Endocrine Organs

Research projects

Dissecting the role of tumor cell heterogeneity in Pancreatic Neuroendocrine Tumor progression

Group Marinoni, Perren, Sadowski   Cancer is a dynamic disease; genetic and epigenetic alterations drive intra-tumoral cell heterogeneity, resulting in the selection of aggressive cell populations capable of driving progression and ultimately metastasis. Pancreatic neuroendocrine tumours (PanNETs) are tumours that arise from the islets of Langerhans. They exhibit intra-tumoral cell heterogeneity, but it is unclear how this evolves during tumour development and how it contributes to progression. Our previous data suggest that epigenetic changes are the major drivers of progression and cell heterogeneity in PanNETs. By integrating epigenetic and transcriptomic profiles, we found that cell dedifferentiation and metabolic changes characterise the progression from small PanNETs to more advanced ones. We are currently investigating the evolution of intra-tumoral heterogeneity of PanNETs through space and time. Specific cell subpopulations identified as driving progression could then be targeted to stop metastasis formation. The identification of targetable pathways that impair metastasis formation will provide a rationale for new treatments.

Targeting Metabolic Supercomplexes in Therapy-Resistant Prostate Cancer

Pandey group  Prof. Dr. phil. Amit V. Pandey

Castration-resistant prostate cancer (CRPC) represents a lethal stage of the disease, primarily driven by the tumor's ability to overcome therapy through the synthesis of its own androgens. 

Our research has advanced beyond studying single enzymes to investigate their higher-order organization into what we term "metabolic supercomplexes" or "metabolons." 

Our central hypothesis is that key enzymes in androgen production, such as CYP17A1, AKR1C3, and STS, do not function in isolation. Instead, they form organized, multi-protein complexes at the interface of cellular compartments, like the endoplasmic reticulum and the cytosol. These supercomplexes act as hyper-efficient production lines, utilizing a mechanism called "substrate channeling" to rapidly convert precursors into potent androgens that fuel cancer growth. 

This model provides a powerful new explanation for the robust resistance observed against drugs like abiraterone. Our current work focuses on characterizing the structure and function of these supercomplexes. The ultimate goal is to develop innovative therapeutic strategies that not only inhibit key enzymes but also disrupt the crucial protein-protein interactions that hold these metabolic machines together, potentially using novel small molecules or advanced nanoparticle-based delivery systems.