Organotypic slice cultures of pancreatic ductal adenocarcinoma as preclinical model for development of personalized treatment strategies

2021 ◽  
Author(s):  
R Braun ◽  
O Lapshyna ◽  
B Heckelmann ◽  
S Eckelmann ◽  
L Bolm ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Personalized Treatment ◽  
Ductal Adenocarcinoma ◽  
Preclinical Model ◽  
Organotypic Slice Cultures

Morphological classification of pancreatic ductal adenocarcinoma that predicts molecular subtypes and correlates with clinical outcome

Gut ◽  
2019 ◽  
Vol 69 (2) ◽  
pp. 317-328 ◽  
Author(s):  
Sangeetha N Kalimuthu ◽  
Gavin W Wilson ◽  
Robert C Grant ◽  
Matthew Seto ◽  
Grainne O’Kane ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Subtypes ◽  
Differentially Expressed Gene ◽  
Biological Significance ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Rna Seq ◽  
Gene Signatures ◽  
Significant Difference ◽  
Morphological Patterns

IntroductionTranscriptional analyses have identified several distinct molecular subtypes in pancreatic ductal adenocarcinoma (PDAC) that have prognostic and potential therapeutic significance. However, to date, an indepth, clinicomorphological correlation of these molecular subtypes has not been performed. We sought to identify specific morphological patterns to compare with known molecular subtypes, interrogate their biological significance, and furthermore reappraise the current grading system in PDAC.DesignWe first assessed 86 primary, chemotherapy-naive PDAC resection specimens with matched RNA-Seq data for specific, reproducible morphological patterns. Differential expression was applied to the gene expression data using the morphological features. We next compared the differentially expressed gene signatures with previously published molecular subtypes. Overall survival (OS) was correlated with the morphological and molecular subtypes.ResultsWe identified four morphological patterns that segregated into two components (‘gland forming’ and ‘non-gland forming’) based on the presence/absence of well-formed glands. A morphological cut-off (≥40% ‘non-gland forming’) was established using RNA-Seq data, which identified two groups (A and B) with gene signatures that correlated with known molecular subtypes. There was a significant difference in OS between the groups. The morphological groups remained significantly prognostic within cancers that were moderately differentiated and classified as ‘classical’ using RNA-Seq.ConclusionOur study has demonstrated that PDACs can be morphologically classified into distinct and biologically relevant categories which predict known molecular subtypes. These results provide the basis for an improved taxonomy of PDAC, which may lend itself to future treatment strategies and the development of deep learning models.

scholarly journals Unraveling Tumor Heterogeneity by Using DNA Barcoding Technologies to Develop Personalized Treatment Strategies in Advanced-Stage PDAC

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4187
Author(s):  
Philip Dujardin ◽  
Anna K. Baginska ◽  
Sebastian Urban ◽  
Barbara M. Grüner
Keyword(s):  
Dna Barcoding ◽  
Tumor Heterogeneity ◽  
Clonal Evolution ◽  
Treatment Strategies ◽  
Therapy Resistance ◽  
Personalized Treatment ◽  
Ductal Adenocarcinoma ◽  
Cell Pool ◽  
Study Heterogeneity ◽  
A Cell

Tumor heterogeneity is a hallmark of many solid tumors, including pancreatic ductal adenocarcinoma (PDAC), and an inherent consequence of the clonal evolution of cancers. As such, it is considered the underlying concept of many characteristics of the disease, including the ability to metastasize, adapt to different microenvironments, and to develop therapy resistance. Undoubtedly, the high mortality of PDAC can be attributed to a high extent to these properties. Despite its apparent importance, studying tumor heterogeneity has been a challenging task, mainly due to its complexity and lack of appropriate methods. However, in recent years molecular DNA barcoding has emerged as a sophisticated tool that allows mapping of individual cells or subpopulations in a cell pool to study heterogeneity and thus devise new personalized treatment strategies. In this review, we provide an overview of genetic and non-genetic inter- and intra-tumor heterogeneity and its impact on (personalized) treatment strategies in PDAC and address how DNA barcoding technologies work and can be applied to study this clinically highly relevant question.

