Scientific Symposium

Modeling Diabetes-Associated Genetic Variants Using Human Stem Cell-Derived Islets

Type 2 diabetes is a multifactorial disease in which pancreatic beta-cell dysfunction and loss contribute to disease progression. Zinc plays an important role in beta-cell biology, including insulin storage and secretion, and is transported into insulin-containing granules by the zinc transporter ZnT8, encoded by SLC30A8. Interestingly, loss-of-function variants in SLC30A8 can protect against type 2 diabetes and beta-cell apoptosis, although the mechanisms underlying this protection remain poorly understood. Using human embryonic stem cell-derived islets carrying the protective R138X loss-offunction variant, we investigated how intracellular zinc depletion affects betacell identity, survival and function. We found that zinc depletion compromises islet identity and function, whereas the SLC30A8 R138X variant protects beta cells from these deleterious effects. These findings provide new insights into the role of ZnT8 in human beta-cell biology and illustrate how stem cell-derived models can be used to investigate the mechanisms underlying protective genetic variants.

Marie Gasser completed a Master’s degree in analytical chemistry and a PhD in biomedical sciences, during which she investigated the impact of environmental pollutants on human adipose tissue, obesity and type 2 diabetes. Dr. Gasser recently completed her postdoctoral research at the CHUM Research Centre in Montreal, Canada. Her interdisciplinary research focuses on understanding how genetic and environmental factors contribute to disease development, with a particular interest in the complex interactions between organs that drive metabolic disease progression.

Same receptor, different rules: decoding tissue selectivity of shared oncogenic drivers in gynecological cancers

The Estrogen Receptor alpha (ERα) is a nuclear receptor that plays a major oncogenic role in both breast and endometrial cancer. Although ERα is a critical oncogenic driver transcription factor in both tumor types, its chromatin occupancy, and consequent downstream transcriptional output, are remarkably different between the two. We aimed to identify the molecular mechanisms underlying these tissue-specific chromatin interactions of ERα. Strikingly, tissue-selective activity persisted in plasmid-based massively parallel reporter assays, implying a non-epigenetic mechanism. Instead, tissuespecific expression of transcriptional co factors served as a critical driver of selective ERα action, leading to the discovery of two novel endometrial cancer ERα co-factors, with strong prognostic potential. These findings lay the foundation for identifying candidate vulnerabilities for tissue-selective treatment of cancer, serving as a blueprint for research in other gynecological malignancies.

Sebastian Gregoricchio obtained his PhD in Molecular and Cellular Biology at the Institute Gustave Roussy (Villejuif/Paris, France) under the supervision of Dr. Christel Guillouf, studying the role of the SPI1/PU.1 transcription factor in enhancer repression in erythroleukemia. He then moved to Amsterdam (The Netherlands) as a postdoctoral fellow in Prof. Wilbert Zwart’s group at the Netherlands Cancer Institute. There he studies nuclear receptors in hormone-dependent cancers and in particular their role in the epigenetic regulation of oncogenic programs by combining both wet-lab and computational (epi-)genomic approaches.

Reading Cancer's Ribosome: From Assembly to Selectivity in Cancer Translation

For decades, ribosomes were viewed as uniform, interchangeable machines, passive molecular machines that faithfully translated whatever mRNAs were available. Although the catalytic and structural roles of rRNA are well established, whether individual rRNA modifications could actively shape which messages are translated remained largely unexplored. We showed that chemical modifications of rRNA, particularly 2′-O-methylation deposited by fibrillarin (FBL) can create specialized “onco-ribosomes” that selectively translate oncogenic mRNAs. Loss of FBL in triplenegative breast cancer cells rewires the ribosome itself, destabilizing rRNA structure, selectively displacing RPS28, and shutting down translation of specific oncogenes MTA1, IRAK1, and TMSB10. These findings reveal site-specific rRNA modification not as a passive housekeeping feature, but as an active and disease-relevant determinant of translational selectivity.

Kanchan Kumari earned her PhD at the Institute of Life Sciences, Bhubaneswar, India. A short postdoctoral year there sharpened her interest in RNA biology. In 2020, she moved to Sweden to join the Aguilo group at Umeå University's Department of Molecular Biology, where she has spent the past six years uncovering how RNA modifications drive breast and ovarian cancer progression.

Mapping and targeting immune - stromal interactions in ovarian cancer

High-grade serous ovarian cancer (HGSOC) is the most lethal gynaecological malignancy and remains largely unresponsive to immunotherapies. We leveraged in vivo proximity-labelling approaches and novel transgenic mouse models to identify novel immunotherapeutic targets specific to the metastatic niche. We show that fibroblasts in micro-metastases are amongst the first sensors of disseminating tumour cells and undergo substantial transcriptomic and phenotypic reprogramming, acquiring diverse immune-regulatory functions. Amongst these, fibroblasts engage both effector and regulatory (Treg) CD4+ T cells and control their function via antigen presentation. Critically, tumour-proximal fibroblasts upregulated the costimulatory ligand GITRL and promoted GITR+ Treg immune suppression; targeting of this novel fibroblast-Treg axis enhanced anti-tumour immunity and prevented metastatic progression, thus offering a new therapeutic avenue for HGSOC.

Julia Moreno-Vicente is a Research Associate at the Cancer Research UK Cambridge Institute, University of Cambridge, where she investigates the immunological regulation of ovarian cancer metastasis. She specialises in cancer immunology and immunotherapy, drawing on expertise in stromal immunology, proximity-labelling approaches and advanced animal models to study cellular interactions within the metastatic niche and inform the development of novel immunotherapeutic strategies.

Genomic Risk and Molecular Mechanisms in Gynecological Cancers

Gynecological cancers are complex diseases in which inherited genetic variation contributes to cancer susceptibility and clinical outcomes. In this presentation, I will discuss my work on genome-wide association studies (GWAS) of endometrial, cervical, and ovarian cancer, integrating large-scale genomic analyses with wet-lab experiments. For endometrial cancer, our GWAS meta analysis identified novel risk loci, with functional studies supporting a tumor-suppressive role for NAV3. In cervical cancer, we highlight the role of HLA and non-HLA variation in disease susceptibility. In ovarian cancer, GWAS of surgical resection outcomes identified genomic variants potentially associated with residual disease and survival. Together, these studies demonstrate how integrating large-scale genomics with functional and multi- OMIC approaches can advance our understanding of the molecular mechanisms underlying gynecological cancers.

Dhanya Ramachandran is a researcher in the Gynecology Research Unit at Hannover Medical School, Germany, investigating genomic risk factors for female cancers. Following a PhD in Molecular Medicine, her current research focuses on identifying genetic susceptibility variants for endometrial, ovarian and cervical cancers through large-scale genome-wide association studies. She utilizes patient-derived material and cell culture models to elucidate their functional roles in cancer development.