BCL3 couples cancer stem cell enrichment with pancreatic cancer molecular subtypes.

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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.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 two independent patient cohorts. We assessed the correlation of BCL3 expression pattern with clinical parameters and subtypes.BCL3 was significantly downregulated in human CSCs. Recapitulating this phenotype in preclinical mouse models of PDAC via Bcl3 genetic knockout enhanced tumor burden, metastasis, EMT, and reduced overall survival. FACS 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.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 predicting subtype characterization in PDAC thereby, allowing for personalized therapeutic approaches.

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Authors: Jiaoyu Ai, Sonja M Wörmann, Kıvanç Görgülü, Mireia Vallespinos, Sladjana Zagorac, Sonia Alcala, Nan Wu, Derya Kabacaoglu, Alexandra Berninger, Diego Navarro, Ezgi Kaya-Aksoy, Dietrich A Ruess, Katrin J Ciecielski, Marlena Kowalska, Ekin I Demir, Güralp O Ceyhan, Irina Heid, Rickmer Braren, Marc Riemann, Sabrina Schreiner, Samuel Hofmann, Maria Kutschke, Martin Jastroch, Julia Slotta-Huspenina, Alexander Muckenhuber, Anna Melissa Schlitter, Roland M Schmid, Katja Steiger, Kalliope N Diakopoulos, Marina Lesina, Bruno Sainz, Hana Algül