Unraveling the early molecular and morphologic evolution of ovarian cancer

• Applicant: Professorin Dr. Kirsten Kübler
• Subject Area: Gynaecology and Obstetrics ; Medical Informatics and Medical Bioinformatics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 568915393

High-grade serous ovarian cancer (HGSOC) remains a lethal gynecologic cancer, with a 5-year survival rate of 43%. This poor prognosis is largely attributed to diagnosis at advanced stages and the lack of early detection tools. In contrast, when detected early, survival exceeds 85%, highlighting the urgent need to define the molecular and cellular mechanisms of disease initiation. Recent molecular and morphologic data indicated that the fallopian tube, which connects the ovary to the uterus, may be the originating site of HGSOC. The overarching goal of this proposal is therefore to uncover the events that mark the earliest steps of transformation in the fallopian tube epithelium, an essential step if we are to develop early diagnosis tools. By combining state-of-the-art single-cell and spatial technologies with artificial intelligence (AI)-based histological analysis, this project bridges molecular and morphological data, filling a critical knowledge gap in our understanding of tumor initiation in HGSOC. The significance of this project lies in its potential to uncover the earliest cellular events in HGSOC that happen in morphologically normal tissue, with potential long-term implications for early detection. This project is innovative in its integrative use of single-cell genomics, spatial transcriptomics, and AI to study early tumor initiation—an approach that has not previously been applied. Our project is divided into three work packages. The first two packages will consist of conducting an in-depth analysis of healthy fallopian tube samples using (i) whole-genome sequencing of single cells, and (ii) spatial transcriptomics assays to reveal genetic alterations in healthy epithelial cells, reconstruct their evolutionary history, and assess their impact on tissue integrity and early cell transformation. The third work package will consist of combining genomic findings with automatic slide image analysis of the very same samples to link genetic impairments to morphologic changes. If successful, this approach could yield morphologic read-outs of early cell changes that reflect the biological consequences of genomic alterations and provide new insights into the tissue architectural dynamics of early transformation. This interdisciplinary study leverages complementary expertise from the German team, with deep knowledge in cancer genomics, cutting-edge sequencing technology platforms and evolution, and the French team, pioneers in bioinformatics, computational histopathology, and AI-based image analysis, making the collaboration uniquely suited to tackle the complex challenge of tumor onset. Beyond HGSOC, the integrative paradigm developed here - linking genomic, transcriptomic, and morphological data in a spatially resolved manner - could be adapted to study early transformation processes in other epithelial cancers, thereby contributing more broadly to the understanding of early tumorigenesis.

• DFG Programme: Research Grants
• International Connection: France
• Co-Investigators: Dr. Peter Arndt; Professorin Dorothee Speiser
• Cooperation Partners: Dr. Florian Massip, Ph.D.; Professor Thomas Walter, Ph.D.