Tumor Metabolism Research

The metabolic requirements and pathways engaged in growing cells, like cancer cells, are vastly different than those of a cell in a state of quiescence. Among these differences are the need for the basic cellular building blocks (carbohydrates, amino acids, fats) which are used to build the protein, nucleotides and lipid membranes required to generate a daughter cell. In a normal, healthy mammalian cell, nutrient uptake and biosynthesis processes are controlled by complex networks of extracellular signaling and these cues are integrated as instructions to tell a cell when, how and to what extent it should engage biosynthetic processes. 

In cancer cells, these networks are hijacked (through gains in oncogenes and loss of tumor suppressors), which allow the cells to obtain nutrients and engage biosynthetic machinery in a cell autonomous manner. In fact, the cell autonomous control of nutrient uptake and metabolism is a principle requirement for the formation of a cancer cell, and metabolic pathways are rewired to support the needs of the tumor: namely, the survival in a non-native, hostile environment and unrestrained growth. 

A consequence of deregulating nutrient uptake and rewiring metabolic pathways is that cancer cells become uniquely dependent on, and vulnerable to disruption of, pathways and processes that normal, healthy cells can live without. Using a variety of biochemical and analytical techniques, we map how these processes are rewired in cancer and use this knowledge to design targeted therapies that exploit such metabolic dependencies. In addition to our work on pancreatic cancer metabolism, we have also explored the intersection between cell signaling and metabolism in a number of other contexts. This work has led to the description of new or differentially utilized pathways in various cancer and stem cell contexts. 


Metabolic Syndrome: F Stands for Fructose and Fat
Lyssiotis CA & Cantley LC. Nature (2013) 502, 181–182.

FoxO3 Coordinates Metabolic Pathways to Maintain Redox Balance in Neural Stem Cells
Yeo H, Lyssiotis CA, Zhang Y, Ying H, Asara JM, Cantley LC & Paik JH. The EMBO Journal (2013) 32, 2589–602.

Glutamine Supports Pancreatic Cancer Growth Through a KRAS-Regulated Metabolic Pathway
*Son J, *Lyssiotis CA [*co-lead authors], Ying H, Wang X, Hua S, Ligorio M, Perera RM, Ferrone CR, Mullarky E, Shyh-Chang N, Kang Y, Fleming JB, Bardeesy N, Asara JM, Haigis MC, DePinho RA, Cantley LC & Kimmelman AC. Nature (2013) 496, 101–105.

Influence of Threonine Metabolism on S-Adenosyl-Methionine and Histone Methylation
Shyh-Chang N, Locasale J, Lyssiotis CA, Zhang Y, Teo RY, Onder T, Unternaehrer J, Ratanasirintrawoot S, Zhu H, Asara JM, Daley GQ & Cantley LC. Science (2012) 339, 222–226.

Phosphoglycerate Dehydrogenase Diverts Glycolytic Flux and Contributes to Oncogenesis
Locasale JW, Grassian AR, Melman T, Lyssiotis CA, Mattaini KR, Bass AJ, Heffron G, Metallo CM, Muranen T, Sharfi H, Sasaki AT, Anastasiou D, Mullarky E, Vokes NI, Sasaki M, Beroukhim R, Stephanopoulos G, Ligon AH, Meyerson M, Richardson AL, Chin L, Wagner G, Asara JM, Brugge JS, Cantley LC & Vander Heiden MG. Nature Genetics (2011) 43, 869–874.