MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities
Julia Rohrberg,
Daniel Van de Mark,
Meelad Amouzgar,
Joyce V. Lee,
Moufida Taileb,
Alexandra Corella,
Seda Kilinc,
Jeremy Williams,
Marie-Lena Jokisch,
Roman Camarda,
Sanjeev Balakrishnan,
Rama Shankar,
Alicia Zhou,
Aaron N. Chang,
Bin Chen,
Hope S. Rugo,
Sophie Dumont,
Andrei Goga
Affiliations
Julia Rohrberg
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
Daniel Van de Mark
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Meelad Amouzgar
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Joyce V. Lee
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Moufida Taileb
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Alexandra Corella
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Seda Kilinc
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Jeremy Williams
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
Marie-Lena Jokisch
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Roman Camarda
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA, USA
Sanjeev Balakrishnan
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Rama Shankar
Department of Pediatrics and Human Development and Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
Alicia Zhou
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Aaron N. Chang
Baylor College of Medicine, Houston, TX, USA
Bin Chen
Department of Pediatrics and Human Development and Department of Pharmacology and Toxicology, College of Human Medicine, Michigan State University, Grand Rapids, MI, USA
Hope S. Rugo
Department of Medicine, University of California, San Francisco, San Francisco, CA, USA
Sophie Dumont
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA
Andrei Goga
Department of Cell & Tissue Biology, University of California, San Francisco, San Francisco, CA, USA; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA; Corresponding author
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
