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
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-me...
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MDPI AG
2021-09-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/13/18/4663 |
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| author | Paula M. Schmidtlein Clara Volz Rüdiger Braun Isabel Thürling Olha Lapshyna Ulrich F. Wellner Björn Konukiewitz Hendrik Lehnert Jens-Uwe Marquardt Hendrik Ungefroren |
| author_facet | Paula M. Schmidtlein Clara Volz Rüdiger Braun Isabel Thürling Olha Lapshyna Ulrich F. Wellner Björn Konukiewitz Hendrik Lehnert Jens-Uwe Marquardt Hendrik Ungefroren |
| author_sort | Paula M. Schmidtlein |
| collection | DOAJ |
| description | 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 β 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 β 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. |
| first_indexed | 2024-03-10T07:50:05Z |
| format | Article |
| id | doaj.art-2e3015c15dde4909ac6d9b44db7c0960 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T07:50:05Z |
| publishDate | 2021-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2e3015c15dde4909ac6d9b44db7c09602023-11-22T12:18:42ZengMDPI AGCancers2072-66942021-09-011318466310.3390/cancers13184663A Comparative Endocrine Trans-Differentiation Approach to Pancreatic Ductal Adenocarcinoma Cells with Different EMT Phenotypes Identifies Quasi-Mesenchymal Tumor Cells as Those with Highest PlasticityPaula M. Schmidtlein0Clara Volz1Rüdiger Braun2Isabel Thürling3Olha Lapshyna4Ulrich F. Wellner5Björn Konukiewitz6Hendrik Lehnert7Jens-Uwe Marquardt8Hendrik Ungefroren9First Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyFirst Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyClinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyFirst Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyClinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyClinic for Surgery, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyInstitute of Pathology, Campus Kiel, University Hospital Schleswig-Holstein, D-24105 Kiel, GermanyUniversity of Salzburg, A-5020 Salzburg, AustriaFirst Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyFirst Department of Medicine, Campus Lübeck, University Hospital Schleswig-Holstein, D-23538 Lübeck, GermanyPancreatic 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 β 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 β 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.https://www.mdpi.com/2072-6694/13/18/4663pancreatic ductal adenocarcinomaplasticityquasi-mesenchymalepithelialtrans-differentiationendocrine |
| spellingShingle | Paula M. Schmidtlein Clara Volz Rüdiger Braun Isabel Thürling Olha Lapshyna Ulrich F. Wellner Björn Konukiewitz Hendrik Lehnert Jens-Uwe Marquardt Hendrik Ungefroren 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 Cancers pancreatic ductal adenocarcinoma plasticity quasi-mesenchymal epithelial trans-differentiation endocrine |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | comparative endocrine trans differentiation approach to pancreatic ductal adenocarcinoma cells with different emt phenotypes identifies quasi mesenchymal tumor cells as those with highest plasticity |
| topic | pancreatic ductal adenocarcinoma plasticity quasi-mesenchymal epithelial trans-differentiation endocrine |
| url | https://www.mdpi.com/2072-6694/13/18/4663 |
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