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Bcl3 Couples Cancer...
Bcl3 Couples Cancer Stem Cell Enrichment With Pancreatic Cancer Molecular Subtypes
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Ai, Jiaoyu (author)
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Wörmann, Sonja M. (author)
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Görgülü, Kıvanç (author)
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Vallespinos, Mireia (author)
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Zagorac, Sladjana (author)
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Alcala, Sonia (author)
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Wu, Nan (author)
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Kabacaoglu, Derya (author)
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Berninger, Alexandra (author)
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Navarro, Diego (author)
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Kaya-Aksoy, Ezgi (author)
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Ruess, Dietrich A. (author)
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Ciecielski, Katrin J. (author)
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Kowalska, Marlena (author)
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Demir, Ihsan Ekin (author)
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Ceyhan, Güralp O. (author)
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Heid, Irina (author)
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Braren, Rickmer (author)
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Riemann, Marc (author)
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Schreiner, Sabrina (author)
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Hofmann, Samuel (author)
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- Kutschke, Maria (author)
- Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
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- Jastroch, Martin (author)
- Stockholms universitet,Institutionen för molekylär biovetenskap, Wenner-Grens institut
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Slotta-Huspenina, Julia (author)
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Muckenhuber, Alexander (author)
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Schlitter, Anna Melissa (author)
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Schmid, Roland M. (author)
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Steiger, Katja (author)
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Diakopoulos, Kalliope N. (author)
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Lesina, Marina (author)
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Sainz Jr, Bruno (author)
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Algül, Hana (author)
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(creator_code:org_t)
- Elsevier BV, 2021
- 2021
- English.
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In: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 161:1, s. 318-332
- Related links:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
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- Background & Aims: The existence of different subtypes of pancreatic ductal adenocarcinoma (PDAC) and their correlation with patient outcome have shifted the emphasis on patient classification for better decision-making algorithms and personalized therapy. The contribution of mechanisms regulating the cancer stem cell (CSC) population in different subtypes remains unknown.Methods: Using RNA-seq, we identified B-cell CLL/lymphoma 3 (BCL3), an atypical nf-κb signaling member, as differing in pancreatic CSCs. To determine the biological consequences of BCL3 silencing in vivo and in vitro, we generated bcl3-deficient preclinical mouse models as well as murine cell lines and correlated our findings with human cell lines, PDX models, and 2 independent patient cohorts. We assessed the correlation of bcl3 expression pattern with clinical parameters and subtypes.Results: Bcl3 was significantly down-regulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via BCL3 genetic knockout enhanced tumor burden, metastasis, epithelial to mesenchymal transition, and reduced overall survival. Fluorescence-activated cell sorting analyses, together with oxygen consumption, sphere formation, and tumorigenicity assays, all indicated that BCL3 loss resulted in CSC compartment expansion promoting cellular dedifferentiation. Overexpression of BCL3 in human PDXs diminished tumor growth by significantly reducing the CSC population and promoting differentiation. Human PDACs with low BCL3 expression correlated with increased metastasis, and BCL3-negative tumors correlated with lower survival and nonclassical subtypes.Conclusions: We demonstrate that bcl3 impacts pancreatic carcinogenesis by restraining CSC expansion and by curtailing an aggressive and metastatic tumor burden in PDAC across species. Levels of BCL3 expression are a useful stratification marker for predicting subtype characterization in PDAC, thereby allowing for personalized therapeutic approaches.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Pancreatic Cancer
- Metastasis
- BCL3
- Cancer Stem Cell Expansion
- PDAC Subtypes
Publication and Content Type
- ref (subject category)
- art (subject category)
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- By the author/editor
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Ai, Jiaoyu
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Wörmann, Sonja M ...
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Görgülü, Kıvanç
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Vallespinos, Mir ...
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Zagorac, Sladjan ...
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Alcala, Sonia
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show more...
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Wu, Nan
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Kabacaoglu, Dery ...
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Berninger, Alexa ...
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Navarro, Diego
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Kaya-Aksoy, Ezgi
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Ruess, Dietrich ...
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Ciecielski, Katr ...
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Kowalska, Marlen ...
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Demir, Ihsan Eki ...
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Ceyhan, Güralp O ...
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Heid, Irina
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Braren, Rickmer
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Riemann, Marc
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Schreiner, Sabri ...
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Hofmann, Samuel
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Kutschke, Maria
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Jastroch, Martin
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Slotta-Huspenina ...
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Muckenhuber, Ale ...
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Schlitter, Anna ...
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Schmid, Roland M ...
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Steiger, Katja
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Diakopoulos, Kal ...
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Lesina, Marina
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Sainz Jr, Bruno
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Algül, Hana
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show less...
- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Clinical Medicin ...
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and Cancer and Oncol ...
- Articles in the publication
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Gastroenterology
- By the university
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Stockholm University