Highlights d MYC overexpression reversibly induces CIN by reprogramming mitotic gene expression d MYC impairs mitotic spindle formation d High TPX2 expression allows cells that overexpress MYC to adapt to spindle stress d TPX2 depletion is synthetic lethal with MYC overexpression
Tumors that overexpress the MYC oncogene, including most receptor triple-negative breast cancers, frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers. Aneuploidy is also associated with rapid tumor evolution and poor patient outcome. We identify that MYC overexpression induces reversible defects in microtubule nucleation and mitotic spindle assembly, in TNBCs and other epithelial cells, promoting chromosome segregation defects, micronuclei and chromosomal instability (CIN). High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with MYC overexpression; whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Attenuating MYC expression reverses mitotic defects, even in established breast tumor cell lines, implicating an ongoing role for high MYC in the persistence of CIN in cancers. Our studies implicate the MYC oncogene as a regulator of spindle assembly and identify a new MYC-TPX2 synthetic-lethal interaction in TNBC that could represent a future therapeutic strategy in MYC-overexpressing cancers. Moreover, our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution. Citation Format: Goga A, Rohrberg J, Corella A, Taileb M, Kilinc S, Jokisch M-L, Camarda R, Zhou A, Balakrishnan S, Chang AN, Klein-Connolly H. MYC dysregulates mitotic spindle function in triple-negative breast cancer creating a dependency on TPX2 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-09-01.
The MYC oncogene promotes tumorigenesis in part by facilitating cell cycle entry thus driving cellular proliferation. Tumors that overexpress MYC frequently demonstrate aneuploidy, numerical chromosome alterations associated with highly aggressive cancers, rapid tumor evolution, and poor patient outcome. While the role of MYC in overcoming the G1/S checkpoint is well established, it remains poorly understood whether MYC induces chromosomal instability (CIN). Here, we identify a direct influence of MYC on mitotic progression. MYC overexpression induces defects in microtubule nucleation and spindle assembly promoting chromosome segregation defects, micronuclei and CIN. We examined which mitotic regulators are required for the survival of MYC-overexpressing cells and found a reliance on high TPX2 expression. TPX2, a master microtubule regulator, is overexpressed together with MYC in multiple cell lines, in mouse tumor models and in aggressive human breast cancers. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in cells with deregulated MYC, whereas TPX2 depletion blocks mitotic progression, induces cell death and prevents tumor growth. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for high MYC in the persistence of a CIN phenotype in tumors. Here, we implicate the MYC oncogene as a regulator of spindle assembly and dynamics and identify a new MYC-TPX2 synthetic-lethal interaction that could represent a future therapeutic strategy in MYC-overexpressing cancers. Our studies suggest that blocking MYC activity can attenuate the emergence of CIN and tumor evolution.
More than 70% of common solid tumors are aneuploid. Aneuploidy has been implicated in tumorigenesis for decades. A direct cause of aneuploidy is chromosomal instability (CIN) that fuels tumor evolution by providing a heterogeneous subpopulation of cells that contributes to the lethal outcome of cancer, metastasis, therapeutic failure, and drug resistance. The oncogene c-MYC is overexpressed in many cancers and has been shown to induce structural and numerical chromosomal aberrations and aneuploidy. While the role of MYC in overcoming the G1/S checkpoint is well established, the role of MYC in altering mitotic dynamics and eliciting CIN remains poorly understood. Here, we identify a direct influence of increased MYC expression on mitotic progression and spindle assembly. We observe MYC-dependent microtubule nucleation and polymerization defects in mitosis. MYC overexpression induces altered spindle morphology promoting chromosome segregation defects resulting in micronuclei formation, CIN and aneuploidy. Importantly, attenuation of MYC expression reverses the mitotic defects observed, even in established tumor cell lines, implicating an ongoing role for MYC in the persistence of a CIN phenotype in tumors. Gene expression data reveal that MYC regulates numerous genes involved in mitosis, kinetochore function and microtubule behavior. We performed a screen to identify microtubule regulators required for the survival of MYC overexpressing cells. MYC overexpressing cells are reliant on high TPX2 expression, a master microtubule regulator. High TPX2 expression is permissive for mitotic spindle assembly and chromosome segregation in MYC high cells, while TPX2 depletion attenuates cell viability and tumor growth in vivo. Our data suggest that TPX2 is a transcriptional target of MYC. We postulate that high levels of TPX2 are required to tolerate mitotic stress induced by MYC. TPX2 compensates for impaired mitotic progression and prevents the development of physiologically intolerable levels of CIN. High levels of TPX2 might be required for tumors with oncogene-induced mitotic stress to faithfully proceed through mitosis providing an explanation for the abundant upregulation of TPX2 in cancer. Thus, we describe a conditional role for MYC in altering spindle assembly and dynamics, resulting in a dependency on TPX2 for tumor survival. Citation Format: Julia Rohrberg, Alexandra Corella, Moufida Taileb, Marie-Lena Jokisch, Roman Camarda, Sanjeev Balakrishnan, Alicia Zhou, Andrei Goga. The oncogene MYC induces chromosomal instability through dysregulating mitotic progression evoking a dependency on TPX2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1462.
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