Michele Crestani

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Crestani

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Michele

ORCID

0000-0002-5089-6664

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Publications 1 - 3 of 3

Emergent seesaw oscillations during cellular directional decision-making
Ron, Jonathan E.; Crestani, Michele; Kux, Johan M.; et al. (2024)
Nature Physics
Motile cells inside living tissues often encounter junctions, where their path branches into several alternative directions of migration. We present a theoretical model of cellular polarization for a cell migrating along a one-dimensional line, arriving at a symmetric Y junction and extending protrusions along the different paths that originate at the junction. The model predicts the spontaneous emergence of deterministic oscillations of growth and cellular polarization between competing protrusions during the directional decision-making process. The oscillations are modified by cellular noise but remain a dominant feature that affects the time it takes the cell to migrate across the junction. These predictions are confirmed experimentally for two different cell types (non-cancerous endothelial and cancerous glioma cells) migrating on a patterned network of thin adhesive lanes with junctions.
PIP4K2B is mechanoresponsive and controls heterochromatin-driven nuclear softening through UHRF1
Poli, Alessandro; Pennacchio, Fabrizio A.; Ghisleni, Andrea; et al. (2023)
Nature Communications
Phosphatidylinositol-5-phosphate (PtdIns5P)-4-kinases (PIP4Ks) are stress-regulated phosphoinositide kinases able to phosphorylate PtdIns5P to PtdIns(4,5)P2. In cancer patients their expression is typically associated with bad prognosis. Among the three PIP4K isoforms expressed in mammalian cells, PIP4K2B is the one with more prominent nuclear localisation. Here, we unveil the role of PIP4K2B as a mechanoresponsive enzyme. PIP4K2B protein level strongly decreases in cells growing on soft substrates. Its direct silencing or pharmacological inhibition, mimicking cell response to softness, triggers a concomitant reduction of the epigenetic regulator UHRF1 and induces changes in nuclear polarity, nuclear envelope tension and chromatin compaction. This substantial rewiring of the nucleus mechanical state drives YAP cytoplasmic retention and impairment of its activity as transcriptional regulator, finally leading to defects in cell spreading and motility. Since YAP signalling is essential for initiation and growth of human malignancies, our data suggest that potential therapeutic approaches targeting PIP4K2B could be beneficial in the control of the altered mechanical properties of cancer cells.
Biomimetic Approach of Brain Vasculature Rapidly Characterizes Inter- and Intra-Patient Migratory Diversity of Glioblastoma
Crestani, Michele; Kakogiannos, Nikolaos; Iori, Simone; et al. (2024)
Small Methods
Glioblastomas exhibit remarkable heterogeneity at various levels, including motility modes and mechanoproperties that contribute to tumor resistance and recurrence. In a recent study using gridded micropatterns mimicking the brain vasculature, glioblastoma cell motility modes, mechanical properties, formin content, and substrate chemistry are linked. Now is presented, SP2G (SPheroid SPreading on Grids), an analytic platform designed to identify the migratory modes of patient-derived glioblastoma cells and rapidly pinpoint the most invasive sub-populations. Tumorspheres are imaged as they spread on gridded micropatterns and analyzed by this semi-automated, open-source, Fiji macro suite that characterizes migration modes accurately. SP2G can reveal intra-patient motility heterogeneity with molecular correlations to specific integrins and EMT markers. This system presents a versatile and potentially pan-cancer workflow to detect diverse invasive tumor sub-populations in patient-derived specimens and offers a valuable tool for therapeutic evaluations at the individual patient level.

Publications 1 - 3 of 3

Michele Crestani

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