Biology subjects

Godinho, S. A.

Publications and source records attributed to Godinho, S. A..

3 recordsLinked to original sources

bioRxiv2023

High prevalence and dependence of centrosome clustering in mesenchymal tumors and leukemia

The presence of supernumerary centrosomes is a hallmark of cancer and is frequently observed in aggressive tumors. Cancer cells with centrosome amplification achieve pseudo-bipolar spindles through specific coping mechanisms in order to survive. However, their distribution and prevalence in cancer remain largely unknown. Here, using the NCI60 panel of cancer cell lines, we show that the presence of coping strategies correlates with centrosome amplification, with the clustering of extra-centrosomes within the two spindle poles being the most widespread mechanism. Moreover, we report an association between centrosome clustering ability and the epithelial-to-mesenchymal transition (EMT) and observe that the induction of mesenchymal characteristics in breast cancer cells with centrosome amplification promotes clustering. Furthermore, we unveil hematological malignancies, which lack epithelial characteristics, as the most proficient in centrosome clustering. Finally, we show that acute lymphoblastic leukemia is particularly sensitive to targeting clustering through inhibition of the spindle assembly checkpoint. Our study reveals how centrosome clustering and the EMT collaborate to promote carcinogenesis, suggesting new possibilities to treat tumors with low epithelial characteristics, in particular leukemias. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=74 SRC="FIGDIR/small/532472v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@12a713dorg.highwire.dtl.DTLVardef@1706edborg.highwire.dtl.DTLVardef@7deea7org.highwire.dtl.DTLVardef@1bf2280_HPS_FORMAT_FIGEXP M_FIG C_FIG O_LICentrosome clustering is widespread in the NCI60 panel and particularly strong in leukemia. C_LIO_LIThe EMT enhances the ability of cancer cells to cope with multiple centrosomes through centrosome clustering. C_LIO_LICentrosome clustering gene expression peaks at the invasive stage and has prognostic value in breast cancer. C_LIO_LIThe inhibition of MPS1 is a good strategy to promote the death of acute lymphoblastic leukemia (ALL) cells with CA. C_LI

cancer biology↗

bioRxiv2022

Centrosome amplification fine-tunes tubulin acetylation to differentially control intracellular organization

Intracellular organelle organisation is conserved in eukaryotic cells and is primarily achieved through active transport by motor proteins along the microtubule cytoskeleton. Microtubule posttranslational modifications (PTMs) contribute to microtubule diversity and differentially regulate motor-mediated transport. Here we show that centrosome amplification induces a global change in organelle positioning towards the cell periphery and facilitates nuclear migration through confined spaces. This reorganisation requires kinesin-1 and is analogous to loss of dynein. Cells with amplified centrosomes display increased levels of acetylated tubulin, a PTM known to enhance kinesin-1 mediated transport. Depletion of -tubulin acetyltransferase 1 (TAT1) to block tubulin acetylation, which has no impact on control cells, rescues the displacement of centrosomes, mitochondria and vimentin, but not Golgi or endosomes. Analyses of the distribution of acetylated microtubules indicates that the polarisation of modified microtubules, rather than levels alone, plays an important role in organelle positioning. We propose that tubulin acetylation differentially impacts kinesin-1-mediated organelle displacement, suggesting that each organelle must have its own sensing and response mechanisms to ensure fine-tuning of its distribution in cells.

cell biology↗

bioRxiv2020

Centrosome amplification mediates small extracellular vesicles secretion via lysosome disruption

Bidirectional communication between cells and their surrounding environment is critical in both normal and pathological settings. Extracellular vesicles (EVs), which facilitate the horizontal transfer of molecules between cells, are recognized as an important constituent of cell-cell communication. In cancer, alterations in EV secretion contribute to the growth and metastasis of tumor cells. However, the mechanisms underlying these changes remain largely unknown. Here, we show that centrosome amplification is associated with and sufficient to promote small extracellular vesicle (SEV) secretion in pancreatic cancer cells. This is a direct result due of lysosomal dysfunction, caused by increased reactive oxygen species (ROS) downstream of extra centrosomes. Defects in lysosome function promotes multivesicular body fusion with the plasma membrane, thereby enhancing SEV secretion. Furthermore, we find that SEVs secreted in response to amplified centrosomes are functionally distinct and activate pancreatic stellate cells (PSCs). These activated PSCs promote the invasion of pancreatic cancer cells in heterotypic 3-D cultures. We propose that SEVs secreted by cancer cells with amplified centrosomes influence the bidirectional communication between the tumor cells and the surrounding stroma to promote malignancy.

cell biology↗