| dc.contributor.advisor | Heßmann, Elisabeth PD Dr. | |
| dc.contributor.author | Hasselluhn, Marie Christin | |
| dc.date.accessioned | 2019-12-17T12:53:11Z | |
| dc.date.available | 2020-05-20T22:50:03Z | |
| dc.date.issued | 2019-12-17 | |
| dc.identifier.uri | http://hdl.handle.net/21.11130/00-1735-0000-0005-12D3-8 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-7778 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 610 | |
| dc.title | Nuclear NFATc1/Smad3 complexes in Smad4-deficient pancreatic cancer | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Heßmann, Elisabeth PD Dr. | |
| dc.date.examination | 2019-05-21 | |
| dc.description.abstracteng | Until today, pancreatic ductal adenocarcinoma (PDAC) is characterized by its extremely high mortality rate and the lack of effective treatment strategies despite reinforced focus on the elucidation of underlying molecular mechanisms in the last decades. The development of novel chemotherapeutic treatment strategies remains a challenge due to its extraordinary heterogeneity with regards to genetic alterations, stromal composition, and tumor cell metabolism. Patient stratification according to molecular subtyping is a promising strategy to efficiently target PDAC in a precision medicine-based approach. Molecular taxonomy aims to exploit specific cancer vulnerabilities to increase chemotherapeutic response and prolong the life expectancy of patients.
In this work, we focused on the large genetic subgroup of SMAD4-deficient PDAC in the context of oncogenic KRAS activation, comprising 55 % of patients. With the help of genetically engineered mouse models (GEMMs), we aimed to comprehend features of Smad4-depleted PDAC in vivo and elucidate synergisms in Kras and TGFβ signaling. This is complemented by in vitro studies, opposing Smad4 wildtype PDAC cells to their respective CRISPR/Cas9-generated Smad4-depleted counterparts. We disclosed induced migratory potential and stemness characteristics as well as increased tolerance to the nucleoside analog Gemcitabine upon loss of Smad4. In contrast, Smad4-depleted PDAC cells demonstrated extraordinary sensitivity towards Mek inhibition by Trametinib.
The TGFβ pathway is strongly intertwined with nuclear factor of activated T cells (NFATc1) signaling, an inflammatory transcription factor pivotal for PDAC evolution. We scrutinized the role of NFATc1 in hijacking Smad3-dependent transcription in favor of oncogenic gene signatures in Smad4 deficiency. Cooperativity studies illuminated direct interplay of NFATc1 and Smad3 transcription factors and conditions permitting or abrogating their nuclear complex formation. With the identification of cJun as a third transcription factor involved in the nuclear complex, we gained a window of opportunity to target the transcription complex by disrupting its assembly with Trametinib. Genome-wide expression studies revealed potential targets of the NFATc1/Smad3/cJun complex and disclosed transcriptional induction of genes associated with improved PDAC patient survival and increased Gemcitabine response upon complex disruption by Trametinib.
Thus, on the one hand, we suggest a mechanism how Smad4-depleted cells evade Gemcitabine-induced cytotoxicity by NFATc1/Smad3/cJun-mediated transcription. On the other hand, we propose a strategy on how to interfere with the transcription factor assembly by effective Mek inhibition mediated by Trametinib, thus restoring Gemcitabine sensitivity in the context of Smad4 deficiency. Together, these data provide a potential novel chemotherapeutic treatment regime with combinatorial Trametinib and Gemcitabine administration for Kras-mutated PDAC patients bearing loss of SMAD4. | de |
| dc.contributor.coReferee | Hahn, Heidi Prof. Dr. | |
| dc.subject.eng | pancreatic cancer | de |
| dc.subject.eng | PDAC | de |
| dc.subject.eng | TGFβ signaling | de |
| dc.subject.eng | NFATc1 signaling | de |
| dc.subject.eng | translational medicine | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-21.11130/00-1735-0000-0005-12D3-8-0 | |
| dc.affiliation.institute | Medizinische Fakultät | |
| dc.subject.gokfull | GOK-MEDIZIN | de |
| dc.subject.gokfull | Innere Medizin - Allgemein- und Gesamtdarstellungen (PPN619875747) | de |
| dc.description.embargoed | 2020-05-20 | |
| dc.identifier.ppn | 1685861113 | |