Pellegata, N. S. | bioRxiv Science

bioRxiv2025

A genetic signature predicts aggressive paraganglioma sensitivity to dual PI3K-CDK4/6 inhibition therapy

Effective medical therapies for metastatic paraganglioma (mPPGL) are currently lacking, leading to dismal prognosis. Building on our knowledge of molecular mechanisms driving PPGL progression, we assessed the therapeutic potential of targeting two critical processes: PI3K signaling and cell cycle regulation. The efficacy of buparlisib (PI3Ki) and ribociclib (CDK4/6i), individually and combined, was assessed in vitro using PPGL cell lines, rat- and patient-derived primary cells, and in vivo using PPGL cells-derived mouse xenografts. The combination therapy demonstrated superior antitumor activity compared to single agents, particularly in vivo. Mechanistically, the efficacy of the combination therapy was associated to the downregulation of FOXM1-controlled genes implicated in mitotic spindle assembly and chromosomal segregation, leading to mitotic catastrophe. Data mining and qRT-PCR showed this genetic signature to be upregulated in human mPPGLs. This suggests that aggressive PPGLs exhibit heightened vulnerability to dual PI3K and CDK4/6 inhibition, offering a promising therapeutic avenue for these challenging cancers.

cancer biology↗

bioRxiv2024

Systematic mapping of MCU-mediated mitochondrial calcium signaling networks

The Mitochondrial Ca2+ Uniporter Channel (MCUC) allows calcium entry into the mitochondrial matrix to regulate energy metabolism but also cell death. Although, several MCUC components have been identified, the molecular basis of mitochondrial Ca2+ signaling networks and their remodeling upon changes in uniporter activity have not been systematically assessed. Using an unbiased and quantitative proteomic approach, we map the MCUC interactome in HEK293 cells under physiological conditions and upon chronic loss or gain of mitochondrial Ca2+ uptake. Besides all previously known subunits of the uniporter, we identify 89 high-confidence interactors linking MCUC to several mitochondrial complexes and pathways, half of which are currently linked to metabolic, neurological, and immunological diseases. As a proof-of-concept, we validate EFHD1 as a binding partner of MCU, EMRE and MCUB with a MICU1-dependent inhibitory effect on Ca2+ uptake. To investigate compensatory mechanisms and functional consequences of mitochondrial Ca2+ dyshomeostasis, we systematically survey the MCU interactome upon silencing of EMRE, MCUB, MICU1 or MICU2. We observe profound changes in the MCU interconnectivity, whereby downregulation of EMRE reduces the number of MCU interactors of over 10-fold, while silencing of MCUB leads to a wider functional network linking MCU to mitochondrial stress response pathways and cell death. Altogether our study provides a comprehensive map of MCUC protein-protein interactions and a rich, high-confidence resource that can be explored to gain insights into the players and mechanisms involved in calcium signal transduction cascades and their relevance in human diseases.

cell biology↗