idw – Informationsdienst Wissenschaft
Nachrichten, Termine, Experten
Nachrichten, Termine, Experten
A team of researchers led by Professor Matthias Mann at the Max Planck Institute of Biochemistry in Munich and Professor Ernst Lengyel at the University of Chicago (USA) has taken a major step toward understanding and treating low-grade serous ovarian cancer (LGSC), a form of ovarian cancer that primarily affects younger women and is largely resistant to standard chemotherapy. By combining cutting-edge Deep Visual Proteomics – a breakthrough technology pioneered by the Matthias Mann’s team – with spatial transcriptomics, the researchers uncovered how benign ovarian tumors progress into invasive and metastatic cancer, and identified a promising new treatment strategy.
In a nutshell:
• Low-grade serous ovarian cancer: a form of ovarian cancer that occurs mainly in younger women and is largely resistant to standard chemotherapy
• Interdisciplinary study: shows how benign borderline ovarian tumors develop into invasive low-grade serous carcinomas
• Methods used: Combination of the recently developed, groundbreaking Deep Visual Proteomics technology with spatial transcriptomics
• Clinical application: Treatment in a mouse model with milciclib in combination with mirvetuximab significantly reduced tumor burden
---
Low-grade serous ovarian cancer
Low-grade serous ovarian cancer, short LGSC, accounts for just 5-10% of all epithelial ovarian cancers, but its distinct biology makes it especially challenging to treat. While the origin of this disease has not been identified, a multitude of patients are initially diagnosed with non-invasive lesions, so called Serous Borderline Tumors. These tumors are typically managed successfully with surgery, however, in some cases they return as invasive LGSC and hence progress to a life-threatening disease. The mechanisms underlying this transition have remained largely unclear.
Ernst Lengyel, internationally recognized gynecological oncologist and translational researcher from Chicago, explains the relevance of the study: "For gynecologic oncologists, metastatic low-grade serous ovarian cancer is one of the most challenging cancers to treat – patients are young when they get sick and it is resistant to chemotherapy. Our intent was to build a clear roadmap of how these tumors progress and evolve to find concrete therapeutic targets that we can pursue in clinical trials."
Deep Visual Proteomics spatially maps the tumor architecture
To address this fundamental question, scientists from the research group led by Matthias Mann, a pioneer in mass spectrometry-based spatial proteomics, and Lengyel's team joint forces. The researcher analyzed patient tissue samples across different stages of disease – from benign serous borderline tumors to potential intermediate lesions and ultimately invasive LGSC and its metastases. Microdissection, a high-precision laser technology was used to extract tumor cells and those from the tumor microenvironment. Using machine learning and ultra-sensitive mass spectrometry, protein signatures were created for each cell type. Protein signatures are recognizable, specific combinations of proteins that allow conclusions to be drawn about the underlying biological processes.
This cutting-edge approach, known as Deep Visual Proteomics, creates molecular maps of thousands of proteins. To complement these results, the study integrated for the first time spatial protein- and RNA-analyses. By this strategy, the researchers were able to locate altered signaling pathways precisely in the tumor tissue and identified how tumor cells interact with their environment. The protein analyses further provided insights into the transition from non-invasive to invasive tumors, and found early signs for a malignant progression in den intermediate stages, the so called micropapillary tumors.
Matthias Mann says: "This study demonstrates the transformative power of MS-based spatial proteomics in cancer research. By mapping thousands of proteins at single-cell resolution, we can now visualize how tumors evolve in real-time within their tissue environment. This level of molecular detail opens entirely new possibilities for developing targeted therapies based on the specific vulnerabilities we uncover in each cancer type."
New molecular players
This new technology did not just unravel novel mechanisms – it pinpointed new molecular players driving the tumor’s evolution. Lisa Schweizer, first author and former doctoral at the Max Planck Institute of Biochemistry, explains: “By profiling the disease at high spatial resolution, we could trace how these tumors evolve along a gradient of malignancy and interact with their environment. One of the striking findings was the presence of proteins that normally have critical functions in the central nervous system. The protein NOVA2, for instance, was present solely in the invasive form of the tumor and in its metastases, while being entirely absent in the more benign tumors. This protein could be part of a molecular ‘switch’ driving tumor cell invasion”.
NOVA2 is part of a protein panel representing new markers of tumor progression identified by the researchers. To confirm their findings, they worked with human cells in culture, generating an artificial environment for cell growth. By removing these proteins from the cells, the team found that they significantly impacted the tumor cells' ability to multiply and invade healthy tissue.
A New Therapy Approach for LGSC
Unlike the more aggressive high-grade ovarian cancers, LGSC grows slowly but infiltrates deeply into healthy tissue, often leading to late recurrences and limited treatment options. Current chemotherapy regimens typically show minimal response rates in LGSC patients. Until now, the molecular mechanisms driving its development were poorly understood, leaving clinicians with few alternatives.
Drawing on molecular data from their spatial maps, the researchers identified 16 potential drug targets and assessed their therapeutic impact in human cell models. Among those, they tested a novel combination therapy: Milciclib paired with Mirvetuximab. While Milciclib inhibits cell replication, Mirvetuximab delivers a toxic payload specifically to cells that express the FOLR1 protein on the cell surface, serving as a targeting mechanism. In mouse models, this treatment significantly reduced tumor burden, offering new hope for patients with chemo-resistant cancer.
