Eliane T Taube

Spatial proteomics of ovarian cancer precursors delineates early disease changes and drug targets

Abstract High-grade serous ovarian cancer (HGSOC) is often detected at an advanced stage, where curative treatment options are limited. Recent advances in ultrasensitive mass spectrometry-based spatial proteomics have provided a unique opportunity to uncover molecular drivers of early tumorigenesis and novel therapeutic targets. Here, we present a comprehensive proteomic analysis of serous tubal intraepithelial carcinoma (STIC), the HGSOC precursor lesion, and concurrent invasive carcinoma, covering more than 10,000 proteins from ultra-low input archival tissue. STIC and HGSOC showed highly similar proteomes, clustering into two subtypes with distinct tumor-immune microenvironments and common remodeling of the extracellular matrix. We discovered cell-of-origin signatures from secretory fallopian tube epithelial cells in STICs and identified early dysregulated pathways of therapeutic relevance. Targeting cholesterol biosynthesis by inhibiting the terminal steps via DHCR7 showed therapeutic effects in ovarian cancer cell lines and synergized with standard-of-care carboplatin treatment. This study demonstrates the power of spatially resolved quantitative proteomics in understanding early carcinogenesis and provides a rich resource for biomarker and drug target research.

Transcriptome Analysis of Matched Cohorts of Long- and Short-term Survivors in Advanced High-grade Serous Tubo-ovarian Cancer

Abstract Purpose: The late-stage diagnosis and the aggressiveness of high-grade serous tubo-ovarian carcinoma (HGSC) often result in poor survival outcomes, yet some patients exhibit an exceptionally long survival rate. This study aimed to identify molecular profiles associated with long-/short-term survival in HGSC, with the goal of better understanding protective factors and developing new treatments. Experimental Design: To discover molecular drivers causing the aggressiveness of HGSC, tumor samples from 12 long-term HGSC survivors (>7 years overall survival) and 12 short-term survivors (<1 year overall survival) were analyzed using targeted RNA sequencing followed by computational analysis. We investigated differentially expressed genes and their functional relevance, inferred differences in cell type composition and signaling pathways, as well as mutation status. To validate our findings, we simulated our study design by using HGSC The Cancer Genome Atlas dataset samples. We evaluated differential patterns of gene expression between these two groups and developed molecular profiles of HGSC that correlate with survival phenotypes. Results: Besides known molecular cancer drivers and indicators of poor prognosis, we identified specific transcriptional changes between short- and long-term survivors of HGSC, which indicate that immune processes play a fundamental role in long-term survivors. Our computational analysis reveals an important role for the ensemble of IFN-γ signaling and the RFX transcription factors, as well as the immune cell composition of the tumor microenvironment. Conclusions: Specific immunologic requirements involving IFN-γ signaling and affected pathways seem to be relevant for long-term survival in the generally considered nonimmunogenic HGSC, necessitating further research to improve diagnostic strategies and targeted therapies.

Mucinous cystic neoplasms of the pancreas and liver share a similar DNA methylation profile with mucinous ovarian tumors

Abstract The origin of mucinous cystic neoplasms (MCNs) remains a major challenge in hepato‐pancreato‐biliary pathology. These cystic tumors are defined by their mucinous epithelium and ovarian‐like stroma, with an estimated 10% risk of progression to invasive carcinoma. The origin of the ovarian‐like stroma remains a subject of debate. In this study, we conducted immunohistochemical profiling, targeted DNA sequencing, and genome‐wide DNA methylation analysis on a cohort of 15 pancreatic MCNs (MCN‐P) and six hepatic MCNs (MCN‐L). Using immunohistochemistry and targeted DNA sequencing, we unequivocally established the diagnosis of MCN. Unsupervised DNA methylation profile analysis of reference classes of pancreatic neoplasms (11 entities and normal pancreatic tissue from 224 unique samples) revealed that MCN‐P predominantly forms a distinct group. In the DNA methylation landscape of liver tumors, encompassing five tumor types and normal bile duct tissue from 136 unique samples, MCN‐L demonstrated a specific methylation profile when compared with all other entities. Furthermore, within the DNA methylation landscape of ovarian tumors – featuring five tumor types, normal Fallopian tube, and normal ovarian tissue from 90 unique samples – we found that both MCN‐P and MCN‐L grouped with mucinous ovarian carcinoma and mucinous borderline ovarian tumors (mBOTs). Notably, low‐grade MCNs exhibited greater DNA methylation similarities to mBOTs, while high‐grade or invasive MCNs were primarily associated with mucinous ovarian carcinomas. When analyzing all samples together (19 tumor types and four normal tissue types, n  = 430), MCNs similarly grouped with mucinous ovarian tumors and normal ovarian tissue. Additionally, in a network analysis of differentially methylated probes, MCN‐P and MCN‐L share significant methylation traits, closely resembling mucinous ovarian tumors. In conclusion, our findings highlight that MCN‐P and MCN‐L are distinct entities in the landscape of pancreatic and hepatic tumors and show DNA methylation profile similarities with mucinous ovarian tumors, suggesting a potential common origin. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

