Matthew Vander Heiden
Our group is interested in understanding how changes in metabolism impact all aspects of cancer progression, including metastasis. Metabolism is regulated at both the whole body and cell level to provide tissues with the nutrients needed for their different physiological functions. These metabolic processes are altered in cancer cells to allow cell proliferation and survival in inappropriate tissue contexts. Cancer metabolism is the target of many useful cancer therapies, including some that prevent or cure metastatic disease. The metabolic dependencies exploited by these therapies are incompletely understood, yet this limited success illustrates the promise of targeting metabolism to treat advanced cancers. However, future progress depends on understanding how metabolic regulation and nutrient utilization are important for tumor progression.
To proliferate cancer cells must regulate metabolism to support cell growth and proliferation. Additionally, tumor cells experience periods of stress, and metabolic plasticity to adapt metabolism to survive nutrient limitation is also needed. The ability to survive nutrient stress is particularly important for metastatic spread. The increased use of glucose by cancer cells is well described, and forms the basis for using FDG-PET scanning to track cancer spread in the clinic. However, there is growing evidence that cancer cells use nutrients other than glucose in different environmental and tissue contexts. Our current understanding of cancer cell metabolism is based primarily on studies of cultured cells in non-physiological nutrient and oxygen conditions. Furthermore, cell culture is primarily a system to study proliferating cancer cells, yet the majority of cells in tumors are not dividing and we postulate that the ability of non-proliferating cells to survive nutrient limitation is critical for metastasis. Thus, we are developing cell culture conditions to examine how cancer cells adapt to nutrient limitation, as well as genetic tools to test which enzymes are rate limiting for both cell proliferation and cell survival. In addition, because it is not clear how best to mimic the nutrient limited conditions experienced by cancer cells in tumors, we are also developing approaches to study tumor metabolism in animal models. This includes use of genetically engineered mice to explore how metabolic regulation impacts cancer phenotypes, as well as methods to track nutrient utilization in tumor tissues using animal models.
One aspect of metabolic regulation we are examining is how cancer cells use glucose to promote proliferation or survival. The activation state of pyruvate kinase impacts the metabolic state of cells, including whether cells can proliferate. Tumors express the Pkm2 isoform of pyruvate kinase because it can exist in either a low activity state that favors cell proliferation, or a high activity state that supports cell survival. We have shown that altered pyruvate kinase activity can impact breast cancer progression, liver metastases, and disease survival. Taking advantage of genetic and pharmacological tools to control pyruvate activity in mouse models of human cancer, we are testing how pyruvate kinase activity impacts the ability of cells to metastasize.
Our studies of tumor metabolism in animal models have suggested that tumor cells can use a remarkable diversity of nutrients other than glucose, and that amino acid metabolism is a major fuel for cancer cells in some contexts. We hypothesize that different nutrient availability based on tissue environment could have a profound impact on metastasis, and are working to understand what nutrients tumors depend on for growth in different body locations. We are particularly interested in whether differential nutrient use impacts tumor growth in different metastatic sites. Of note, amino acid metabolism at the organismal levels is regulated across tissues, suggesting amino acid availability in different organs may impact the ability of tumors to grow in different sites. We expect that this work will provide new insight into an understudied area of tumor biology and inform how best to disrupt nutrient utilization for the treatment and/or prevention of metastatic disease.