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

Marin, N. M.; Marteil, G.; Fresmann, N. C.; de Almeida, B. P.; Dores, K.; Fragoso, R.; Vaz, J. C.; Leal, J. B. P.; Taborda Barata, J. P.; Godinho, S. A.; Barbosa-Morais, N. L.; Bettencourt-Dias, M.

doi:10.1101/2023.03.13.532472

bioRxiv · 10.1101/2023.03.13.532472

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

Marin, N. M.·Marteil, G.·Fresmann, N. C.·de Almeida, B. P.·Dores, K.·Fragoso, R.·Vaz, J. C.·Leal, J. B. P.·Taborda Barata, J. P.·Godinho, S. A.·Barbosa-Morais, N. L.·Bettencourt-Dias, M.

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Abstract

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

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Marin, N. M., Marteil, G., Fresmann, N. C., de Almeida, B. P., Dores, K., Fragoso, R., Vaz, J. C., Leal, J. B. P., Taborda Barata, J. P., Godinho, S. A., Barbosa-Morais, N. L., Bettencourt-Dias, M.. 2023-03-17. High prevalence and dependence of centrosome clustering in mesenchymal tumors and leukemia. https://doi.org/10.1101/2023.03.13.532472

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