AHRR and SFRP2 in primary versus recurrent high-grade serous ovarian carcinoma and their prognostic implication

Abstract Background The aim of this study was to analyse transcriptomic differences between primary and recurrent high-grade serous ovarian carcinoma (HGSOC) to identify prognostic biomarkers. Methods We analysed 19 paired primary and recurrent HGSOC samples using targeted RNA sequencing. We selected the best candidates using in silico survival and pathway analysis and validated the biomarkers using immunohistochemistry on a cohort of 44 paired samples, an additional cohort of 504 primary HGSOCs and explored their function. Results We identified 233 differential expressed genes. Twenty-three showed a significant prognostic value for PFS and OS in silico. Seven markers (AHRR, COL5A2, FABP4, HMGCS2, ITGA5, SFRP2 and WNT9B) were chosen for validation at the protein level. AHRR expression was higher in primary tumours (p < 0.0001) and correlated with better patient survival (p < 0.05). Stromal SFRP2 expression was higher in recurrent samples (p = 0.009) and protein expression in primary tumours was associated with worse patient survival (p = 0.022). In multivariate analysis, tumour AHRR and SFRP2 remained independent prognostic markers. In vitro studies supported the anti-tumorigenic role of AHRR and the oncogenic function of SFRP2. Conclusions Our results underline the relevance of AHRR and SFRP2 proteins in aryl-hydrocarbon receptor and Wnt-signalling, respectively, and might lead to establishing them as biomarkers in HGSOC.

LRP1B—a prognostic marker in tubo-ovarian high-grade serous carcinoma

Low-density lipoprotein (LDL) receptor-related protein 1B (LRP1B) is a member of the LDL receptor family and has often been discussed as a tumor suppressor gene, as its down-regulation is correlated with a poor prognosis in multiple carcinoma entities. Due to the high metastasis rate into the fatty peritoneal cavity and current research findings showing a dysregulation of lipid metabolism in tubo-ovarian high-grade serous carcinoma (HGSC), we questioned the prognostic impact of the LRP1B protein expression. We examined a well-characterized large cohort of 571 patients with primary HGSC and analyzed the LRP1B protein expression via immunohistochemical staining (both in tumor and stroma cells separately), performed precise bioimage analysis with QuPath, and calculated the prognostic impact using SPSS. Our results demonstrate that LRP1B functions as a significant prognostic marker for overall survival (OS) and progression-free survival (PFS) in HGSC on the protein level. High cytoplasmic expression of LRP1B in tumor, stroma, and combined tumor and stroma cells has a significantly positive association with a mean prolongation of the OS by 42 months (P = .005), 29 months (P = .005), and 25 months (P = .001), respectively. Additionally, the mean PFS was 18 months longer in tumor (P = .002), 19 months in stroma (P = .004), and 19 months in both cell types combined (P = .01). Our results remained significant in multivariate analysis. We envision LRP1B as a potential prognostic tool that could help us understand the functional role of lipid metabolism in advanced HGSC, especially regarding liposomal medications.

Increased expression of IDO1 is associated with improved survival and increased number of TILs in patients with high-grade serous ovarian cancer

The enzyme indoleamine 2,3-dioxygenase 1 (IDO1) plays a crucial role in regulating the immune system's response to tumors, but its exact role in cancer, especially in high-grade serous ovarian cancer (HGSOC), remains controversial. We aimed to investigate the prognostic impact of IDO1 expression and its correlation with tumor-infiltrating lymphocytes (TILs) in HGSOC. Immunohistochemical (IHC) staining and bioimage analysis using the QuPath software were employed to assess IDO1 protein expression in a well-characterized cohort of 507 patients with primary HGSOC. Statistical evaluation was performed using SPSS, and in silico validation considering IDO1 mRNA expression in bulk and single-cell gene expression datasets was conducted. Additionally, IDO1 expression in interferon-gamma (IFNG) stimulated HGSOC cell lines was analyzed. Our findings revealed that IDO1 protein and mRNA expression serve as positive prognostic markers for overall survival (OS) and progression-free survival (PFS) in HGSOC. High IDO1 expression was associated with a significant improvement in OS by 21 months (p < 0.001) and PFS by 6 months (p = 0.016). Notably, elevated IDO1 expression correlated with an increased number of CD3+ (p < 0.001), CD4+ (p < 0.001), and CD8+ TILs (p < 0.001). Furthermore, high IDO1 mRNA expression and protein level were found to be associated with enhanced responsiveness to pro-inflammatory cytokines, particularly IFNG. Our study provides evidence that IDO1 expression serves as a positive prognostic marker in HGSOC and is associated with an increased number of CD3+, CD4+ and CD8+ TILs. Understanding the intricate relationship between IDO1, TILs, and the tumor microenvironment may hold the key to improving outcomes in HGSOC.