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Selectively triggering mitotic failure

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The region on chromosome 17 hosting the TRIM37 gene is amplified in a number of cancers — most frequently neuroblastoma and breast cancer — and is associated with genomic instability, tumour progression and poor prognosis. Writing in Nature, two papers now report that elevated levels of the ubiquitin ligase TRIM37 confer sensitivity of cancer cells to inhibition of polo-like kinase 4 (PLK4), which results in mitotic failure and cell death.

PLK4 plays a critical role in the duplication of centrosomes — which catalyse the generation of microtubules for assembly of the mitotic spindle — required for cell division. Inhibition of PLK4 using the small molecule centrinone (developed previously by the team behind the new paper from Meitinger et al.) results in cell division without centrosome duplication, generating centrosomeless cells. Cells without centrosomes remain capable of forming a mitotic spindle, although formation is delayed. Many cancer cell lines can proliferate without centrosomes, but others, such as the MCF-7 breast cancer cell line and the CHP134 neuroblastoma cell line (which have high TRIM37 levels due to amplification of 17q or the 17q22/23 region), fail to do so, raising the possibility of PLK4 inhibition as a therapeutic strategy for certain cancers.

As the absence of TRIM37 has previously been reported to confer resistance to centrosome loss in normal RPE-1 cells, the two new studies set out to investigate the potential role of overexpression of this ubiquitin ligase in mediating the hypersensitivity of certain cancer cells to centrosome depletion. Both papers report that elevation of TRIM37 enhances sensitivity to centrinone-mediated PLK4 inhibition.

Specifically, Yeow et al. show that MCF-7 and other 17q23 amplified breast cancer lines are hypersensitive to the PLK4 inhibitor, with centrinone treatment inducing growth arrest, morphological aberrations and cell death; effects that were suppressed by knockdown of TRIM37. In addition, in a human colorectal carcinoma cell line that is insensitive to centrosome loss, overexpression of TRIM37 at levels comparable to those in MCF-7 cells inhibited survival.

Meitinger et al. similarly report sensitivity of 17q23-amplified breast cancer cell lines to centrinone and extend their analysis to neuroblastoma cell lines, showing that those with amplification of TRIM37 failed to proliferate when treated with centrinone, while the non-amplified cell lines continued to proliferate, albeit at a reduced rate. Furthermore, the effects of TRIM37 were bidirectional; overexpression of TRIM37 in RPE-1 cells inhibited acentrosomal spindle assembly, leading to mitotic failure, whereas loss of TRIM37 accelerated acentrosomal spindle assembly and improved proliferation.

Mechanistically, both papers report that upon centrinone-induced centrosome loss, overexpression of TRIM37 blocks the formation of non-centrosomal pericentriolar material (PCM) foci (structures with microtubule-nucleating capacity that are required for successful cell division). Specifically, TRIM37 overexpression led to degradation of centrosomal proteins including CEP192.

Finally, both groups extend their analysis to in vivo models. Yeow et al. show that in patient-derived organoid models of breast cancer, those cultures with high or intermediate levels of TRIM37 protein were sensitive to centrinone, while the PLK4 inhibitor was ineffective in those with low TRIM37 levels. Meanwhile, Meitinger et al. show that in a neuroblastoma xenograft mouse model that exhibits TRIM37 amplification, induction of a PLK4 short hairpin RNA suppressed tumour growth, consistent with the reduction in centrosome number and rapid loss of cell viability in vitro.

In summary, inhibition of PLK4 offers an attractive approach for selectively triggering mitotic failure in cancer types with amplification of the TRIM37 locus.

References

  1. 1.

    Yeow, Z. et al.Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer. Nature https://doi.org/10.1038/s41586-020-2690-1 (2020)

  2. 2.

    Meitinger, F. et al. TRIM37 controls cancer-specific vulnerability to PLK4 inhibition. Nature https://doi.org/10.1038/s41586-020-2710-1 (2020)

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