Investigator
Zhejiang University
Distinct functional heterogeneity of TP53 R175 mutations in platinum-resistant ovarian cancer: unveiling molecular mechanisms and therapeutic targets
Abstract Ovarian cancer (OC) is a highly aggressive malignancy in women, and platinum resistance remains a major clinical obstacle. p53 mutations are prevalent in OC and exhibit functional heterogeneity that is associated with therapeutic response and disease progression. However, the roles and mechanisms underlying the functional heterogeneity of p53 mutations in platinum-resistant OC remain elusive. This investigation delineated that p53 mutations within the Loop 2, Loop 3, and β-strand S10 regions were closely linked to platinum resistance. In particular, functional assays unveiled that p53 R175H and p53 R175G mutations at Arg175 revealed distinct roles in tumor cell migration and drug resistance, with p53 R175G conferring resistance to agents targeting p53 R175H . Through multi-omics sequencing analysis, it was discerned that p53 R175H and p53 R175G promoted tumor progression through distinct cofactors and regulatory networks. p53 R175H mediated upregulation of extracellular matrix-related genes, whereas p53 R175G activated pathways associated with cytokine receptor interaction and membrane trafficking. Notably, the chromatin remodeling protein CHD1 selectively interacted with p53 R175G , but not p53 R175H , and regulated the transcriptional activity of p53 R175G , including target genes such as IL7R . Moreover, CHD1 knockdown or pharmacological inhibition of IL7R synergistically enhanced platinum sensitivity, suggesting promising combination therapies specifically targeting the R175G mutation. The findings revealed that p53 mutations at the same residue exhibited distinct functional properties and relied on unique cofactors, offering valuable insights for precision therapy in OC.
Proteomic landscape of epithelial ovarian cancer
Epithelial ovarian cancer (EOC) is a deadly disease with limited diagnostic biomarkers and therapeutic targets. Here we conduct a comprehensive proteomic profiling of ovarian tissue and plasma samples from 813 patients with different histotypes and therapeutic regimens, covering the expression of 10,715 proteins. We identify eight proteins associated with tumor malignancy in the tissue specimens, which are further validated as potential circulating biomarkers in plasma. Targeted proteomics assays are developed for 12 tissue proteins and 7 blood proteins, and machine learning models are constructed to predict one-year recurrence, which are validated in an independent cohort. These findings contribute to the understanding of EOC pathogenesis and provide potential biomarkers for early detection and monitoring of the disease. Additionally, by integrating mutation analysis with proteomic data, we identify multiple proteins related to DNA damage in recurrent resistant tumors, shedding light on the molecular mechanisms underlying treatment resistance. This study provides a multi-histotype proteomic landscape of EOC, advancing our knowledge for improved diagnosis and treatment strategies.
POLM variant G312R promotes ovarian tumorigenesis through genomic instability and COL11A1-NF-κB axis
Our research reveals that POLM plays an important role in ovarian cancer development, especially the mutation G312R. We uncover the POLMG312R mutation as a driver of genomic instability in ovarian cancer via aberrant ribonucleotide incorporation. We reveal that POLMG312R upregulates COL11A1 and activates NF-κB signaling, contributing to tumor progression and chemoresistance. This study identifies the POLM-COL11A1-NF-κB axis as a novel oncogenic pathway.
