Shared extracellular vesicle miRNA profiles of matched ductal pancreatic adenocarcinoma organoids and blood plasma samples show the power of organoid technology

AbstractExtracellular vesicles (EV) are considered as a promising diagnostic tool for pancreatic ductal adenocarcinoma (PDAC), a disease with a poor 5-year survival that has not improved in the past years. PDAC patient-derived 3D organoids maintain the intratumoral cellular heterogeneity, characteristic for the tumor in vivo.Thus, they represent an ideal in vitro model system to study human cancers. Here we show that the miRNA cargo of EVs from PDAC organoids largely differs among patients. However, we detected a common set of EV miRNAs that were present in matched organoids and blood plasma samples of individual patients. Importantly, the levels of EV miR-21 and miR-195 were higher in PDAC blood EV preparations than in healthy controls, albeit we found no difference compared to chronic pancreatitis (CP) samples. In addition, here we report that the accumulation of collagen I, a characteristic change in the extracellular matrix (ECM) in both CP and PDAC, largely increases EV release from pancreatic ductal organoids. This provides a possible explanation why both CP and PDAC patient-derived plasma samples have an elevated amount of CD63 + EVs. Collectively, we show that PDAC patient-derived organoids represent a highly relevant model to analyze the cargo of tumor cell-derived EVs. Furthermore, we provide evidence that not only driver mutations, but also changes in the ECM may critically modify EV release from pancreatic ductal cells.

Download Full-text

ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice

Gastroenterology ◽

10.1053/j.gastro.2018.03.039 ◽

2018 ◽

Vol 155 (1) ◽

pp. 194-209.e2 ◽

Cited By ~ 23

Author(s):

Yoshito Kimura ◽

Akihisa Fukuda ◽

Satoshi Ogawa ◽

Takahisa Maruno ◽

Yutaka Takada ◽

...

Keyword(s):

Pancreatic Ductal Adenocarcinoma ◽

Ductal Adenocarcinoma ◽

Ductal Cells ◽

Pancreatic Ductal Cells

Download Full-text

Identification and Validation of Circulating Micrornas as Prognostic Biomarkers in Pancreatic Ductal Adenocarcinoma Patients Undergoing Surgical Resection

Journal of Clinical Medicine ◽

10.3390/jcm9082440 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2440

Author(s):

Natalia Gablo ◽

Karolina Trachtova ◽

Vladimir Prochazka ◽

Jan Hlavsa ◽

Tomas Grolich ◽

...

Keyword(s):

Blood Plasma ◽

Pancreatic Ductal Adenocarcinoma ◽

Surgical Resection ◽

Poor Prognosis ◽

Ductal Adenocarcinoma ◽

Small Rna Sequencing ◽

High Morbidity ◽

Plasma Samples ◽

Circulating Micrornas ◽

Patients With Poor Prognosis

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal and aggressive cancers with a less than 6% five-year survival rate. Circulating microRNAs (miRNAs) are emerging as a useful tool for non-invasive diagnosis and prognosis estimation in the various cancer types, including PDAC. Our study aimed to evaluate whether miRNAs in the pre-operative blood plasma specimen have the potential to predict the prognosis of PDAC patients. In total, 112 PDAC patients planned for surgical resection were enrolled in our prospective study. To identify prognostic miRNAs, we used small RNA sequencing in 24 plasma samples of PDAC patients with poor prognosis (overall survival (OS) < 16 months) and 24 plasma samples of PDAC patients with a good prognosis (OS > 20 months). qPCR validation of selected miRNA candidates was performed in the independent cohort of PDAC patients (n = 64). In the discovery phase of the study, we identified 44 miRNAs with significantly different levels in the plasma samples of the group of good and poor prognosis patients. Among these miRNAs, 23 showed lower levels, and 21 showed higher levels in plasma specimens from PDAC patients with poor prognosis. Eleven miRNAs were selected for the validation, but only miR-99a-5p and miR-365a-3p were confirmed to have significantly lower levels and miR-200c-3p higher levels in plasma samples of poor prognosis cases. Using the combination of these 3-miRNA levels, we were able to identify the patients with poor prognosis with sensitivity 85% and specificity 80% (Area Under the Curve = 0.890). Overall, 3-miRNA prognostic score associated with OS was identified in the pre-operative blood plasma samples of PDAC patients undergoing surgical resection. Following further independent validations, the detection of these miRNA may enable identification of PDAC patients who have no survival benefit from the surgical treatment, which is associated with the high morbidity rates.

