The AURKA/TPX2 axis drives colon tumorigenesis cooperatively with MYC.

The MYC oncogene has long been established as a central driver in many types of human cancers including colorectal cancer. However, the realization of MYC-targeting therapies remains elusive; as a result, synthetic lethal therapeutic approaches are alternatively being explored. A synthetic lethal therapeutic approach aims to kill MYC-driven tumors by targeting a certain co-regulator on the MYC pathway. We analyzed copy number and expression profiles from 130 colorectal cancer tumors together with publicly available datasets to identify co-regulators on the MYC pathway. Candidates were functionally tested by in vitro assays using colorectal cancer and normal fibroblast cell lines. Additionally, survival analyses were carried out on another 159 colorectal cancer patients and public datasets. Our in silico screening identified two MYC co-regulator candidates, AURKA and TPX2, which are interacting mitotic regulators located on chromosome 20q. We found the two candidates showed frequent co-amplification with the MYC locus while expression levels of MYC and the two genes were positively correlated with those of MYC downstream target genes across multiple cancer types. In vitro, the aberrant expression of MYC, AURKA and TPX2 resulted in more aggressive anchorage-independent growth in normal fibroblast cells. Furthermore, knockdown of AURKA or TPX2, or treatment with an AURKA-specific inhibitor effectively suppressed the proliferation of MYC-expressing colorectal cancer cells. Additionally, combined high expression of MYC, AURKA and TPX2 proved to be a poor prognostic indicator of colorectal cancer patient survival. Through bioinformatic analyses and experiments, we proposed TPX2 and AURKA as novel co-regulators on the MYC pathway. Inhibiting the AURKA/TPX2 axis would be a novel synthetic lethal therapeutic approach for MYC-driven cancers.

Takahashi Y ，Sheridan P ，Niida A ，Sawada G ，Uchi R ，Mizuno H ，Kurashige J ，Sugimachi K ，Sasaki S ，Shimada Y ，Hase K ，Kusunoki M ，Kudo S ，Watanabe M ，Yamada K ，Sugihara K ，Yamamoto H ，Suzuki A ，Doki Y ，Miyano S ，Mori M ，Mimori K ... -  《-》

Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer.

Gomes-Filho SM ，Dos Santos EO ，Bertoldi ERM ，Scalabrini LC ，Heidrich V ，Dazzani B ，Levantini E ，Reis EM ，Bassères DS ... -  《-》

TPX2 and AURKA promote 20q amplicon-driven colorectal adenoma to carcinoma progression.

Sillars-Hardebol AH ，Carvalho B ，Tijssen M ，Beliën JA ，de Wit M ，Delis-van Diemen PM ，Pontén F ，van de Wiel MA ，Fijneman RJ ，Meijer GA ... -  《-》

AurkA nuclear localization is promoted by TPX2 and counteracted by protein degradation.

The AurkA kinase is a well-known mitotic regulator, frequently overexpressed in tumors. The microtubule-binding protein TPX2 controls AurkA activity, localization, and stability in mitosis. Non-mitotic roles of AurkA are emerging, and increased nuclear localization in interphase has been correlated with AurkA oncogenic potential. Still, the mechanisms leading to AurkA nuclear accumulation are poorly explored. Here, we investigated these mechanisms under physiological or overexpression conditions. We observed that AurkA nuclear localization is influenced by the cell cycle phase and nuclear export, but not by its kinase activity. Importantly, AURKA overexpression is not sufficient to determine its accumulation in interphase nuclei, which is instead obtained when AURKA and TPX2 are co-overexpressed or, to a higher extent, when proteasome activity is impaired. Expression analyses show that AURKA, TPX2, and the import regulator CSE1L are co-overexpressed in tumors. Finally, using MCF10A mammospheres we show that TPX2 co-overexpression drives protumorigenic processes downstream of nuclear AurkA. We propose that AURKA/TPX2 co-overexpression in cancer represents a key determinant of AurkA nuclear oncogenic functions.

Asteriti IA ，Polverino F ，Stagni V ，Sterbini V ，Ascanelli C ，Naso FD ，Mastrangelo A ，Rosa A ，Paiardini A ，Lindon C ，Guarguaglini G ... -  《Life Science Alliance》

Taxane-mediated radiosensitization derives from chromosomal missegregation on tripolar mitotic spindles orchestrated by AURKA and TPX2.

Orth M ，Unger K ，Schoetz U ，Belka C ，Lauber K ... -  《-》