Biology subjects

Rimel, B.

Publications and source records attributed to Rimel, B..

3 recordsLinked to original sources

bioRxiv2025

The mutational landscape defines the proteome and spatial organization of tumor, stroma and immune cells in ovarian cancer

High-grade serous ovarian cancer (HGSOC) is a highly aggressive and lethal form of ovarian cancer. Challenges to diagnosis and treatment include a lack of effective screening methods for early detection, the absence of cancer-specific symptoms, and the development of chemoresistance. The genomic instability of HGSOC, further complicated by homologous recombination deficiency (HRD), leads to heterogeneity in HGSOC tumors and patient response to treatment. This makes it challenging to develop a single, effective diagnostic and treatment approach for this disease. Proteogenomic studies have provided some insight into HGSOC biology, but a deeper understanding of the tumor proteome through chemotherapy and disease recurrence is needed. Here we have profiled the proteome of tumors from 29 HGSOC patients before and after multiple rounds of chemotherapy. The proteome of HGSOC tumors remained unchanged for individual patients even after numerous rounds of chemotherapy. Differential expression analysis revealed known and novel proteins associated with chemoresistance and HRD status, further supported by similar changes at the genetic and epigenetic levels. We found that HRD affected proteins related to immune pathways. HRD was also associated with more shared T cell receptor (TCR) CDR3 repertoires of tumor-infiltrating T cells and increased neoantigen counts. ERAP1, a protein involved in peptide trimming before antigen presentation to immune cells via MHC-class I, was overexpressed in homologous recombination proficient (HRP) tumors and negatively correlated to neoantigen count. Its potential role in immune suppression in HRP tumors makes it an attractive therapeutic target that may be effective in combination with immunotherapy, particularly for HRP tumors. 26-plex immunostaining of HGSOC whole tissues further revealed significant differences in the spatial proximities of immune cells to each other and to tumor cells based on HRD status. Through proteomic and imaging analysis, this work has shown that the immune landscape of HGSOC tumors is influenced by homologous recombination status and identified candidate drivers of HGSOC biology.

cancer biology↗

bioRxiv2025

The mutational and clonality profile of HGSOC is established early in tumor development and conserved throughout therapy resistance

High grade serous ovarian cancer (HGSOC) is the most lethal gynecologic malignancy, killing more than 9,000 women each year in the United States alone. Nearly 80% of patients with HGSOC tumors will experience recurrence within 5 years, but little is known about the mechanisms that drive this process. Intratumor heterogeneity is believed to be a key feature of recurrence and resistance in HGSOC tumors, with early studies reporting diverse and complex mechanisms of the seeding of metastatic sites, including metastasis reseeding the primary tumor. Few studies have investigated temporal changes to clonality and structural variants through disease recurrence and the development of chemoresistance as surgical debulking is not frequently performed at this later stage. We performed multi-omic profiling in paired chemo-naive and chemoresistant tumors from 32 HGSOC patients to investigate the mutational and genomic landscape of disease progression. Somatic mutation profiles were largely conserved through disease progression. Mutational burdens did not significantly differ across recurrence but were driven by homologous recombination repair deficiency status. Clonal composition and dynamics were measured through variant allele frequency alterations as tumors progressed from primary chemo-naive to recurrent chemo-resistant tumors. A novel candidate driver gene, MDC1, from the homologous recombination repair pathway, was significantly mutated and over-represented in patients with homologous recombination proficient tumors, with somatic mutations clustered in a single exon. Tumor evolution and phylogeny revealed that few changes in clonal abundance and complexity occur across the disease course in these patients. Taking structural variants into account, homologous recombination repair proficient (HRP) tumors tend to be polyclonal while homologous recombination repair deficient (HRD) tumors tend to be monoclonal, accompanied by a longer progression-free survival than the HRP patients. Three distinct classes of tumors were identified by structural variant signature analysis: tumors defined by DNA losses, tumors defined by DNA gains, and tumors defined by copy number neutral changes, which were largely defined by HRD status. Each class displayed distinct regions of the chromosome that were frequently affected by large scale SV events (>5Mb). Although no regions were frequently altered in recurrent tumors, GO analysis revealed that recurrent tumors have a significantly reduced immune response, which was not seen in the primary tumors. Ultra long read sequencing validated a majority of the SVs identified in short read sequencing and identified additional SVs undetected by short reads. These analyses identify that the phenotype of high grade serous ovarian tumors as defined by mutation and clonality profiles is established early in disease development and remain largely unchanged through chemotherapy and recurrence. This, when considered with the significant inter-patient heterogeneity identified in HGSOC, demonstrates the need for personalized therapies based on tumor profiling.

genomics↗

bioRxiv2020

Single-cell Transcriptomics Identifies Gene Expression Networks Driving Differentiation and Tumorigenesis in the Human Fallopian Tube

The human fallopian tube harbors the cell-of-origin for the majority of high-grade serous ovarian cancers (HGSCs), but its cellular composition, particularly the epithelial component, is poorly characterized. We performed single-cell transcriptomic profiling in 12 primary fallopian specimens from 8 patients, analyzing around 53,000 individual cells to map the major immune, fibroblastic and epithelial cell types present in this organ. We identified 10 epithelial sub-populations, characterized by diverse transcriptional programs including SOX17 (enriched in secretory epithelial cells), TTF3 and RFX3 (enriched in ciliated cells) and NR2F2 (enriched in early, partially differentiated secretory cells). Based on transcriptional signatures, we reconstructed a trajectory whereby secretory cells differentiate into ciliated cells via a RUNX3high intermediate. Computational deconvolution of the cellular composition of advanced HGSCs based on epithelial subset signatures identified the early secretory population as a likely precursor state for the majority of HGSCs. The signature of this rare population of cells comprised both epithelial (EPCAM, KRT) and mesenchymal (THY1, ACTA2) features, and was enriched in mesenchymal-type HGSCs (P = 6.7 x 10-27), a group known to have particularly poor prognoses. This cellular and molecular compendium of the human fallopian tube in cancer-free women is expected to advance our understanding of the earliest stages of fallopian epithelial neoplasia.

genomics↗