MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities

Rohrberg, Julia; Mark, Daniel Van de; Amouzgar, Meelad; Lee, Joyce V.; Taileb, Moufida; Corella, Alexandra; Kilinc, Seda; Williams, Jeremy; Jokisch, Marie‐Lena; Camarda, Roman; Balakrishnan, Sanjeev; Shankar, Rama; Zhou, Alicia Y.; Chang, Aaron N.; Chen, Bin; Rugo, Hope S.; Dumont, Sophie; Goga, Andrei

doi:10.1016/j.celrep.2020.02.041

Cited by 54 publications

(69 citation statements)

References 106 publications

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“…CD36 and the SLC27 gene family responsible for creating the fatty acid transport proteins (FATPs) have been shown to be critical in both the uptake and activation of long-chain fatty acids for fatty acid oxidation (β-oxidation) [ 51 , 52 ]. We analyzed RNA sequencing data of MTB-TOM tumors [ 53 ] to investigate how regulating MYC expression affects CD36 and FATP-family expression. When MYC was turned off through dox withdrawal, at an RNA level, Slc27a3 was the mRNA sequence in the family that decreased in expression, though not significantly ( Supplementary Figure S2A ).…”

Section: Resultsmentioning

confidence: 99%

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In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

Madonna

Duer

Lee

et al. 2021

Cancers

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Targeting a tumor’s metabolic dependencies is a clinically actionable therapeutic approach; however, identifying subtypes of tumors likely to respond remains difficult. The use of lipids as a nutrient source is of particular importance, especially in breast cancer. Imaging techniques offer the opportunity to quantify nutrient use in preclinical tumor models to guide development of new drugs that restrict uptake or utilization of these nutrients. We describe a fast and dynamic approach to image fatty acid uptake in vivo and demonstrate its relevance to study both tumor metabolic reprogramming directly, as well as the effectiveness of drugs targeting lipid metabolism. Specifically, we developed a quantitative optical approach to spatially and longitudinally map the kinetics of long-chain fatty acid uptake in in vivo murine models of breast cancer using a fluorescently labeled palmitate molecule, Bodipy FL c16. We chose intra-vital microscopy of mammary tumor windows to validate our approach in two orthotopic breast cancer models: a MYC-overexpressing, transgenic, triple-negative breast cancer (TNBC) model and a murine model of the 4T1 family. Following injection, Bodipy FL c16 fluorescence increased and reached its maximum after approximately 30 min, with the signal remaining stable during the 30–80 min post-injection period. We used the fluorescence at 60 min (Bodipy60), the mid-point in the plateau region, as a summary parameter to quantify Bodipy FL c16 fluorescence in subsequent experiments. Using our imaging platform, we observed a two- to four-fold decrease in fatty acid uptake in response to the downregulation of the MYC oncogene, consistent with findings from in vitro metabolic assays. In contrast, our imaging studies report an increase in fatty acid uptake with tumor aggressiveness (6NR, 4T07, and 4T1), and uptake was significantly decreased after treatment with a fatty acid transport inhibitor, perphenazine, in both normal mammary pads and in the most aggressive 4T1 tumor model. Our approach fills an important gap between in vitro assays providing rich metabolic information at static time points and imaging approaches visualizing metabolism in whole organs at a reduced resolution.

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Section: Resultsmentioning

confidence: 99%

“…The differential expression data from RNA-sequencing on the MTB-TOM tumors and 4T1 and 67NR cell lines were downloaded from GEO (GSE130922 and GSE104765) [ 53 , 61 ]. Data is reported as Log2FC after DESeq2 analysis [ 94 ] in R software.…”

Section: Methodsmentioning

confidence: 99%

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

Madonna

Duer

Lee

et al. 2021

Cancers

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“…Beyond the SUMO pathway, mitotic genes, like TPX2, BIRC5/survivin, and EG5/kinesin‐5, can function as safeguards. Please see also the two recent publication of the Goga 93 and Taylor 92 laboratories for a detailed discussion. …”

Section: Myc and Its Connection With The Sumo Pathwaymentioning

confidence: 99%

“… 92 Furthermore, increased MYC expression is associated with misaligned chromosomes in metaphase with subsequent lagging chromosomes in anaphase. 93 This association is relevant from the therapeutic view, as MYC was demonstrated to be a critical determinant of cell fates occurring upon the treatment of cells with various perturbations affecting mitosis. 86 , 92 Such observations are clinically relevant, as demonstrated by the increased responsiveness of MYC -amplified breast cancers to docetaxel-containing neoadjuvant chemotherapies.…”

Section: Myc and Its Connection With The Sumo Pathwaymentioning

confidence: 99%

The SUMO pathway in pancreatic cancer: insights and inhibition

et al. 2020

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An urgent medical need to develop novel treatment strategies for patients with pancreatic ductal adenocarcinoma (PDAC) exists. However, despite various efforts in the histopathological and molecular subtyping of PDAC, novel targeted or specific therapies have not been established. Posttranslational modifications (PTMs) with ubiquitin-like proteins, including small ubiquitin-like modifiers (SUMOs), mediate numerous processes that can contribute to the fitness and survival of cancer cells. The contribution of SUMOylation to transcriptional control, DNA repair pathways, mitotic progression, and oncogenic signalling has been described. Here we review functions of the SUMO pathway in PDAC, with a special focus on its connection to an aggressive subtype of the disease characterised by high MYC activity, and discuss SUMOylation inhibitors under development for precise PDAC therapies.

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“…Dysregulation of transcription factors is associated with increased chromosome segregation errors in a variety of contexts (Astrinidis et al, 2010;Ishak, Coschi, Roes, & Dick, 2017; H.-S. Lee et al, 2018;Rohrberg et al, 2020;Weiler et al, 2017). However, several barriers have obfuscated the direct role of transcription factors in chromosome segregation.…”

Section: Introductionmentioning

confidence: 99%

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

Flashner

Swift

Sowash

et al. 2020

Preprint

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Mitotic chromosome assembly is essential for faithful chromosome segregation. Despite their salient role directing interphase chromatin organization, little is known about how transcription factors mediate this process during mitosis. Here, we characterize a mitosis-specific role for transcription factor specificity protein 1 (Sp1). Sp1 localizes to mitotic centromeres and auxininduced rapid Sp1 degradation results in chromosome segregation errors and aberrant mitotic progression. These defects are driven by anomalous mitotic chromosome assembly. Sp1 degradation results in chromosome condensation defects through reduced condensin complex I localization. Sp1 also mediates the localization and activation of Aurora B kinase early in mitosis, which is essential for condensin complex I recruitment. Underscoring the clinical significance of our findings, aberrant Sp1 expression correlates with aneuploidy in several human cancers, including kidney renal papillary cell carcinoma, ovarian serous cystadenocarcinoma, mesothelioma, cholangiocarcinoma, and hepatocellular carcinoma. Our results suggest that Sp1 protects genomic integrity during mitosis by promoting chromosome assembly.

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MYC Dysregulates Mitosis, Revealing Cancer Vulnerabilities

Abstract: 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

Cited by 54 publications

References 106 publications

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

In Vivo Optical Metabolic Imaging of Long-Chain Fatty Acid Uptake in Orthotopic Models of Triple-Negative Breast Cancer

The SUMO pathway in pancreatic cancer: insights and inhibition

Transcription factor Sp1 regulates mitotic fidelity through Aurora B kinase-mediated condensin I localization

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