Genome-wide analysis of the CUX1 transcriptional network mediating resistance to apoptosis in pancreatic cancer
Final Report Abstract
Based on these experiments we were able to characterize the WNT5A – NFATc1 axis as effector signaling pathway of CUX1. In addition, we could identify a functional antagonism between CUX1-dependent and NFkB-dependent transcriptional networks. Furthermore, we identified recruitment of histone deacetylases to the repressor complex of CUX1 that modulates transcriptional activity of NFkB p65 at the promoter of proinflammatory chemokines such as CXCL10 in addition to steric displacement by CUX1, indicating a protumoral, immunosuppressive and proangiogenic role of CUX1. The in vivo evaluation of Cux1 in a genetic mouse model in the context of activated K-Ras shows a significant acceleration of tumor progression via Cux1-dependent activation of Mek-Erk signaling through upregulation of the ADAM17 sheddase. Experiments with a conditional mouse model are part of an ongoing DFG-grant.
Publications
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WNT5A-NFAT signaling mediates resistance to apoptosis in pancreatic cancer. Neoplasia. 2013 Jan;15(1):11-22
Griesmann H, Ripka S, Pralle M, Ellenrieder V, Baumgart S, Buchholz M, Pilarsky C, Aust D, Gress TM, Michl P
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CUX1: a modulator of tumour aggressiveness in pancreatic neuroendocrine neoplasms. Endocr Relat Cancer. 2014;21(6):879-90
Krug S, Kühnemuth B, Griesmann H, Neesse A, Mühlberg L, Boch M, Kortenhaus J, Fendrich V, Wiese D, Sipos B, Friemel J, Gress TM, Michl P
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The role of CUX1 in antagonizing NF-κB signaling in TAMs. Oncoimmunology. 2014 Mar 27;3:e28270
Kühnemuth B, Michl P
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CUX1 modulates polarization of tumor-associated macrophages by antagonizing NF-κB signaling. Oncogene. 2015 Jan 8;34(2):177-87
Kühnemuth B, Mühlberg L, Schipper M, Griesmann H, Neesse A, Milosevic N, Wissniowski T, Buchholz M, Gress TM, Michl P
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Pharmacological macrophage inhibition decreases metastasis formation in a genetic model of pancreatic cancer. Gut. 2016 Mar 24
Griesmann H, Drexel C, Milosevic N, Sipos B, Rosendahl J, Gress TM, Michl P