Organotypic slice cultures of pancreatic ductal adenocarcinoma preserve the tumor microenvironment and provide a platform for drug response

Pancreatology ◽  
2018 ◽  
Vol 18 (8) ◽  
pp. 913-927 ◽  
Author(s):  
Chae Yoon Lim ◽  
Jae Hyuck Chang ◽  
Won Sun Lee ◽  
Kang Min Lee ◽  
Young Chul Yoon ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Drug Response ◽  
Ductal Adenocarcinoma ◽  
Organotypic Slice Cultures

scholarly journals Targeted Therapies for Pancreatic Cancer: Overview of Current Treatments and New Opportunities for Personalized Oncology

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 799 ◽  
Author(s):  
Cédric Leroux ◽  
Georgia Konstantinidou
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Patient Outcomes ◽  
Targeted Therapies ◽  
Median Overall Survival ◽  
Advanced Disease ◽  
Treatment Strategies ◽  
Ductal Adenocarcinoma ◽  
Cancer Associated Fibroblasts ◽  
Personalized Oncology

Cytotoxic chemotherapy remains the only treatment option for most pancreatic ductal adenocarcinoma patients. Currently, the median overall survival of patients with advanced disease rarely exceeds 1 year. The complex network of pancreatic cancer composed of immune cells, endothelial cells, and cancer-associated fibroblasts confers intratumoral and intertumoral heterogeneity with distinct proliferative and metastatic propensity. This heterogeneity can explain why tumors do not behave uniformly and are able to escape therapy. The advance in technology of whole-genome sequencing has now provided the possibility of identifying every somatic mutation, copy-number change, and structural variant in a given cancer, giving rise to personalized targeted therapies. In this review, we provide an overview of the current and emerging treatment strategies in pancreatic cancer. By highlighting new paradigms in pancreatic ductal adenocarcinoma treatment, we hope to stimulate new thoughts for clinical trials aimed at improving patient outcomes.

Molecular and immunohistochemical subtyping of pancreatic ductal adenocarcinoma (PDAC): A step towards personalized treatment and individual prognosis

Pancreatology ◽  
2013 ◽  
Vol 13 (3) ◽  
pp. S86
Author(s):  
Anna Melissa Schlitter ◽  
Angela Segler ◽  
Björn Konukiewitz ◽  
Bo Kong ◽  
Jäger Karsten ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Personalized Treatment ◽  
Ductal Adenocarcinoma

Low expression of DDX5 is associated with poor prognosis in patients with pancreatic ductal adenocarcinoma

2020 ◽  
pp. jclinpath-2020-207002
Author(s):  
Masashi Morimachi ◽  
Kenichi Hirabayashi ◽  
Yumi Takanashi ◽  
Aya Kawanishi ◽  
Tsubasa Saika ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Islet Cells ◽  
Tumour Size ◽  
Treatment Strategies ◽  
Immunohistochemical Analysis ◽  
Ductal Adenocarcinoma ◽  
Clinicopathological Parameters ◽  
Pancreatic Ducts ◽  
Venous Involvement ◽  
Dead Box

AimsPancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies. Hence, there is a need for new markers and treatment strategies. P68/DEAD box protein 5 (DDX5) is an ATP-dependent RNA helicase of the DEAD box protein family. It is a prognostic marker for several cancers. In this study, we aimed to evaluate the expression and clinical relevance of DDX5 in PDAC.MethodsDDX5 expression in tissue microarray blocks containing 230 PDAC samples was examined using immunohistochemical analysis. DDX5 expression was considered high when more than 50% of the cells were stained and low when less than 50% of the cells were stained. We investigated the association between DDX5 expression and clinicopathological parameters, including patient survival.ResultsThe nuclei of normal pancreatic ducts, normal acinar cells and PDAC cells were stained positive for DDX5 although the intensity and distribution of DDX5 expression varied. Islet cells showed strong and diffuse staining of DDX5. DDX5 expression was low and high in 148 (64.3%) and 82 cases (35.7%), respectively. Low DDX5 expression was significantly associated with an advanced pT factor (pT2–pT3: tumour size,>20 mm), lymphatic involvement, advanced tumour-node-metastasis (TNM) stage (stages IIB, III, and IV), and venous involvement. In addition, the multivariate analysis revealed that DDX5 expression is an independent prognostic factor for PDAC.ConclusionThese results suggest that DDX5 plays an important role in tumour invasiveness and PDAC prognosis.

