Research lines

• Ras GTPases: regulation and new roles in tumorigenesis

  Ras proteins are GTPases that regulate signal transduction pathways, which control cell proliferation, differentiation, survival and apoptosis. K-Ras oncogenic mutations (one of the Ras isoforms) are highly frequent in colorectal, pancreas and lung cancers. Unfortunately, at this moment we do not have suitable K-Ras inhibitors for therapy. To better understand the regulation of K-Ras and look for strategies to inhibit its oncogenic action, our group is analyzing new proteins that might be interacting with K-Ras and regulate its function. We have shown that calmodulin and hnRNPA2 proteins bind specifically to K-Ras and modifies its functionality: Calmodulin inhibits K-Ras phosphorylation at ser181 in colorectal cancer cells; and the hnRNPA2 protein promotes signaling of K-Ras in pancreatic adenocarcinoma cells.  Most important phosphorylation of KRAS and hnRNPA2 interaction modulates important oncogenic properties of KRAS such tumor growth, metastasis, and RNA loading into extracellular vesicles. We are also studying how intracellular trafficking of KRAS and other small GTPases (ex.: RAC1) regulate important cellular processes such as proliferation, cell migration and mobility.  

• Intracellular cholesterol transport and membrane repair in lysosomal diseases

  The endolysosomal (LE/Lys) compartment is the main intracellular reservoir of cholesterol and acts as a sorting center from which cholesterol is delivered to the plasma membrane, endoplasmic reticulum (ER) or other intracellular destinations. Mutations in the NPC intracellular cholesterol transporter 1 (NPC1) protein lead to abnormal cholesterol accumulation in LE/Lys, causing Niemann-Pick type C (NPC) disease. Although NPC1 is essential for cholesterol export from LE/Lys, the underlying mechanisms remain incompletely understood. 

  Current therapies to reduce cholesterol accumulation in NPC are limited, underscoring the need for novel therapeutical strategies, including the identification of new molecular targets and small molecules that could help restore normal cholesterol cellular distribution. We hypothesize that elucidating how intracellular cholesterol distribution is regulated -by modulating the location, interaction partners, and function of LE/Lys and membrane contact sites (MCS)- will provide valuable insights to advance therapeutic approaches for cholesterol-related disorders such as NPC. 

  To address these questions, we use advanced cellular, molecular and imaging techniques, including patient-derived iPSCs-differentiated neurons, proximity ligation assay (PLA) microscopy, transmission electron microscopy (TEM), proximity-dependent biotinylation (PDB) proteomics, and mouse models. 

• Cell Death, Senescence, and Cancer Precision Medicine

  Led by Dr. J. Montero. 

  The Montero Lab studies cell death, senescence and cancer precision medicine at the University of Barcelona's Department of Biomedical Sciences. Focusing on the molecular mechanisms driving tumor progression and resistance, the lab works to uncover therapeutic targets that can prevent cancer spread, with a strong emphasis on translational research that bridges basic science with potential clinical applications. In summary, our work involves creating innovative tools and discovering new therapies for personalized cancer treatment. We collaborate with numerous oncologists and researchers worldwide on several exciting translational medicine projects. 

  • We utilize the novel technique dynamic BH3 profiling (DBP) as a precision medicine tool for various cancers, both pediatric and adult, to assist clinicians in identifying the most effective treatment for each patient. 

  • We employ DBP and other functional technologies to discover new therapies aimed at preventing tumor resistance to treatments. 

  • Our laboratory investigates the cellular process of senescence to uncover novel senolytic strategies. 

  • By using advanced biotechnology tools, we develop innovative technologies for personalized cancer treatment. 

• Replication Stress and Autophagy in Chromosome Instability

  Led by C. Mauvezin.

  Genomic instability is a hallmark of tumor cells, resulting from errors in mitotic progression such as prolonged mitosis, DNA damage on bridged chromosomes or misaligned chromosomes. A better understanding of the upstream triggers of CIN are a long-standing objective in cancer research. Our laboratory is specifically interested in the interconnection between replicative stress, autophagy and CIN biomarkers. We showed that after severe replicative stress, untransformed cells enter into senescence, whereas most tumor cells are capable to recover and resume proliferation, often accumulating genomic alterations in the process. Interestingly, the reinitiation of DNA synthesis in tumor cells relies on the firing of new replication origin, thus making this event a possible target for cancer therapy upon replication stress induction. In addition, we uncovered a protective role for autophagy and lysosomes in mitosis, thus opening new avenues for CIN-targeted therapy in cancer. Importantly, we have characterized the toroidal nuclei as a new CIN biomarker, providing a novel tool for monitoring genome integrity in cancer cells.