MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities

Abstract

Summary: Tumors that overexpress the MYC oncogene are frequently aneuploid, a state associated with highly aggressive cancers and tumor evolution. However, how MYC causes aneuploidy is not well understood. Here, we show that MYC overexpression induces mitotic spindle assembly defects and chromosomal instability (CIN) through effects on microtubule nucleation and organization. Attenuating MYC expression reverses mitotic defects, even in established tumor cell lines, indicating an ongoing role for MYC in CIN. MYC reprograms mitotic gene expression, and we identify TPX2 to be permissive for spindle assembly in MYC-high cells. TPX2 depletion blocks mitotic progression, induces cell death, and prevents tumor growth. Further elevating TPX2 expression reduces mitotic defects in MYC-high cells. MYC and TPX2 expression may be useful biomarkers to stratify patients for anti-mitotic therapies. Our studies implicate MYC as a regulator of mitosis and suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution. : Rohrberg et al. identify a reversible role of the MYC oncogene for inducing chromosomal instability by inducing error-prone mitosis. MYC-high tumor cells rely on the mitotic regulator TPX2 to survive the altered mitotic program, revealing a synthetic-lethal interaction between MYC overexpression and TPX2 loss as a potential therapeutic strategy. Keywords: MYC, TPX2, mitotic spindle assembly, chromosomal instability, CIN, mitosis, microtubules, synthetic-lethality, receptor triple-negative breast cancer, TNBC