Skip Ribbon Commands
Skip to main content
Translate
Donations
menu iconMenu
search iconSearch

Oncogene Mutation Hijacks Splicing Process to Promote Growth and Survival

 

May 31, 2013  |  

An international team of researchers – led by principal investigator Paul S. Mischel, MD, a member of the Ludwig Institute for Cancer Research and professor in the Department of Pathology at the University of California, San Diego School of Medicine – has found that a singular gene mutation helps brain cancer cells to not just survive, but grow tumors rapidly by altering the splicing of genes that control cellular metabolism.

The findings are published online in the journal Cell Metabolism.

GBM 
Glioblastoma multiforme
Mischel, who heads the Ludwig Institute’s molecular pathology laboratory based at UC San Diego, and colleagues focused upon a process called alternative splicing, in which a single gene encodes for multiple proteins by including or excluding different, specific regions of DNA.

Alternative splicing is a tightly regulated and normal activity in healthy cells. For Mischel and colleagues in Los Angeles, Ohio and Japan, the question was whether mutations of a gene called EGFRvIII caused differential alternative splicing in glioblastoma multiformes (GBMs), the most common and aggressive type of malignant brain tumor. Median survival after GBM diagnosis is just 15 months with standard-of care radiation and chemotherapy. Without treatment, it is less than five months.

The scientists were particularly interested in whether the EGFRvIII mutation induced alternative splicing events that resulted in deregulation of normal cellular metabolism. “We focused on the ‘Warburg Effect,’ a common metabolic derangement in cancer that enables tumor cells to metabolize glucose in a way that provides both a sufficient supply of energy and a source of building blocks that can be used for growth,” Mischel said.

They discovered a complex but compelling series of consequential events: The EGFRvIII mutation controls expression of a splicing factor called HNRNPA1, which initiates an alternatively spliced form of a regulatory protein called Max. The alternative form is called Delta Max.

Max is associated with MYC, a gene that drives tumor growth and the Warburg Effect in cancer. “Unlike the regular form of Max,” said Mischel, “Delta Max actually enhances c-MYC activity, specifically by promoting the glycolytic phenotype of the tumor cells.” In other words, the EGFRvIII mutation and subsequent alternative splicing commandeer the cell’s metabolic machinery in a way that lets it take up and use glucose to promote rapid tumor growth.

Mischel noted that the findings are specific to the EGFRvIII mutation and GBMs. It’s not known whether other oncogenes are able to exploit alternative splicing in similar fashion.

The findings, according to Mischel, provide two clear insights. First, they highlight the central role of EGFRvIII in GBM pathogenesis and its critical role in altering cellular metabolism in tumors. Second, they show that oncogenes can regulate cell metabolism through alternative splicing, which may provide a new set of targets for oncogene-specific drug development.

Co-authors are Ivan Babic, Kenta Masui and Beatrice Gini, Ludwig Institute for Cancer Research, UCSD; Erik S. Anderson, Department of Microbiology, Immunology and Molecular Genetics, UCLA; Kazuhiro Tanaka, Department of Neurosurgery, Kobe University, Japan; Deliang Guo, Department of Radiation Oncology, Ohio State University Medical Center; Bing Li and Siavash K. Kurdistani, Department of Biological Chemistry, UCLA; Shaojun Zhu, David Nathanson and Rui Li, Carolina Espindola Camacho and Heather R. Christofk, Department of Molecular and Medical Pharmacology, UCLA; Yuchao Gu, Ludwig Institute for Cancer Research, UCSD and Department of Molecular and Medical Pharmacology, UCLA; Genaro R. Villa, Ludwig Institute for Cancer Research, UCSD and Department of Molecular and Medical Pharmacology, UCLA; David Akhavan, Department of Molecular and Medical Pharmacology, UCLA; Sergey Mareninov, Department of Pathology and Laboratory Medicine, UCLA; Ascia Eskin and Stanley F. Nelson, Department of Human genetics, David Geffen School of Medicine, UCLA; William H. Yong, Department of Pathology and Laboratory Medicine, UCLA; Webster K. Cavenee, Ludwig Institute for Cancer Research, UCSD and UCSD Moores Cancer Center; Timothy F. Cloughesy, Department of Neurology, David Geffen School of Medicine, UCLA; and Douglas L. Black, Howard Hughes Medical Institute and Department of Microbiology, Immunology and Molecular Genetics, UCLA.

Funding for this research came, in part, from National Institutes of Health grants CA119347, NS73831, R01 GM084317 and P01 CA95616, the Ben and Catherine Ivy Foundation, Art of the Brain Fund, Accelerate brain Cancer Cure, the Fred Miller Family, the John W. Carson Foundation, the Ziering Family Foundation, the Henry Singleton Brain Cancer Fund and National Cancer Institute grant P30CA23100.

# # #

Media Contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu


Related Specialties

Brain Tumor Center



Media Contact

Related News

5/21/2015
Using human embryonic stem cells, researchers at University of California, San Diego School of Medicine and Moores Cancer Center and Sanford-Burnham Medical Research Institute created a model that all ...
5/8/2015
Therapies that specifically target mutations in a person’s cancer have been much-heralded in recent years, yet cancer cells often find a way around them. To address this, researchers at University of ...
5/1/2015
Researchers at UC San Diego School of Medicine conducted the first population-based study that characterizes the association and temporal relationship between gastrointestinal stromal tumors (GIST) an ...
5/1/2015
In proof-of-concept experiments, researchers at University of California, San Diego School of Medicine demonstrate the ability to tune medically relevant cell behaviors by manipulating a key hub in ce ...
4/29/2015
Researchers at University of California San Diego School of Medicine report pancreatic cancer rates are highest in countries with the least amount of sunlight. Low sunlight levels were due to a combin ...
4/20/2015
Researchers at the University of California, San Diego School of Medicine and Moores Cancer Center have discovered a molecular mechanism that connects breast tissue stiffness to tumor metastasis and p ...
4/20/2015
A decrease in the amount of time spent eating and an increase in overnight fasting reduces glucose levels and may reduce the risk of breast cancer among women, report University of California, San Die ...
4/9/2015
A family of proteins called G proteins are a recognized component of the communication system the human body uses to sense hormones and other chemicals in the bloodstream and to send messages to cells ...


Share This Article



Follow Us