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A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest Plasticity.
Schmidtlein, Paula M; Volz, Clara; Braun, Rüdiger; Thürling, Isabel; Lapshyna, Olha; Wellner, Ulrich F; Konukiewitz, Björn; Lehnert, Hendrik; Marquardt, Jens-Uwe; Ungefroren, Hendrik.
Afiliação
  • Schmidtlein PM; First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Volz C; First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Braun R; Clinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Thürling I; First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Lapshyna O; Clinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Wellner UF; Clinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Konukiewitz B; Institute of Pathology, Campus Kiel, University Hospital Schleswig-Holstein, D-24105 Kiel, Germany.
  • Lehnert H; University of Salzburg, A-5020 Salzburg, Austria.
  • Marquardt JU; First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
  • Ungefroren H; First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, Germany.
Cancers (Basel) ; 13(18)2021 Sep 17.
Article em En | MEDLINE | ID: mdl-34572891
ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and therapy-resistant cancer types which is largely due to tumor heterogeneity, cancer cell de-differentiation, and early metastatic spread. The major molecular subtypes of PDAC are designated classical/epithelial (E) and quasi-mesenchymal (QM) subtypes, with the latter having the worst prognosis. Epithelial-mesenchymal transition (EMT) and the reverse process, mesenchymal-epithelial transition (MET), are involved in regulating invasion/metastasis and stem cell generation in cancer cells but also early pancreatic endocrine differentiation or de-differentiation of adult pancreatic islet cells in vitro, suggesting that pancreatic ductal exocrine and endocrine cells share common EMT programs. Using a panel of PDAC-derived cell lines classified by epithelial/mesenchymal expression as either E or QM, we compared their trans-differentiation (TD) potential to endocrine progenitor or ß cell-like cells since studies with human pancreatic cancer cells for possible future TD therapy in PDAC patients are not available so far. We observed that QM cell lines responded strongly to TD culture using as inducers 5'-aza-2'-deoxycytidine or growth factors/cytokines, while their E counterparts were refractory or showed only a weak response. Moreover, the gain of plasticity was associated with a decrease in proliferative and migratory activities and was directly related to epigenetic changes acquired during selection of a metastatic phenotype as revealed by TD experiments using the paired isogenic COLO 357-L3.6pl model. Our data indicate that a QM phenotype in PDAC coincides with increased plasticity and heightened trans-differentiation potential to activate a pancreatic ß cell-specific transcriptional program. We strongly assume that this specific biological feature has potential to be exploited clinically in TD-based therapy to convert metastatic PDAC cells into less malignant or even benign cells.
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Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2021 Tipo de documento: Article