A team of researchers led by Prof. Matthias Mann from the Max Planck Institute of Biochemistry in Martinsried and Prof. Ernst Lengyel from the University of Chicago has made a significant advance in the understanding and potential treatment of low-grade serous ovarian cancer (LGSC). This rare form of ovarian cancer, which accounts for around five to ten percent of epithelial ovarian cancers, mainly affects younger women and is largely resistant to conventional chemotherapy. The study, published in the journal “Cancer Cell”, provides new insights into tumor development and suggests a promising therapeutic strategy that significantly reduced tumor burden in preclinical models.

The scientists combined innovative deep visual proteomics technology with spatial transcriptomics to decipher the molecular mechanisms that transform benign serous borderline tumors into invasive, metastatic carcinomas. These borderline tumors, which are often successfully treated surgically, can in some cases recur as LGSC and then become life-threatening. Until now, the processes that control this transition were largely unknown. By analyzing tissue samples from different stages of the disease – from benign tumors to micropapillary intermediate stages to invasive LGSC and their metastases – the team was able to create detailed molecular maps.

High-precision laser microdissection was used to isolate tumor cells and cells from the tumor environment. Machine learning and ultra-high sensitivity mass spectrometry were used to generate protein signatures for each cell type, providing insight into the underlying biological processes. Deep visual proteomics technology enabled the mapping of thousands of proteins at single-cell resolution, while the integration of spatial protein and RNA analyses localized altered signaling pathways in tumor tissue. These analyses revealed how tumor cells interact with their environment and pointed to early signs of malignant progression in micropapillary tumors.

A key finding of the study was the identification of new molecular players that drive tumor progression. Particularly striking was the protein NOVA2, which was exclusively detectable in invasive tumors and metastases, while it was absent in benign tumors. This protein could represent a molecular switch that promotes the invasion of tumor cells. Other proteins have been identified as markers for tumor development. Experiments with human cell cultures and artificial growth environments showed that the removal of these proteins significantly restricted the proliferation and invasion of tumor cells into healthy tissue.

Based on the molecular data, 16 potential drug targets were identified and tested in cell models. A novel combination therapy of milciclib, which inhibits cell proliferation, and mirvetuximab, which delivers targeted toxic substances to tumor cells with FOLR1 protein on the surface, showed remarkable results in mouse models. The treatment significantly reduced tumor burden and offers hope for patients with this chemoresistant form of cancer, for which only limited treatment options currently exist. Unlike high-grade ovarian cancer, LGSC grows slowly but invades deep into healthy tissue, leading to late recurrence.

The results mark an important step in understanding the complex biology of LGSC and highlight the potential of spatial omics technologies for cancer research. Although further clinical trials are needed to confirm the safety and efficacy of the proposed therapy, this approach could significantly improve treatment prospects for affected patients. The study shows how interdisciplinary collaboration and innovative technologies can open up new avenues in the fight against difficult-to-treat cancers.

Original Paper:

Spatial proteo-transcriptomic profiling reveals the molecular landscape of borderline ovarian tumors and their invasive progression – ScienceDirect

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