Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer

Yeow, Zhong Y.; Lambrus, Bramwell G.; Marlow, Rebecca; Zhan, Kevin; Durin, Mary-Anne; Evans, Lauren T.; Scott, Phillip M.; Phan, Thao P; Park, Elizabeth M.; Ruiz, Lorena A.; Moralli, Daniela; Knight, Eleanor; Badder, Luned; Novo, Daniela; Haider, Syed; Green, Catherine; Tutt, Andrew; Lord, Christopher J.; Chapman, Jessica R.; Holland, Andrew J.

doi:10.1038/s41586-020-2690-1

Cited by 76 publications

(79 citation statements)

References 42 publications

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“…4e ). Neuroblastoma and breast cancer cells with genomic amplification of TRIM37 are highly sensitive to PLK4 inhibition; an independent effort reached a similar conclusion for 17q23 -amplified breast cancers 29 . In these, as well as in other cancer types with amplification of the TRIM37 locus, PLK4 inhibition offers a new approach for selectively triggering mitotic failure.…”

Section: Discussionmentioning

confidence: 79%

TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

Meitinger

Ohta

Lee

et al. 2020

Nature

120

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Centrosomes catalyze microtubule formation for mitotic spindle assembly 1 . Centrosomes duplicate once per cell cycle in a process controlled the kinase PLK4 2 , 3 . Following chemical PLK4 inhibition, cell division in the absence of centrosome duplication generates centrosome-less cells that exhibit delayed, acentrosomal spindle assembly 4 . Whether PLK4 inhibitors can be leveraged for cancer treatment is not yet clear. Here, we show that acentrosomal spindle assembly following PLK4 inhibition depends on levels of the centrosomal ubiquitin ligase TRIM37. Low TRIM37 accelerates acentrosomal spindle assembly and improves proliferation following PLK4 inhibition, whereas high TRIM37 inhibits acentrosomal spindle assembly, leading to mitotic failure and cessation of proliferation. The Chr17q region containing the TRIM37 gene is frequently amplified in neuroblastoma and in breast cancer 5 – 8 , which renders these cancer types highly sensitive to PLK4 inhibition. TRIM37 inactivation improves acentrosomal mitosis because TRIM37 prevents PLK4 self-assembly into centrosome-independent condensates that serve as ectopic microtubule-organizing centers. By contrast, elevated TRIM37 expression inhibits acentrosomal spindle assembly via a distinct mechanism that involves degradation of the centrosomal component CEP192. Thus, TRIM37 is a critical determinant of mitotic vulnerability to PLK4 inhibition. Linkage of TRIM37 to prevalent cancer-associated genomic changes, including 17q gain in neuroblastoma and 17q23 amplification in breast cancer, may offer an opportunity to use PLK4 inhibition to trigger selective mitotic failure and provide new avenues to treatments for these cancers.

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Section: Discussionmentioning

confidence: 79%

TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

Meitinger

Ohta

Lee

et al. 2020

Nature

120

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“…Furthermore, TRIM37 overexpression has been linked to increased cell invasion and metastasis in colorectal and hepatocellular carcinoma ( Hu and Gan, 2017 ; Jiang et al, 2015 ). Cancer cells overexpressing TRIM37 are hypersensitive to the absence of centrioles upon treatment with the PLK4 inhibitor Centrinone, because excess TRIM37 interferes with acentriolar spindle assembly, inducing mitotic failure ( Meitinger et al, 2020 ; Yeow et al, 2020 ). Moreover, such cells assemble small condensates harboring the centrosomal proteins CEP192 and CEP152, as well as inactive PLK4 ( Meitinger et al, 2020 ; Meitinger et al, 2016 ).…”

Section: Introductionmentioning

confidence: 99%

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin

Balestra

Domínguez-Calvo

Wolf

et al. 2021

eLife

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TRIM37 is an E3 ubiquitin ligase mutated in Mulibrey nanism, a disease with impaired organ growth and increased tumor formation. TRIM37 depletion from tissue culture cells results in supernumerary foci bearing the centriolar protein Centrin. Here, we characterize these centriolar protein assemblies (Cenpas) to uncover the mechanism of action of TRIM37. We find that an atypical de novo assembly pathway can generate Cenpas that act as microtubule organizing centers (MTOCs), including in Mulibrey patient cells. Correlative light electron microscopy reveals that Cenpas are centriole-related or electron-dense structures with stripes. TRIM37 regulates the stability and solubility of Centrobin, which accumulates in elongated entities resembling the striped electron dense structures upon TRIM37 depletion. Furthermore, Cenpas formation upon TRIM37 depletion requires PLK4, as well as two parallel pathways relying respectively on Centrobin and PLK1. Overall, our work uncovers how TRIM37 prevents Cenpas formation, which would otherwise threaten genome integrity, including in Mulibrey patients.

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“…Whether this acceleration is due to the ability of centrioles to organize PCM matrix or whether they have the capacity to accelerate spindle assembly independent of the matrix is not clear. Recent work has shown that spindle assembly in human cells that lack centrioles is accompanied by the coalescence of PCM proteins into foci at the spindle poles during mitosis ( Meitinger et al, 2020 ; Yeow et al, 2020 ). Similar foci containing PCM proteins have also been observed in acentriolar Drosophila cells ( Baumbach et al, 2015 ; Debec et al, 1995 ; Moutinho-Pereira et al, 2009 ).…”

Section: Introductionmentioning

confidence: 99%

Centriole-independent mitotic spindle assembly relies on the PCNT–CDK5RAP2 pericentriolar matrix

Watanabe

Meitinger

Shiau

et al. 2020

Journal of Cell Biology

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Centrosomes, composed of centrioles that recruit a pericentriolar material (PCM) matrix assembled from PCNT and CDK5RAP2, catalyze mitotic spindle assembly. Here, we inhibit centriole formation and/or remove PCNT–CDK5RAP2 in RPE1 cells to address their relative contributions to spindle formation. While CDK5RAP2 and PCNT are normally dispensable for spindle formation, they become essential when centrioles are absent. Acentriolar spindle assembly is accompanied by the formation of foci containing PCNT and CDK5RAP2 via a microtubule and Polo-like kinase 1–dependent process. Foci formation and spindle assembly require PCNT-CDK5RAP2–dependent matrix assembly and the ability of CDK5RAP2 to recruit γ-tubulin complexes. Thus, the PCM matrix can self-organize independently of centrioles to generate microtubules for spindle assembly; conversely, an alternative centriole-anchored mechanism supports spindle assembly when the PCM matrix is absent. Extension to three cancer cell lines revealed similar results in HeLa cells, whereas DLD1 and U2OS cells could assemble spindles in the absence of centrioles and PCNT-CDK5RAP2, suggesting cell type variation in spindle assembly mechanisms.

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Targeting TRIM37-driven centrosome dysfunction in 17q23-amplified breast cancer

Cited by 76 publications

References 42 publications

TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

TRIM37 controls cancer-specific vulnerability to PLK4 inhibition

TRIM37 prevents formation of centriolar protein assemblies by regulating Centrobin

Centriole-independent mitotic spindle assembly relies on the PCNT–CDK5RAP2 pericentriolar matrix

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