Download Full-text

Faculty Opinions recommendation of Oncogenic KRas suppresses inflammation-associated senescence of pancreatic ductal cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.6649956.7482056 ◽

2010 ◽

Author(s):

Filippo Giancotti ◽

Tomoyo Okada

Keyword(s):

Ductal Cells ◽

Pancreatic Ductal Cells

Download Full-text

Faculty Opinions recommendation of Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726281818.793518427 ◽

2016 ◽

Author(s):

Anna Gloyn ◽

Nicola Beer

Keyword(s):

Proinflammatory Cytokines ◽

Ductal Cells ◽

Endocrine Differentiation ◽

Pancreatic Ductal Cells

Download Full-text

Faculty Opinions recommendation of Proinflammatory Cytokines Induce Endocrine Differentiation in Pancreatic Ductal Cells via STAT3-Dependent NGN3 Activation.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.726281818.793517289 ◽

2016 ◽

Author(s):

Beatriz Sosa-Pineda

Keyword(s):

Proinflammatory Cytokines ◽

Ductal Cells ◽

Endocrine Differentiation ◽

Pancreatic Ductal Cells

Download Full-text

Ductal Cell Reprogramming to Insulin-Producing Beta-Like Cells as a Potential Beta Cell Replacement Source for Chronic Pancreatitis

Current Stem Cell Research & Therapy ◽

10.2174/1574888x13666180918092729 ◽

2019 ◽

Vol 14 (1) ◽

pp. 65-74 ◽

Cited By ~ 7

Author(s):

Aravinth P. Jawahar ◽

Siddharth Narayanan ◽

Gopalakrishnan Loganathan ◽

Jithu Pradeep ◽

Gary C. Vitale ◽

...

Keyword(s):

Chronic Pancreatitis ◽

Beta Cell ◽

Lineage Tracing ◽

Clinical Tool ◽

Glucose Levels ◽

Ductal Cells ◽

Pancreatic Ductal Cells ◽

Insulin Producing Cells ◽

Ductal Cell ◽

Recent Advances

Islet cell auto-transplantation is a novel strategy for maintaining blood glucose levels and improving the quality of life in patients with chronic pancreatitis (CP). Despite the many recent advances associated with this therapy, obtaining a good yield of islet infusate still remains a pressing challenge. Reprogramming technology, by making use of the pancreatic exocrine compartment, can open the possibility of generating novel insulin-producing cells. Several lineage-tracing studies present evidence that exocrine cells undergo dedifferentiation into a progenitor-like state from which they can be manipulated to form insulin-producing cells. This review will present an overview of recent reports that demonstrate the potential of utilizing pancreatic ductal cells (PDCs) for reprogramming into insulin- producing cells, focusing on the recent advances and the conflicting views. A large pool of ductal cells is released along with islets during the human islet isolation process, but these cells are separated from the pure islets during the purification process. By identifying and improving existing ductal cell culture methods and developing a better understanding of mechanisms by which these cells can be manipulated to form hormone-producing islet-like cells, PDCs could prove to be a strong clinical tool in providing an alternative beta cell source, thus helping CP patients maintain their long-term glucose levels.

Download Full-text

Chylous Ascites, Unusual Association with Ductal Pancreatic Adenocarcinoma with Plasmacytoid Morphology: A Case Report and Literature Review

The Surgery Journal ◽

10.1055/s-0041-1728651 ◽

2021 ◽

Vol 07 (03) ◽

pp. e158-e162

Author(s):

Catalin Bogdan Satala ◽

Ioan Jung ◽

Tivadar Jr. Bara ◽

Vlad Tudorache ◽

Simona Gurzu

Keyword(s):

