Project Details
Projekt
Exploiting oncogenic transcriptional reprogramming in misp53 PDAC subtypes
Subject Area
Gastroenterology
Term
since 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 426671079
Specific gain-of-function (GOF) misp53 mutations can foster tumor progression and therapy resistance in pancreatic cancer (PDAC) by promoting oncogenic transcriptional programs. Thereby, missense p53 mutants (misp53) can build mutation-specific and mutation-overlapping transcription factor (TF) networks, e,g. by forming complexes with other signaling-regulated TFs to reprogram target gene signatures. Importantly, different misp53 mutants are capable of acquiring allele-specific GOF activities on TF networks that are not necessarily shared by other mutants. In the first funding period, we have identified and characterized misp53R248Q/W and misp53R273H/C mutant-specific transcriptional complexes, e.g. misp53R248Q/W-β-catenin and misp53R248Q/W-pSTAT3 complexes, and emphasized their functional implication in key aspects of PDAC progression. In the next funding period, we will extend our studies and thoroughly investigate the mechanisms, regulation, and clinical relevance of misp53 mutation-specific TF regulatory networks in PDAC aggressiveness. Specifically, we will focus on the three hotspot mutations misp53R175H/C, misp53R248Q/W and misp53R273H/C and examine their oncogenic capacities in misp53 mutation-specific patient-derived preclinical models (with CP1). In addition, we will perform candidate-based (e.g. Wnt-inhibitors, STAT3- and cell cycle-inhibitors) and unbiased drug screening experiments (with CP1) to identify misp53 mutation-specific vulnerabilities. We will validate our findings both in vitro and in vivo by taking advantage of established mutant-specific preclinical models as well as primary tumor samples along with clinical data from early and late-stage CRU5002 patient cohorts. We will determine the therapeutic efficacy (e.g. tumor formation, cell proliferation, etc.) of identified drugs alone and in combination with chemotherapy (CTX) in misp53 mutation-specific and -overlapping approaches. In cooperation with SP4, SP7 and SP8, we plan to characterize tumor subtype-overlapping functions of misp53 mutations in transcriptional and metabolic reprogramming, and therapeutic vulnerabilities. We anticipate that these studies will significantly improve our understanding of hotspot misp53 mutations in subtype-specific regulation of genome dynamics and plasticity and will help inform stratification-based decisions for tailored therapies in PDAC.
DFG Programme
Clinical Research Units