scholarly journals Molecular Characteristics of Pancreatic Ductal Adenocarcinoma

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Niki A. Ottenhof ◽  
Roeland F. de Wilde ◽  
Anirban Maitra ◽  
Ralph H. Hruban ◽  
G. Johan A. Offerhaus
Keyword(s):  
Pancreatic Cancer ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Treatment Strategies ◽  
Genetic Alterations ◽  
Targeted Treatment ◽  
Ductal Adenocarcinoma ◽  
Molecular Characteristics ◽  
Genetic Characteristics ◽  
Complete Sequencing ◽  
Made In

Pancreatic cancer is an almost universally lethal disease and despite extensive research over the last decades, this has not changed significantly. Nevertheless, much progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) suggesting that different therapeutic strategies based on these new insights are forthcoming. Increasing focus exists on designing the so-called targeted treatment strategies in which the genetic characteristics of a tumor guide therapy. In the past, the focus of research was on identifying the most frequently affected genes in PDAC, but with the complete sequencing of the pancreatic cancer genome the focus has shifted to defining the biological function that the altered genes play. In this paper we aimed to put the genetic alterations present in pancreatic cancer in the context of their role in signaling pathways. In addition, this paper provides an update of the recent advances made in the development of the targeted treatment approach in PDAC.

scholarly journals Exploring the Complementarity of Pancreatic Ductal Adenocarcinoma Preclinical Models

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2473
Author(s):  
Owen Hoare ◽  
Nicolas Fraunhoffer ◽  
Abdessamad Elkaoutari ◽  
Odile Gayet ◽  
Martin Bigonnet ◽  
...  
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Drug Sensitivity ◽  
In Vitro Models ◽  
Ductal Adenocarcinoma ◽  
Preclinical Model ◽  
Preclinical Models ◽  
Clinical Reality ◽  
First Time

Purpose: Compare pancreatic ductal adenocarcinoma (PDAC), preclinical models, by their transcriptome and drug response landscapes to evaluate their complementarity. Experimental Design: Three paired PDAC preclinical models—patient-derived xenografts (PDX), xenograft-derived pancreatic organoids (XDPO) and xenograft-derived primary cell cultures (XDPCC)—were derived from 20 patients and analyzed at the transcriptomic and chemosensitivity level. Transcriptomic characterization was performed using the basal-like/classical subtyping and the PDAC molecular gradient (PAMG). Chemosensitivity for gemcitabine, irinotecan, 5-fluorouracil and oxaliplatin was established and the associated biological pathways were determined using independent component analysis (ICA) on the transcriptome of each model. The selection criteria used to identify the different components was the chemosensitivity score (CSS) found for each drug in each model. Results: PDX was the most dispersed model whereas XDPO and XDPCC were mainly classical and basal-like, respectively. Chemosensitivity scoring determines that PDX and XDPO display a positive correlation for three out of four drugs tested, whereas PDX and XDPCC did not correlate. No match was observed for each tumor chemosensitivity in the different models. Finally, pathway analysis shows a significant association between PDX and XDPO for the chemosensitivity-associated pathways and PDX and XDPCC for the chemoresistance-associated pathways. Conclusions: Each PDAC preclinical model possesses a unique basal-like/classical transcriptomic phenotype that strongly influences their global chemosensitivity. Each preclinical model is imperfect but complementary, suggesting that a more representative approach of the clinical reality could be obtained by combining them. Translational Relevance: The identification of molecular signatures that underpin drug sensitivity to chemotherapy in PDAC remains clinically challenging. Importantly, the vast majority of studies using preclinical in vivo and in vitro models fail when transferred to patients in a clinical setting despite initially promising results. This study presents for the first time a comparison between three preclinical models directly derived from the same patients. We show that their applicability to preclinical studies should be considered with a complementary focus, avoiding tumor-based direct extrapolations, which might generate misleading conclusions and consequently the overlook of clinically relevant features.

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