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PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin 1

ABSTRACT: Endometrial epithelia (EE) are known to harbor cancer driver mutations in the absence of any pathologies, including mutations in PIK3CA. Insulin plays an important role in regulating uterine metabolism during pregnancy, and hyperinsulinemia is associated with conditions impacting fertility. Hyperinsulinemia also promotes cancer, but the direct action of insulin on mutated EE is unknown. Here, we treated EE cells carrying the PIK3CAH1047R oncogene with insulin and examined differential transcriptomes by RNA-seq. While cells responded to insulin, the magnitude of differential gene expression (DGE) was 9 times greater in PIK3CAH1047R cells, representing a synergistic effect between insulin signaling and PIK3CAH1047R. Interferon signaling and the unfolded protein response (UPR) were enriched pathways among affected genes. Insulin treatment in normal cells activated normal endoplasmic reticulum stress (ERS) response programs, while PIK3CAH1047R cells activated programs necessary to avoid ERS-induced apoptosis. PIK3CAH1047R expression alone resulted in fewer differentially expressed genes, however, top among these was overexpression of Viperin (RSAD2), which is involved in viral response and upregulated in the endometrium during early pregnancy. The transcriptional changes induced by insulin in PIK3CAH1047R cells were rescued by knockdown of Viperin, while overexpression alone was insufficient to induce a DGE response to insulin, suggesting that Viperin is necessary but not sufficient for the synergistic effect of PIK3CAH1047R and insulin treatment. We identified interferon signaling, viral response, and protein targeting pathways that are induced by insulin but dependent on Viperin in PIK3CAH1047R mutant cells. These results suggest a differential response to insulin signaling in mutated EE.

ORGANISM(S): Homo sapiens

PROVIDER: GSE215259 | GEO | 2023/05/09

REPOSITORIES: GEO

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Project description:The rising incidence of pancreatic cancer is largely driven by the skyrocketing prevalence of obesity and type 2 diabetes (T2D). Hyperinsulinemia is a cardinal feature of both conditions, and is independently associated with increased cancer incidence and mortality. Our previous studies demonstrated that genetically reducing insulin production suppressed formation of pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in mice with mutant Kras. However, we found that hyperinsulinemia affected many cell types in the pancreatic microenvironment. Thus, it remained unclear whether hyperinsulinemia exerted its effects directly on the cells that give rise to PanINs or indirectly on the tumor microenvironment, and molecular mechanisms involved were unknown. Here, we tested whether insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are necessary for the effects of hyperinsulinemia on obesity-associated pancreatic cancer development. Loss of Insr in KrasG12D-expressing acinar cells did not prevent hyperinsulinemia or weight gain associated with high fat diet (HFD) consumption in mice. However, solely reducing Insr in KrasG12D-expressing acinar cells significantly reduced formation of PanIN and tumors, in a gene dose-dependent manner. Mechanistically, proteomic analyses showed that hyperinsulinemia acts through Insr to drive the excess production of digestive enzymes in acinar cells by modulating the activity of the spliceosome, ribosome, and secretory machinery. This resulted in increased inflammation, which was abrogated by acinar-specific Insr knockout. We confirmed that insulin increased the conversion of wild-type acinar cells into acinar-to-ductal metaplasia (ADM) in a trypsin-dependent manner. Collectively, these data demonstrate that hyperinsulinemia acting via acinar cells insulin receptors promotes inflammatory conditions that cooperate with Kras signaling to increase the risk of developing pancreatic cancer, mechanistically linking obesity and pancreatic cancer.

Project description:Sanchez2017 - Inflammatory responses during acute hyperinsulinemia This model is described in the article: The CD4+ T cell regulatory network mediates inflammatory responses during acute hyperinsulinemia: a simulation study Mariana E. Martinez-Sanchez, Marcia Hiriart, Elena R. Alvarez-Buylla BMC Systems Biology Abstract: Obesity is frequently linked to insulin resistance, high insulin levels, chronic inflammation, and alterations in the behaviour of CD4+ T cells. Despite the biomedical importance of this condition, the system-level mechanisms that alter CD4+ T cell differentiation and plasticity are not well understood. We model how hyperinsulinemia alters the dynamics of the CD4+ T regulatory network, and this, in turn, modulates cell differentiation and plasticity. Different polarizing microenvironments are simulated under basal and high levels of insulin to assess impacts on cell-fate attainment and robustness in response to transient perturbations. In the presence of high levels of insulin Th1 and Th17 become more stable to transient perturbations, and their basin sizes are augmented, Tr1 cells become less stable or disappear, while TGF? producing cells remain unaltered. Hence, the model provides a dynamic system-level framework and explanation to further understand the documented and apparently paradoxical role of TGF? in both inflammation and regulation of immune responses, as well as the emergence of the adipose Treg phenotype. Furthermore, our simulations provide new predictions on the impact of the microenvironment in the coexistence of the different cell types, suggesting that in pro-Th1, pro-Th2 and pro-Th17 environments effector and regulatory cells can coexist, but that high levels of insulin severely diminish regulatory cells, especially in a pro-Th17 environment. This work provides a first step towards a system-level formal and dynamic framework to integrate further experimental data in the study of complex inflammatory diseases. This model is hosted on BioModels Database and identified by: MODEL1606020000. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

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PIK3CA mutation in endometrial epithelia promotes Viperin-dependent inflammatory response to insulin 1

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