Misp53 mutation-specific oncogenic transcription factor complexes in PDAC progression
by Laura Urbach
Date of Examination:2024-06-10
Date of issue:2024-07-02
Advisor:Dr. Shiv K. Singh
Referee:Dr. Shiv K. Singh
Referee:Prof. Dr. Argyris Papantonis
Persistent Address:
http://dx.doi.org/10.53846/goediss-10588
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Abstract
English
Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second-leading cause of cancer related death by 2040 with a 5-year survival rate of only 11%. PDAC aggressiveness is attributed to its high heterogeneity and molecular plasticity determined by various genetic, transcriptional, and environmental factors. For instance, whole-genome sequencing of PDAC patient specimens has identified driver mutations, which are strongly associated with disease aggressiveness and therapy response. Among these, TP53 gene mutations accounting for over 70% of PDAC cases have been particularly linked to the poorly differentiated basal-like (BL) subtype and late-stage metastatic tumors of PDAC. Notably, TP53 mutations select for hotspot missense mutations (misp53) at codons R175, R248, and R273, impairing the p53-mediated tumor suppressive functions while empowering misp53 to gain novel oncogenic properties (gain-of-function, GOF) that can fuel PDAC progression and aggressiveness. By using PDAC patient and cell line transcriptome data, combined with patient-derived cells and preclinical models, we identified hotspot misp53-driven mutant-specific transcriptional programs determining PDAC plasticity. The DNA contact mutants arising from codon R273 (misp53R273H/C) are substantially linked to cell cycle progression, metastasis formation and BL subtype aggressiveness. Integration with genome-wide ChIP-seq and mass spectrometry data uncovered misp53R273H/C-specificity in controlling G1/S transition through oncogenic complex formation with transcriptional cell cycle repressors such as p-Rb and DREAM complex members (e.g. RBBP4 and E2F4). Disruption of misp53R273H/C-specific GOFs led to G1 arrest in vitro and reduced tumor growth and metastasis accompanied by prolonged preclinical survival. In addition, we identified the CDK4/6 inhibitor ‘Palbociclib’ as a potent misp53R273H/C-specific GOF inhibitor, which reduced the expression of misp53R273H/C and its downstream G1/S targets Cyclin A and Cyclin E. However, both genetic and pharmaceutical deregulation of misp53R273H/C leads to survival and proliferation rescue through compensatory MAPK/ERK signaling. We found that inhibiting both the GOF misp53R273H/C and the MAPK/ERK pathway can effectively block the misp53R273H/C-specific oncogenic functions and PDAC plasticity. This suggests that MAPK/ERK pathway inhibition can be used as a therapeutic vulnerability to overcome the oncogenicity caused by misp53R273H/C. In conclusion, this study unveiled misp53 mutant-specificity in determining PDAC subtype plasticity and aggressiveness. This adds another factor contributing to the molecular heterogeneity of PDAC. Further, the results highlight the potential relevance of distinct hotspot misp53 mutants and their associated GOFs for subtype-based stratification and identification of novel therapeutic targets, which can aid in improving PDAC patient outcomes.
Keywords: hotspot TP53 mutations; Gain-of-function (GOF); mutant-specific subtyping; Pancreatic Cancer (PDAC)
