Horta, C. | Search bioRxiv

bioRxiv2022

Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype

Polo-like kinase 4 (Plk4), the major regulator of centriole biogenesis, has emerged as a putative therapeutic target in cancer due to its abnormal expression in human carcinomas, leading to centrosome number deregulation, mitotic defects and chromosomal instability. Moreover, Plk4 deregulation promotes tumor growth and metastasis in mouse models and is significantly associated with poor patient prognosis. Here, we further investigate the role of Plk4 in carcinogenesis and show that its overexpression significantly potentiates resistance to cell death by anoikis of non-tumorigenic p53 knock-out (p53KO) mammary epithelial cells. Importantly, this effect is independent of Plk4s role in centrosome biogenesis, suggesting that this kinase has additional cellular functions. Interestingly, the Plk4-induced anoikis resistance is associated with the induction of a stable hybrid epithelial-mesenchymal phenotype and is partially dependent on P-cadherin upregulation. Furthermore, we found that the conditioned media of Plk4-induced p53KO mammary epithelial cells also induces anoikis resistance of breast cancer cells in a paracrine way, being also partially dependent on soluble P-cadherin secretion. Our work shows, for the first time, that high expression levels of Plk4 induce anoikis resistance of both mammary epithelial cells with p53KO background, as well as of breast cancer cells exposed to their secretome, which is partially mediated through P-cadherin upregulation. These results reinforce the idea that Plk4, independently of its role in centrosome biogenesis, functions as an oncogene, by impacting the tumor microenvironment to promote malignancy.

cancer biology↗

bioRxiv2022

Condensin II is required for efficient Spindle Assembly Checkpoint activation in Drosophila male meiosis

Reductional nuclear division in meiosis is essential for diploid life. A fundamental event in meiosis is chromatin condensation, through mechanisms not yet fully understood. Current data suggest that Condensins are key players in building and sustaining mitotic and meiotic chromosome structure. In Drosophila, Condensin II appears to be dispensable for faithful mitosis in somatic tissues yet essential in the germline. Previous work has demonstrated that in Drosophila male meiosis, Condensin II is required for the segregation of homologous chromosomes into distinct territories during prophase I, possibly through the resolution of chromosomal intertwines. Here we show that in addition to this well-established function in meiotic chromatin assembly, Condensin II is required for robust Spindle Assembly Checkpoint (SAC) signaling in male meiosis. In the absence of Condensin II, spermatocytes undergo faster meiotic divisions and display reduced ability to prolong meiosis in the presence of spindle poisons. This is attributed to the inability to recruit a key SAC component (Mad1) to the kinetochore. Importantly, we demonstrate that the absence of a robust SAC response in Condensin II mutants, and consequent accelerated meiosis, is a strong contributor to the meiotic defects associated with these mutants. We show that artificial prolongation of meiotic divisions, using conditions that delay anaphase onset in a SAC-independent manner, is sufficient to rescue segregation defects and aneuploidy associated with Condensin II mutations. We therefore conclude that Condensin II can be dispensable for the resolution of topological problems and chromosome condensation if cells are able to prolong meiosis. Yet, the newly found role of this complex in the robustness of the SAC reduces meiotic timing leading to severe chromosome segregation defects.

cell biology↗