The role of sphingolipid metabolism in the tumor immune microenvironment has, over the last decade, gained more attention, particularly in cancer research. However, despite numerous studies exploring the relationship between sphingolipid metabolism and cancer, to date, the specific regulatory mechanisms remain somewhat unclear. Hence, further studies are needed to understand the role of sphingolipids in cancer better.
Now, an interdisciplinary research team led by Yusuf Hannun, MD, the Joel Strum Kenny Professor in Cancer Research in the Renaissance School of Medicine (RSOM) at Stony Brook University, has received an US $11 million five-year grant from the National Institutes of Health (NIH) to investigate the role of sphingolipids (SLs), a class of bioactive fat molecules that have a key role in the regulation of cell signaling in many of the major cell pathways and functions in cancers. [1]
The grant, awarded by the National Institute of Health’s (NIH) National Cancer Institute (NCI), runs to the end of August 2030. It is the only NIH Program Project Grant, also known as P01, awarded this year to a State University of New York (SUNY) institution. These NIH P01 grants support long-term research programs that have a specific primary objective or a basic theme.
Regulating essential functions
Sphingolipids are essential components of cell membranes. They regulate cell signaling and immune responses, and, as a result, are important in tumor biology research. The essential functions controlled by the sphingolipid class of lipids include functions that are critically related to cancer processes, including differentiation, cell death, metastasis, and response to cellular stress.
For example, research has shown that unique and substantial changes in sphingolipid metabolism accompany all breast cancer subtypes. Alterations in sphingolipid metabolite levels, including ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, as well as in their biosynthetic and catabolic enzymatic pathways, have emerged as possible molecular mechanisms by which breast cancer cells grow, respond to, or escape therapeutic interventions and, as a result, may have a diagnostic and prognostic value.[3]
Additionally, some SLs also play a key role in the action of chemotherapeutic agents used to treat cancer.
“This award represents a major milestone for our institution and an important advancement in cancer research,” noted Raymond Bergan, MD, Director of the Stony Brook Cancer Center.
“The NIH grant is yet another measure of the stature of our Cancer Center and its national leadership in understanding the role of lipids and metabolism in the formation of cancer and how that knowledge can be applied to prevention and treatment,” Bergan added.
Many aspects of cancer treatment
Hannun, Principal Investigator of the NIH Grant, explains that one unique aspect of investigating sphingolipids in cancer is that their roles are important in so many aspects of cancer treatment, including chemotherapy, immunotherapy, radiation therapy, and metabolic approaches.
“While our research with the help of this grant will be broad and far-reaching, we will initially focus on sphingolipids in breast cancer development and therapy, the action of DNA-damaging chemotherapies, and mitigating the toxicity of chemotherapy,” Hannun said.
To date, the team has focused on sphingolipids in breast cancer and, to a lesser degree, liver cancer. They will continue to target sphingolipid research around these forms of cancer, but also in lung cancer and leukemia.
An Experienced Investigative Team
The investigative team that Hannun has assembled for the sphingolipids research program has collectively worked in this area of cancer research for decades, having jointly published more than 250 peer-reviewed manuscripts. The group brings expertise from multiple disciplines, including Biochemistry, Medicine, Pathology, Physiology, and Pharmacology.
Over the years, they have made seminal contributions to the field. These include identifying several enzymes of sphingolipid metabolism as important targets for developing novel cancer therapeutics, developing lead compounds for anticancer therapeutics, discovering the essential functions of specific sphingolipid enzymes in regulating cancer biology, such as migration, survival, inflammatory, and immune responses, and exploring the roles of SLs in cancer therapeutics, including their use as biomarkers.
Leading team members include Daniel Canals, PhD, Research Assistant Professor in the Department of Medicine, whose work focuses on the molecular mechanism of sphingolipids in migration and adhesion of cancer cells critical to regulating cancer progression and metastasis, and an expert in advanced analysis of sphingolipids; Christopher Clarke, PhD, Associate Professor of Research in the Cancer Center, who studies oncogene signaling and how this reprograms sphingolipidmetabolism to promote cancer development and progression; Chiara Luberto, PhD, Associate Professor, Department of Physiology and Biophysics, whose lab currently investigates regulation of sphingolipids in breast cancer and rare leukemias to leverage sphingolipid metabolism in enhancing response to chemotherapy; Cungui Mao, PhD, Professor of Medicine in the Division of Gastroenterology and Hepatology, whose work has centered on metabolism and signaling functions of sphingolipids in different species from yeast to mammals with a current focus on how to mitigate some of the most debilitating and dose-limiting actions of key chemotherapy agents; and Fabiola Velazquez, PhD, an expert in pre-clinical models who researches a particularly active type of SLs as a potential novel anticancer intervention.
Beyond translational research
Together, they will collaborate with other scientists at Stony Brook and around the country to advance sphingolipid research findings from basic and translational work to new treatments.
This group, formally known as The Lipid Cancer Laboratory, is a key component of a larger group of investigators researching lipids in cancer within the Lipid Signaling and Metabolism in Cancer Program. It is one of three major broad research programs dedicated to cancer discovery and therapeutics in the Stony Brook Cancer Center.
Currently, the only approved sphingolipid-based therapeutics in medicine are for inflammatory bowel disease and multiple sclerosis. There are also some ongoing pre-clinical and clinical studies with sphingolipid-based compounds as treatment options for cancer. However, developing a complete picture of the possible impact of sphingolipid metabolism on the development and progression of cancer may help provide novel avenues to improve and personalize therapeutic interventions.[3]
Reference
[1] Ogretmen B. Sphingolipid metabolism in cancer signalling and therapy. Nat Rev Cancer. 2018 Jan;18(1):33-50. doi: 10.1038/nrc.2017.96. Epub 2017 Nov 17. PMID: 29147025; PMCID: PMC5818153.
[2] El Ridi R, Duan J, Jin J. Editorial: Sphingolipid metabolism dysfunction in cancer. Front Endocrinol (Lausanne). 2023 Jun 9;14:1208616. doi: 10.3389/fendo.2023.1208616. PMID: 37361527; PMCID: PMC10289221.
[3] Corsetto PA, Zava S, Rizzo AM, Colombo I. The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response. Int J Mol Sci. 2023 Jan 20;24(3):2107. doi: 10.3390/ijms24032107. PMID: 36768427; PMCID: PMC9916652.
Featured image: Yusuf Hannun, MD, center, with his team that investigates sphingolipids (SLs) and their role in cancer. The work is supported by an $11 million grant from the National Institutes of Health. Lab members, from the left: Fabiola Velazquez, Chiara Luberto, Daniel Canals, Christopher Clarke, and Cungui Mao. Phot courtesy: © 2025 Jeanne Neville, Stony Brook Medicine; used with permission.
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