While clinical trials are still needed to evaluate the safety and efficacy of the proposed therapy in patients, the findings represent a significant advance in understanding LGSC. Beyond ovarian cancer, this work highlights the broader potential of spatial omics technologies to decode complex disease ecosystems and guide precision therapies.
Lisa Schweizer concludes: “While clinical studies will be required to confirm the efficacy and impact of the suggested therapies in patients, our results represent substantial progress in understanding LGSC. Beyond ovarian cancer, our work highlights the potential of spatial omics technologies to decipher complex disease ecosystems and to develop of efficient therapies.”
The study was published in the journal Cancer Cell.
---
Glossary
Deep Visual Proteomics: a spatial proteomics method developed in the laboratory of Professor Matthias Mann (Mund et al., Nature Biotechnology, 2022). This method combines modern microscopy, artificial intelligence, laser microdissection and ultra-sensitive mass spectrometry.
Low-grade serous cancer: short LGSC is a slow-growing but invasive form of epithelial ovarian cancer that typically affects younger women. Unlike high-grade serous carcinoma, LGSC has fewer genetic mutations, responds poorly to standard chemotherapy, and is often associated with prior serous borderline tumors.
Mass spectrometry: is an analytical technique that separates and measures ions according to their mass-to-charge ratio to identify and quantify chemical substances or molecules. It is a cornerstone technology in proteomics, enabling the identification and quantification of thousands of proteins in complex biological samples.
Microdissection: is a microscopic procedure in which individual cells or groups of cells are cut out of a tissue section using a laser.
Milciclib: An investigational oral drug that inhibits cyclin-dependent kinases (CDKs). These enzymes are involved in cell cycle regulation, and their inhibition can slow or stop the growth of cancer cells
Mirvetuximab: An antibody-drug conjugate (ADC) designed to selectively target cancer cells expressing the protein folate receptor alpha (FOLR1) on their surface. It delivers a cytotoxic agent directly to these cells, thereby minimizing damage to healthy tissue.
Protein panel: is a collection of several proteins that are analyzed together as a biomarker pattern in order to detect and monitor certain diseases or to assess the course of a disease. Such panels are often used in diagnostics to obtain meaningful results by simultaneously measuring different proteins from a sample (e.g. blood or plasma).
Proteome: comprises the totality of all proteins in a living organism, a tissue or a cell at a specific point in time. The proteome is highly dynamic and reacts to the requirements of the cell, as well as to diseases or environmental influences.
Proteomics: is the study of the proteome.
Serous Borderline Tumors: Non-invasive epithelial tumors of the ovary that show abnormal cell growth but lack the capacity to invade surrounding tissues. These tumors generally have a favorable prognosis and are often curable with surgery. However, a small percentage can progress to low-grade serous carcinoma over time.
Prof. Dr. Matthias Mann
Department of Proteomics and Signal Transduction
Max Planck Institute of Biochemistry
Am Klopferspitz 18
82152 Planegg/ Martinsried
Germany
E-Mail: mmann@biochem.mpg.de
http://www.biochem.mpg.de/mann
Lisa Schweizer, Hilary A. Kenny, Rahul Krishnan, Lucy Kelliher, Agnes Bilecz, Janna Heide, Leonhard Donle, Aasa Shimizu, Andreas Metousis, Rachelle Mendoza, Thierry M. Nordmann, Sarah Rauch, Sabrina Richter, Yan Li, Florian A. Rosenberger, Maximilian T. Strauss, Katherine C. Kurnit, Marvin Thielert, Edwin Rodriguez, Johannes B. Müller-Reif, S. Diane Yamada, Fabian J. Theis, Andreas Mund, Ricardo R. Lastra, Matthias Mann, and Ernst Lengyel: Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression, Cancer Cell, June 2025
DOI: https://doi.org/10.1016/j.ccell.2025.06.004
https://www.cell.com/cancer-cell/fulltext/S1535-6108(25)00253-3
https://www.biochem.mpg.de/when-tumors-turn-invasive-new-research-on-ovarian-can... - Press Release on the Website of the MPI of Biochemistry
Tissue section of a serous Borderline tumor. In this microscopy image, cells have been stained using ...
Source: Photo: Lisa Schweizer
Copyright: MPI of Biochemistry
Criteria of this press release:
Journalists, Scientists and scholars, Students, all interested persons
Biology, Medicine
transregional, national
Research results, Scientific Publications
English
Tissue section of a serous Borderline tumor. In this microscopy image, cells have been stained using ...
Source: Photo: Lisa Schweizer
Copyright: MPI of Biochemistry
You can combine search terms with and, or and/or not, e.g. Philo not logy.
You can use brackets to separate combinations from each other, e.g. (Philo not logy) or (Psycho and logy).
Coherent groups of words will be located as complete phrases if you put them into quotation marks, e.g. “Federal Republic of Germany”.
You can also use the advanced search without entering search terms. It will then follow the criteria you have selected (e.g. country or subject area).
If you have not selected any criteria in a given category, the entire category will be searched (e.g. all subject areas or all countries).
