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

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 EMT collaborate to promote carcinogenesis, suggesting new possibilities to treat tumors with low epithelial characteristics, in particular leukemias.

Adaptation of human cell populations to different levels of centriole amplification involves a two-step response

“…We chose to use MCF10A-PLK4, a cell line derived from non-transformed breast tissue 11 , where PLK4 overexpression is induced by adding doxycycline (Dox) to the culture medium. This system is widely used to study the implications of altered centrosome number in cell physiology and breast cancer 11,13,21,42,43 , widening the implications of our study.…”