Biology subjects

Herranz, H.

Publications and source records attributed to Herranz, H..

4 recordsLinked to original sources

bioRxiv2024

Control of mitochondrial dynamics by dPGC1 limits Yorkie-induced oncogenic growth in Drosophila

Mitochondrial function and dynamics are essential for maintaining cellular homeostasis and overall health. Disruptions in these processes can contribute to various diseases, including cancer. The Hippo signaling pathway, a key regulator of tissue growth, plays a central role in cancer through its main effector, the Yes-associated protein (YAP), known as Yorkie (Yki) in Drosophila. In this model organism, Yki upregulation drives benign tissue overgrowth in imaginal discs. Our research shows that the conserved metabolic regulator dPGC1 restricts Yki-driven tissue hyperplasia and helps maintain epithelial integrity in vivo. Combined Yki upregulation and dPGC1 depletion results in tumors characterized by enlarged mitochondria and upregulation of genes promoting mitochondrial fusion, a condition that is both necessary and sufficient for Yki-driven oncogenic growth. We further demonstrate that mitochondrial enlargement is associated with increased levels of the cell cycle regulator Cyclin E, which is critical for tumor development. These findings identify dPGC1 as a context-dependent tumor suppressor that coordinates mitochondrial dynamics and cell cycle regulation in response to oncogene activation, with implications for understanding cancer development in humans.

developmental biology↗

bioRxiv2022

Ketones facilitate transcriptional resolution of secondary DNA structures in premature aging

There is currently no established intervention for Cockayne syndrome, a disease characterized by progressive early onset neurodegeneration with features of premature aging. Here, we tested if acetyl-CoA precursors, citrate and beta-hydroxybutyrate, could reduce features of Cockayne syndrome in three model systems. We identified the gene Helicase 89B as a homologue of CSB in drosophila and found that the ketone beta-hydroxybutyrate rescued features of premature aging in Hel89B deficient flies. In mammals, loss of the citrate carrier Indy exacerbated the phenotype of Csbm/m mice which was rescued by a ketogenic diet. The rescue effect appeared to be mediated through ketone stimulated histone acetylation and facilitation of transcriptional readthrough of secondary DNA structures. These findings link a ketogenic diet with transcriptional resolution of secondary structures and DNA repair.

physiology↗

bioRxiv2020

Insulin signaling mediates neurodegeneration in glioma

Cell to cell communication facilitates tissue development and physiology. Under pathological conditions, brain tumors disrupt glia-neuron communication signals that in consequence, promote tumor expansion at the expense of surrounding healthy tissue. The glioblastoma is the most aggressive and frequent brain tumor. This type of glioma expands and infiltrates into the brain, causing neuronal degeneration and neurological decay, among other symptoms. Here we describe how the glioblastoma produce ImpL2, an antagonist of the insulin pathway, which is regulated by the microRNA miR-8. ImpL2 targets neighboring neurons and causes mitochondrial disruption as well as synapse loss, both early symptoms of neurodegeneration. Furthermore, glioblastoma progression requires insulin pathway attenuation in neurons. Restoration of neuronal insulin activity is sufficient to rescue the synapse loss and to delay the premature death caused by glioma. Therefore, signals from GB to neuron emerge as a potential field of study to prevent neurodegeneration and to develop anti-tumoral strategies. Significance StatementGlioblastoma (GB) is the most aggressive type of brain tumour and currently there is no cure or effective treatment. Patients course with neurological decay and previous data in animal models indicate that GB cause a neurodegenerative process. We describe here a molecule named ImpL2 that is produced by GB cells and impact on neighbouring neurons. ImpL2 is an antagonist of the insulin pathway and signaling reduction in neurons causes mitochondrial defects and synapse loss. These mechanisms underlying GB-induced neurodegeneration plays a central role in the premature death caused by this tumour. Restoration of insulin signaling in neurons prevents tumour progression and rescues the lethality caused by GB in Drosophila models.

neuroscience↗

bioRxiv2019

Genome-wide RNAi screen for context-dependent tumor suppressors identified using in vivo models for neoplasia in Drosophila

Genetic approaches in Drosophila have successfully identified many genes involved in regulation of growth control as well as genetic interactions relevant to the initiation and progression of cancer in vivo. Here, we report on large-scale RNAi-based screens to identify potential tumor suppressor genes that interact with known cancer-drivers: The Epidermal Growth Factor Receptor and the Hippo pathway transcriptional cofactor Yorkie. These screens were designed to identify genes whose depletion drove tissue expressing EGFR or Yki from a state of benign overgrowth into neoplastic transformation in vivo. We also report on an independent screen aimed to identify genes whose depletion suppressed formation of neoplastic tumors in an existing EGFR-dependent neoplasia model. Many of the positives identified here are known to be functional in growth control pathways. We also find a number of novel connections to Yki and EGFR driven tissue growth, mostly unique to one of the two. Thus, resources provided here would be useful to all researchers who study negative regulators of growth in the context of activated EGFR and/or Yki and positive regulators of growth in the context of activated EGFR.

developmental biology↗