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Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

ABSTRACT: Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered specific alterations in DNA methylation and transcription as well as in signaling pathways involved in tumor-stromal cross-talk. The analysis of these pathways indicates therapeutic opportunities for targeting both compartments and their interactions. In particular, we show that inhibiting NPC1L1 with Ezetimibe, a clinically available drug, might be an efficient approach for treating pancreatic cancers. These findings uncover the complex and diverse interplay between PDAC tumors and the stroma and demonstrate the pivotal role of xenografts for drug discovery and relevance to PDAC.

SUBMITTER: Nicolle R

PROVIDER: S-EPMC6082139 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Nicolle Rémy R Blum Yuna Y Marisa Laetitia L Loncle Celine C Gayet Odile O Moutardier Vincent V Turrini Olivier O Giovannini Marc M Bian Benjamin B Bigonnet Martin M Rubis Marion M Elarouci Nabila N Armenoult Lucile L Ayadi Mira M Duconseil Pauline P Gasmi Mohamed M Ouaissi Mehdi M Maignan Aurélie A Lomberk Gwen G Boher Jean-Marie JM Ewald Jacques J Bories Erwan E Garnier Jonathan J Goncalves Anthony A Poizat Flora F Raoul Jean-Luc JL Secq Veronique V Garcia Stephane S Grandval Philippe P Barraud-Blanc Marine M Norguet Emmanuelle E Gilabert Marine M Delpero Jean-Robert JR Roques Julie J Calvo Ezequiel E Guillaumond Fabienne F Vasseur Sophie S Urrutia Raul R de Reyniès Aurélien A Dusetti Nelson N Iovanna Juan J

Cell reports 20171101 9

Preclinical models based on patient-derived xenografts have remarkable specificity in distinguishing transformed human tumor cells from non-transformed murine stromal cells computationally. We obtained 29 pancreatic ductal adenocarcinoma (PDAC) xenografts from either resectable or non-resectable patients (surgery and endoscopic ultrasound-guided fine-needle aspirate, respectively). Extensive multiomic profiling revealed two subtypes with distinct clinical outcomes. These subtypes uncovered speci ...[more]

PMID: 29186684

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Project description:BackgroundType 2 diabetes mellitus (T2DM) known as non-insulin-dependent diabetes mellitus, which is increasingly acknowledged as being associated with an increased risk for a series of cancers. Pancreatic cancer is currently the fourth most common cause of cancer-related mortality, which has been proved to be worsened by internal diabetic condition. However, the underlying molecular mechanisms are less addressed. Furthermore, current knowledge revealed that therapeutic strategy by anti-diabetes for pancreatic cancer under diabetes condition have no satisfactory efficacy, and nor by chemotherapy in our study.MethodsTo clarify these mysteries and widen our knowledge, both obesity-associated and non-obese-associated T2DM mouse models were generated by chemical induction with streptozotocin (STZ) and leptin receptor knockout (db/db) in mice. Then, the process of tumor progression was researched, and the gene expression profiling of pancreatic cancer in mice was performed using RNA-seq.ResultsOur results showed that pancreatic cancer malignancy was increased with notable proliferation and metastatic potential in two diabetic mice model. Totally, 136 and 64 significantly differentially expressed genes (DEGs) were identified in STZ and db/db mice by transcriptomic analysis. The results also suggested that different carcinogenesis-related genes and potential molecular mechanisms contribute to the malignancy of pancreatic cancer in obesity-associated and non-obesity-associated T2DM. In obesity-associated db/db mice, the GO subcategories associated with most of the genes with downregulated expression are involved in the immune response. However, in non-obesity-associated STZ mice, in addition to the immune response category, the enriched subcategories also included angiogenesis and the extracellular matrix. While, two genes respectively encoding MMP-2 and MMP-9 were simultaneously abnormal up-regulated in pancreatic cancer tissue from diabetic mice of both STZ and db/db, that could act as potential therapeutic targets for significantly suppressing the malignant progression. Furthermore, an optimizing therapeutic strategy was further proposed that combining MMP-2/9 inhibitor with gemcitabine significantly enhanced anti-tumor effects on pancreatic cancer under diabetic condition, providing a theoretical basis for clinical applications.ConclusionsGenerally, this study provides a comprehensive insight into diabetes as a risk factor for pancreatic cancer and has the potential to guide the development of enhanced treatment strategies.

Dataset Information

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

Publications

Pancreatic Adenocarcinoma Therapeutic Targets Revealed by Tumor-Stroma Cross-Talk Analyses in Patient-Derived Xenografts.

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