Pancreatic Cancer ◽

Tumor Cells ◽

Surgical Intervention ◽

Chylous Ascites ◽

Distal Portion ◽

Ductal Adenocarcinoma ◽

Lymph Vessels ◽

Lymphangiosis Carcinomatosa ◽

Ductal Pancreatic Adenocarcinoma ◽

Tumor Emboli

AbstractChylous ascites represents a relatively uncommon condition. In this paper, we present a case of chyloperitoneum associated with pancreatic ductal adenocarcinoma (PDAC) and a review of literature regarding chylous ascites. A 76-year-old male patient was admitted in emergency department with acute abdomen. A pancreatic cancer was suspected. Subtotal spleno-pancreatectomy, for a nodular mass infiltrating the mild and distal portion of the pancreas, was necessary. During surgical intervention in the peritoneal cavity, a moderate quantity of whitish and thick consistency fluid with milk-like appearance was observed to be accumulated. After examination of the fluid, chyloperitoneum was diagnosed. The histologic examination showed a PDAC, with multiple emboli in lymph vessels, with tumor cells with plasmacytoid morphology, diagnosed as lymphangiosis carcinomatosa. The patient died at 3 weeks after surgical intervention. In patients with pancreatic cancer and chylous ascites, suspicion of tumor-related blockage of the lymphatic flow should be suspected. Prognosis of PDAC should be evaluated not only based on the number of lymph node metastases, but also considering the number of lymph vessels with tumor emboli and the architecture of tumor cells. This is the first reported case of a PDAC with plasmacytoid morphology of lymphangiosis carcinomatosa.

Download Full-text

Alterations in lipid profile upon uterine fibroids and its recurrence

Scientific Reports ◽

10.1038/s41598-021-89859-0 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Narine M. Tonoyan ◽

Vitaliy V. Chagovets ◽

Natalia L. Starodubtseva ◽

Alisa O. Tokareva ◽

Konstantin Chingin ◽

...

Keyword(s):

Mass Spectrometry ◽

Blood Plasma ◽

Lipid Profile ◽

Plasma Levels ◽

Uterine Fibroids ◽

Control Group ◽

Cholesterol Esters ◽

Plasma Samples ◽

Diagnostic Models ◽

First Time

AbstractUterine fibroids (UF) is the most common (about 70% cases) type of gynecological disease, with the recurrence rate varying from 11 to 40%. Because UF has no distinct symptomatology and is often asymptomatic, the specific and sensitive diagnosis of UF as well as the assessment for the probability of UF recurrence pose considerable challenge. The aim of this study was to characterize alterations in the lipid profile of tissues associated with the first-time diagnosed UF and recurrent uterine fibroids (RUF) and to explore the potential of mass spectrometry (MS) lipidomics analysis of blood plasma samples for the sensitive and specific determination of UF and RUF with low invasiveness of analysis. MS analysis of lipid levels in the myometrium tissues, fibroids tissues and blood plasma samples was carried out on 66 patients, including 35 patients with first-time diagnosed UF and 31 patients with RUF. The control group consisted of 15 patients who underwent surgical treatment for the intrauterine septum. Fibroids and myometrium tissue samples were analyzed using direct MS approach. Blood plasma samples were analyzed using high performance liquid chromatography hyphened with mass spectrometry (HPLC/MS). MS data were processed by discriminant analysis with projection into latent structures (OPLS-DA). Significant differences were found between the first-time UF, RUF and control group in the levels of lipids involved in the metabolism of glycerophospholipids, sphingolipids, lipids with an ether bond, triglycerides and fatty acids. Significant differences between the control group and the groups with UF and RUF were found in the blood plasma levels of cholesterol esters, triacylglycerols, (lyso) phosphatidylcholines and sphingomyelins. Significant differences between the UF and RUF groups were found in the blood plasma levels of cholesterol esters, phosphotidylcholines, sphingomyelins and triacylglycerols. Diagnostic models based on the selected differential lipids using logistic regression showed sensitivity and specificity of 88% and 86% for the diagnosis of first-time UF and 95% and 79% for RUF, accordingly. This study confirms the involvement of lipids in the pathogenesis of uterine fibroids. A diagnostically significant panel of differential lipid species has been identified for the diagnosis of UF and RUF by low-invasive blood plasma analysis. The developed diagnostic models demonstrated high potential for clinical use and further research in this direction.

Download Full-text