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A multi-omics approach identifies pancreatic cancer cell extracellular vesicles as mediators of the unfolded protein response in normal pancreatic epithelial cells

ABSTRACT: The early molecular mechanisms of pancreas cancer development remain elusive. A key driver of poor patient outcomes remains late-stage diagnosis of disease, typically when patients present with pancreatic ductal adenocarcinoma (PDAC). Currently, no diagnostics exist to identify indolent disease. It is crucial to identify the early molecular events that drive the transformation of naïve cells to a neoplastic phenotype. Extracellular vesicles (EVs) are nanometer sized lipid-bilayer particles released from cells of almost all known tissue types. EVs carry an array of biomolecules which are internalized by neighboring and distant cells, critical for facilitating intracellular communication. Although cancer derived EVs impact a myriad of cancer progression events including tumor proliferation, immune escape, and metastasis, their role in mediating early onset of PDAC is unknown. In this study, we report on alterations in the gene expression profiles of normal pancreatic epithelial cells upon internalization of PDAC cell derived EVs (cEVs). Leveraging a layered multi-omics approach, we show that cEVs induce endoplasmic reticulum (ER) stress and the unfolded protein response in recipient normal pancreatic epithelial cells within 24 hours. Consequently, cEV treated cells demonstrated increased proliferation. cEV cargo was enriched for an array of biomolecules which can induce or regulate ER stress and the UPR, including lipid species esterified to palmitic acid, sphingomyelins, metabolites which regulate tRNA charging and protein trafficking and degradation proteins. These results highlight a role for pancreatic cancer cEVs to induce stress in recipient normal pancreas cells; studying these genetic, metabolic and proteomic perturbations may lead to valuable insight to disease etiology and early biomarker identification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181625 | GEO | 2022/06/23

REPOSITORIES: GEO

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Project description:Background: With less than a 5% survival rate pancreatic adenocarcinoma (PDAC) is almost uniformly lethal. In order to make a significant impact on survival of patients with this malignancy, it is necessary to diagnose the disease early, when curative surgery is still possible. Detailed knowledge of the natural history of the disease and molecular events leading to its progression is therefore critical. Methods and Findings: We have analysed the precursor lesions, PanINs, from prophylactic pancreatectomy specimens of patients from four different kindreds with high risk of familial pancreatic cancer who were treated for histologically proven PanIN-2/3. Thus, the material was procured before pancreatic cancer has developed, rather than from PanINs in a tissue field that already contains cancer. Genome-wide transcriptional profiling using such unique specimens was performed. Bulk frozen sections displaying the most extensive but not microdissected PanIN-2/3 lesions were used in order to obtain the holistic view of both the precursor lesions and their microenvironment. A panel of 76 commonly dysregulated genes that underlie neoplastic progression from normal pancreas to PanINs and PDAC were identified. In addition to shared genes some differences between the PanINs of individual families as well as between the PanINs and PDACs were also seen. This was particularly pronounced in the stromal and immune responses. Conclusions: Our comprehensive analysis of precursor lesions without the invasive component provides the definitive molecular proof that PanIN lesions beget cancer from a molecular standpoint. We demonstrate the need for accumulation of transcriptomic changes during the progression of PanIN to PDAC, both in the epithelium and in the surrounding stroma. An identified 76-gene signature of PDAC progression presents a rich candidate pool for the development of early diagnostic and/or surveillance markers as well as potential novel preventive/therapeutic targets for both familial and sporadic pancreatic adenocarcinoma. Gene expression of 13 PanIN samples was compared to profiling data of whole biopsies from normal donor pancreas (N1 to 4, two replicated samples) and sporadic PDAC (PDAC1 to 6).Ttwo PDAC samples (PDAC 3 and 4) and a replicate of one normal specimen (N4) were removed during the hybridisation quality assessment.