Tumor Metabolism Research

The metabolic requirements and pathways engaged in cell growth, 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 tightly controlled by the endogenously hardwired cell cycles as well as the complex networks of extracellular signaling. These cues are integrated as instructions to tell a cell when, how and to what extent it should engage biosynthetic processes; and if things go wrong, when to initiate cell death.

In cancer cells, the cellular processes are hijacked (through gains in oncogenes and loss of tumor suppressors), which allow them to escape from controlled cell cycle and 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 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. To date, we still know very little of how the oncogenic changes impact the phenotypic metabolic profile of the tumor cells. Is there any tissue specificity? Are there any other factors that contribute to the rewired metabolism of tumor cells? 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.

In addition to the rewired metabolism in tumor cells, in order to sustain the unrestrained growth, tumor cells often adapt to and manipulate its surroundings for their survival and continuous growth, namely the tumor microenvironment. There are many cellular and biomolecular players in the tumor microenvironments, for example the cancer-associated fibroblasts, tumor-associated microphages, the extracellular matrix etc. Tumor cells constantly interact with these players by exchanging biochemical and biophysical cues to survive and thrive at a population scale. Despite the vast amount of research efforts in the area of tumor microenvironment, we are still lack of fundamental understanding of the complex role of the tumor microenvironment. In our lab, we aim to approach this area of study from the perspective of tumor metabolism: how do the tumor cells alter their microenvironment to gain population fitness and in turn how these cellular and biomolecular players in the tumor microenvironment contribute to the tumor growth metabolically. We are actively investigating these interactions at multiple fronts, to name a few: crosstalk between tumor cells and cancer-associated fibroblasts, between tumor cells and tumor-associated microphages and between tumor cells and the immune populations. These studies provide insights on how the tumor microenvironment facilitate/restrain tumor growth and how we can exploit these mechanisms to therapeutically intervene tumor growth at a population scale.