oncogenic Kras driven acinar to ductal metaplasia and PDA precursor lesions.ConclusionsNr5a2 is a key regulator of acinar plasticity. It is required for maintenance of acinar identity and re-establishing acinar fate during regeneration. Nr5a2 also constrains pancreatic neoplasia driven by oncogenic Kras, providing functional evidence supporting a potential role as a susceptibility gene for human PDA.
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Project description:Maintenance of cell type identity is crucial for health, yet little is known of the regulation that sustains the long-term stability of differentiated phenotypes. To investigate the roles that key transcriptional regulators play in adult differentiated cells, we examined the effects of depletion of the developmental master regulator PTF1A on the specialized phenotype of the adult pancreatic acinar cell in vivo Transcriptome sequencing and chromatin immunoprecipitation sequencing results showed that PTF1A maintains the expression of genes for all cellular processes dedicated to the production of the secretory digestive enzymes, a highly attuned surveillance of unfolded proteins, and a heightened unfolded protein response (UPR). Control by PTF1A is direct on target genes and indirect through a ten-member transcription factor network. Depletion of PTF1A causes an imbalance that overwhelms the UPR, induces cellular injury, and provokes acinar metaplasia. Compromised cellular identity occurs by derepression of characteristic stomach genes, some of which are also associated with pancreatic ductal cells. The loss of acinar cell homeostasis, differentiation, and identity is directly relevant to the pathologies of pancreatitis and pancreatic adenocarcinoma.
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Project description:Despite a reduced function and volume of the exocrine pancreas in type 1 diabetes, the acinar cells remain understudied in type 1 diabetes research. The hypothesis of this study is that the acinar tissue is altered in subjects with type 1 diabetes compared with subjects without diabetes. The cell density, expression of digestive enzymes, and transcriptome of acinar tissue at varying distances from islets were analyzed using histology, immunostaining, and AmpliSeq RNA sequencing of laser capture microdissected tissue. Pancreases examined were from organ donors with or without type 1 diabetes. We demonstrate preserved acinar nuclei density and find no support of acinar atrophy in type 1 diabetes. Staining for digestive enzymes (amylase, lipase, and trypsin) demonstrated an evenly distributed expression in the exocrine parenchyma; although occasional amylase-negative regions appeared in tissue that had been formalin-fixed and paraffin-embedded, this phenomenon was not evident in frozen tissue. Gene set enrichment analysis of whole transcriptome data identified transcriptional alterations in type 1 diabetes that were present in the acinar tissue independent of the distance from islets. Among these, the two most enriched gene sets were Myc Targets V2 and Estrogen Response Early. Taken together, these new data emphasize the involvement of the entire pancreas in type 1 diabetes pathology. The alteration of the gene sets Myc Targets V2 and Estrogen Response Early is a possible link to the increased incidence of pancreatic cancer in type 1 diabetes.
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human malignancies. To investigate the cellular origin(s) of this cancer, we determined the effect of PDAC-relevant gene mutations in distinct cell types of the adult pancreas. We show that a subpopulation of Pdx1-expressing cells is susceptible to oncogenic K-Ras-induced transformation without tissue injury, whereas insulin-expressing endocrine cells are completely refractory to transformation under these conditions. However, chronic pancreatic injury can alter their endocrine fate and allow them to serve as the cell of origin for exocrine neoplasia. These results suggest that one mechanism by which inflammation and/or tissue damage can promote neoplasia is by altering the fate of differentiated cells that are normally refractory to oncogenic stimulation.
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Project description:Methylation-mediated silencing of G0-G1 switch gene 2 (G0S2) has been detected in a variety of solid tumors, whereas G0S2 induction is associated with remissions in patients with acute promyelocytic leukemia, implying that G0S2 may possess tumor suppressor activity. In this study, we clearly demonstrate that G0S2 opposes oncogene-induced transformation using G0s2-null immortalized mouse embryonic fibroblasts (MEF). G0s2-null MEFs were readily transformed with HRAS or EGFR treatment compared with wild-type MEFs. Importantly, restoration of G0S2 reversed HRAS-driven transformation. G0S2 is known to regulate fat metabolism by attenuating adipose triglyceride lipase (ATGL), but repression of oncogene-induced transformation by G0S2 was independent of ATGL inhibition. Gene expression analysis revealed an upregulation of gene signatures associated with transformation, proliferation, and MYC targets in G0s2-null MEFs. RNAi-mediated ablation and pharmacologic inhibition of MYC abrogated oncogene-induced transformation of G0s2-null MEFs. Furthermore, we found that G0S2 was highly expressed in normal breast tissues compared with malignant tissue. Intriguingly, high levels of G0S2 were also associated with a decrease in breast cancer recurrence rates, especially in estrogen receptor-positive subtypes, and overexpression of G0S2 repressed the proliferation of breast cancer cells in vitro. Taken together, these findings indicate that G0S2 functions as a tumor suppressor in part by opposing MYC activity, prompting further investigation of the mechanisms by which G0S2 silencing mediates MYC-induced oncogenesis in other malignancies.
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