Addiction to Life-Saving, Self-Digestion Process Can Aid Cancer Cells in Tumor Growth
New Brunswick, N.J.– A team of investigators at The Cancer Institute of New Jersey (CINJ); Rutgers, The State University of New Jersey; and Princeton University, have determined that cancer cells are “addicted” to a self-preservation process known as autophagy. They also showed that the inhibition of that process could prove to be a valuable treatment approach for aggressive cancers. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
Autophagy is a cellular self-cannibalization process where cells eat themselves to survive starvation. Eileen White, PhD, associate director for basic science at CINJ, and collaborators previously discovered that cancer cells can take advantage of the autophagy survival pathway to aid their growth into tumors. In this new study, Dr. White and colleagues have found that cancer cells induce autophagy and this self-cannibalization process enables the growth of the most aggressive tumors.
The latest research, which appears online and in the March print editions of Genes & Development, focuses on cancer genes known as H-ras and K-ras that are activated in many aggressive cancers with poor prognoses. These cancers, which are acutely sensitive to autophagy inhibition, have high levels of autophagy that provide cancer cells with sufficient nutrition to survive by recycling parts of themselves. In collaboration with the Joshua Rabinowitz and Hilary Coller laboratories at Princeton University, investigators were able to show that autophagy in these aggressive cancers provides fuel to the powerhouses of the cell, the mitochondria. By spurring the mitochondria to generate a steady supply of energy for tumor cells, autophagy keeps those cells alive and growing. These tumor cells are “addicted” to autophagy to support the metabolism of cancer cells.
By identifying that this autophagy “addiction” is prevalent in cancers with Ras mutations, such as lung, pancreatic and colon, a metabolic vulnerability of cancer cells is revealed – a vulnerability the authors say can be utilized for cancer therapy. “What this finding suggests is that patients with these poor-prognosis cancers may benefit from treatment that targets autophagy inhibition,” said White, an adjunct professor of surgery at UMDNJ-Robert Wood Johnson Medical School, and a professor of molecular biology and biochemistry at Rutgers University, who is the senior author of the research publication.
White further notes while exploration involving autophagy inhibition drugs can lead to a more individualized treatment approach, more needs to be done. “Ideally, further examination of the autophagy cycle will lead to the identification of a certain point along that pathway that will compromise cancer cell survival. Once illuminated, that step in the process can be exploited so that researchers can find ways to maximize the benefits of autophagy inhibitors and improve clinical outcomes,” she stated.
“Especially for oncogenes, such as Ras, that cannot be directly targeted with current drugs, identifying associated metabolic vulnerabilities points to important therapeutic opportunities,” added Joshua Rabinowitz, MD, PhD, CINJ member and associate professor of chemistry at the Lewis-Sigler Institute for Integrative Genomics at Princeton.
Along with White and Rabinowitz, the author team includes Jessie Yanxiang Guo, CINJ and Rutgers University; Hsin-Yi Chen, CINJ and Rutgers University; Robin Mathew, CINJ and UMDNJ-Robert Wood Johnson Medical School; Jing Fan, Princeton University; Anne M. Strohecker, CINJ and UMDNJ-Robert Wood Johnson Medical School; Gizem Karsli-Uzunbas, CINJ and Rutgers University; Jurre J. Jamphorst, Princeton University; Guanghua Chen, CINJ and Rutgers University; Johanna M.S. Lemmons, Princeton University; Vassiliki Karantza, CINJ and UMDNJ-Robert Wood Johnson Medical School; Hilary A. Coller, CINJ and Princeton University; Robert S. DiPaola, CINJ and UMDNJ-Robert Wood Johnson Medical School; and Celine Gelinas, CINJ, UMDNJ-Robert Wood Johnson Medical School, and Rutgers University.
This work was supported by grants from the National Institutes of Health, CINJ, the New Jersey Commission on Cancer Research and the Department of Defense.
About The Cancer Institute of New Jersey
The Cancer Institute of New Jersey (www.cinj.org) is the state’s first and only National Cancer Institute-designated Comprehensive Cancer Center dedicated to improving the detection, treatment and care of patients with cancer, and serving as an education resource for cancer prevention. CINJ’s physician-scientists engage in translational research, transforming their laboratory discoveries into clinical practice, quite literally bringing research to life. To make a tax-deductible gift to support CINJ, call 732-235-8614 or visit www.cinjfoundation.org. CINJ is a Center of Excellence of UMDNJ-Robert Wood Johnson Medical School.
The CINJ Network is comprised of hospitals throughout the state and provides the highest quality cancer care and rapid dissemination of important discoveries into the community. Flagship Hospital: Robert Wood Johnson University Hospital. System Partner: Meridian Health (Jersey Shore University Medical Center, Ocean Medical Center, Riverview Medical Center, Southern Ocean Medical Center, and Bayshore Community Hospital). Major Clinical Research Affiliate Hospitals: Carol G. Simon Cancer Center at Morristown Memorial Hospital, Carol G. Simon Cancer Center at Overlook Hospital, and Cooper University Hospital. Affiliate Hospitals: CentraState Healthcare System, JFK Medical Center, Mountainside Hospital, Raritan Bay Medical Center, Robert Wood Johnson University Hospital Hamilton (CINJ Hamilton), Somerset Medical Center, The University Hospital/UMDNJ-New Jersey Medical School*, and University Medical Center at Princeton. *Academic Affiliate