Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease, therefore stratification of patients is essential to predict their responses to therapies and to choose the best treatment. PDAC-derived organoids were produced from PDTX and Endoscopic Ultrasound-Guided Fine-Needle Aspiration (EUS-FNA) biopsies. A signature based on 16 genes targets of the c-MYC oncogene was applied to classify samples into two sub-groups with distinctive phenotypes named MYC-high and MYC-low. The analysis of 9 PDTXs and the corresponding derived organoids revealed that this signature which was previously designed from PDTX is transferable to the organoid model. Primary organoids from 24 PDAC patients were treated with NHWD-870 or JQ1, two inhibitors of c-MYC transcription. Notably, the comparison of their effect between the two sub-groups showed that both compounds are more efficient in MYC-high than in MYC-low samples, being NHWD-870 the more potent treatment. In conclusion, this study shows that the molecular signatures could be applied to organoids obtained directly from PDAC patients to predict the treatment response and could help to take the more appropriate therapeutic decision for each patient in a clinical timeframe.
Highlights
Pancreatic ductal adenocarcinoma (PDAC) is the 12th most commonly occurring cancer in men and the 11th in women
We derived organoids from Patient-derived tumor xenografts (PDTX) obtained from PDAC tumors and compared the phenotype of both models by morphologic and transcriptomic criteria
From these data we may assume that expression of the genes associated to the MYC-signature is strongly conserved between PDTX and their derived organoids
Summary
Pancreatic ductal adenocarcinoma (PDAC) is the 12th most commonly occurring cancer in men and the 11th in women. One promising approach could be to determine novel therapy response biomarkers focused on the pathways that are critical for tumor growth and progression In this context, the transcription factor c-MYC drives the expression of up to 1,500 genes involved in proliferation, cell metabolism, and apoptosis [8,9,10]. The transcription factor c-MYC drives the expression of up to 1,500 genes involved in proliferation, cell metabolism, and apoptosis [8,9,10] This oncogene is implicated in the pathogenesis of one-third of all human malignancies and concerning PDAC etiology, c-MYC was found amplified in more than 30% of them [11]. This increased sensitivity is mediated by a combination of cell cycle arrest followed by an increase in apoptosis rate, in several in vivo and in vitro PDAC models like PDTX, 2D cell monolayer and 3D aggregates [14]
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