Biology subjects

Cirillo, G.

Publications and source records attributed to Cirillo, G..

3 recordsLinked to original sources

bioRxiv2025

Mapping glioblastoma spreading: connexin43 and glial dynamic in mouse and human glioblastoma microenvironment

High-grade gliomas (HGGs), including astrocytoma and glioblastoma (GBM), constitute the most prevalent primary tumors of the central nervous system (CNS). GBM cells demonstrate a notable ability to infiltrate the brain parenchyma, precluding complete surgical resection. Here we investigated the spreading of GBM cells and the response of the CNS microenvironment focusing on glial cells, which are essential interactors to GBM. We used acute and organotypic slices from the mouse brain and peritumoral cortex of patients with HGGs. We found that human peritumoral tissue from cortical resection was characterized by high levels of the astrocytic Connexin43 protein (Cx43) and discrete infiltration of microglia. In contrast, the tumor core exhibited high myeloid infiltration and an altered extracellular matrix (ECM) composition, which was poor in CD44. We tracked mouse and primary human-labeled-GBM cells in 2D cultures and in co-culture with organotypic slices generated from mouse brain and human peritumoral tissues. We found that the implanted GBM cells infiltrated the brain tissue, implying early glial modifications including an increase in Cx43 expression and distribution. Furthermore, the blockage of Cx43 hemichannels was accompanied by morphological changes and polarization of human GBM cells, typical for migration phenomena. The present study sheds light on the dynamics of GBM cells spreading in the living brain tissue, suggesting that the progression of the tumor correlates with changes within the host brain. Our findings identify the upregulation of Cx43 expression as a highly consistent modification in both mouse and human tissue that may be crucial for GBM infiltration.

neuroscience↗

bioRxiv2025

Sustained dynamics of saccadic inhibition and adaptive oculomotor responses during continuous exploration

In natural environments, stimuli often recur across time and space, requiring the visual system to remain sensitive to novelty while managing predictability. A central question in systems neuroscience is how motor systems adapt to repeated sensory events without compromising responsiveness. We investigated this adaptive capacity using saccadic inhibition (SI)--a reflexive suppression of eye movements triggered by sudden visual transients--as a probe of oculomotor dynamics during naturalistic viewing. Human participants (N = 21) freely explored visual arrays while brief gaze-contingent flashes appeared five times at random intervals, either foveally or parafoveally. SI reliably occurred [~]120 ms post-flash across repetitions and locations, indicating robust sensory-driven inhibition. However, the rebound phase--reflecting saccade reprogramming--showed a progressive decline. In a second experiment (N = 19), only the first or the fifth flash was visible on each trial. In this case, neither inhibition nor rebound was altered, suggesting that the rebound decline is driven by repeated sensory stimulation rather than exploration time. This dissociation reveals selective habituation of motor re-engagement mechanisms, while reflexive inhibitory gating remains stable. We propose that inhibition is mediated by circuitry that transiently suppresses saccade initiation and resists habituation. By contrast, the weakening rebound reflects a separate, habituation-prone route that reduces saccade generation to irrelevant events. Functionally, this imbalance implies a recalibration within the saccade generator, preserving inhibitory capacity while constraining motor output. Our findings uncover a distinct form of oculomotor habituation and demonstrate how SI reveals dynamic decoupling of sensory input and motor output under repeated stimulation. Significance StatementThe ability to interrupt and resume eye movements in response to environmental changes is fundamental to visual exploration. We investigated how this process unfolds across repeated visual transients in naturalistic conditions. Our findings show that saccadic inhibition remains stable across time, whereas the subsequent rebound phase habituates. This dissociation suggests that distinct processes mediate reflexive interruption and motor recovery habituation. Our data indicate that dynamic modulation of motor gating circuits is a mechanism for optimizing oculomotor behavior. These results deepen our understanding of visual-motor coordination, provide insight about the constraints governing the underlying system circuitry, and may inform clinical tools for assessing sensorimotor adaptability in health and disease.

neuroscience↗

bioRxiv2022

Copper chelation inhibits TGF-β pathways and suppresses epithelial-mesenchymal transition in cancer

Copper is a trace element essential to cellular function with elevated levels implicated in cancer progression. Clinical trials using copper chelators are associated with improved patient survival, however, the molecular mechanisms by which copper depletion inhibits tumor progression are poorly understood. This remains a major hurdle to the clinical translation of copper chelators. Epithelial-mesenchymal transition (EMT) is often exploited by malignant cells to promote growth and metastasis. Transforming growth factor (TGF)-{beta} is a master regulator of EMT and facilitates cancer progression through changes in the tumor and its microenvironment. Herein, we report that a reduction of copper with the chelating agent tetraethylenepentamine (TEPA) inhibited EMT in vitro in three diverse cancer cell types; human triple-negative breast cancer (TNBC), neuroblastoma (NB), and diffuse intrinsic pontine glioma (DIPG) cell lines. Single-molecule imaging demonstrated EMT markers including Vimentin, {beta}-catenin, ZEB1, and p-SMAD2 had increased expression with copper treatment and this pro-mesenchymal shift was rescued by the addition of TEPA. Moreover, SNAI1, ZEB1, and p-SMAD2 demonstrated increased accumulation in the cytoplasm after treating with TEPA. Transcriptomic analyses revealed a significant downregulation of the EMT pathway, including canonical (TGF-{beta}/SMAD2&3) and non-canonical (TGF-{beta}/PI3K/AKT and TGF-{beta}/RAS/RAF/MEK/ERK) TGF signaling pathways. Matrix metalloproteinases MMP-9 and MMP-14 proteins which activate latent TGF-{beta} complexes were also downregulated by TEPA treatment. These molecular changes are consistent with reduced plasma levels of TGF-{beta} we observed in cancer models treated with TEPA. Importantly, copper chelation reduced metastasis to the lung in a TNBC orthotopic syngeneic mouse model. Our studies suggest copper chelation therapy can be used to inhibit EMT-induced metastasis by targeting TGF-{beta} signalling. Because on-target anti-TGF-{beta} therapies are failing in the clinic, copper chelation presents itself as a potential therapy for targeting TGF-{beta} in cancer.

cancer biology↗