The Ye Lab is currently investigated three areas of cancer metabolism resarch: 

Project 1:

What is the connection between the Warburg effect and cancer dedifferentiation?

The Warburg effect is a metabolic hallmark of all cancer cells, characterized by increased glucose uptake and glycolysis for lactate generation. The generation and excretion of lactate would appear be a waste of carbon backbone and energy that is needed for proliferation. It was proposed by Warburg that the cause and consequence of the Warburg effect were the injury of respiration and cell dedifferentiation, respectively. One common factor that damages mitochondrial respiration is hypoxia, which is a metabolic stress that blocks cell differentiation and promotes cancer progression. The underlying mechanism by which this occurs is poorly understood, and no effective therapeutic strategy has been developed to overcome this resistance to differentiation. Using a neuroblastoma (NB) differentiation model, we have discovered that hypoxia represses the differentiation induced by retinoic acid (RA) as demonstrated by loss of neuron differentiation markers and changes in cell morphology, associated with reduction of global histone acetylation, that are caused by the induction of pyruvate dehydrogenase kinases (PDKs). PDKs phosphorylate pyruvate dehydrogenase (PDH), thereby blocking pyruvate entry into the TCA cycle, reducing acetyl-CoA generation, and promoting the Warburg effect. Genetic and pharmaceutical inhibition of PDK restores histone acetylation and NB cell differentiation morphology. Acetate supplementation restores histone acetylation, along with differentiation markers expression and neuron differentiation. In addition, ATAC-Seq analysis demonstrated that hypoxia treatment significantly reduces global chromatin accessibility, which can be restored by acetate supplementation. These findings suggest that (1) combining RA and acetate supplementation represents a potentially effective therapeutic strategy for neuroblastoma treatment; (2) diverting pyruvate away from acetyl-CoA generation is a key mechanism by which the Warburg effect blocks cell differentiation.

Project 2:

What is the cause and  consequence of metabolic reprogramming during cancer metastasis?

Metastasis is the major cause of mortality in breast cancer patients. Many studies have focused on how changes in cell motility, invasion and stromal interaction contribute to this process. However, the roles of altered metabolic pathways during metastasis are largely unknown.

To identify the metabolic vulnerability of metastatic cancer cells, we performed an unbiased metabolomic profiling on metastatic breast cancer cells versus the parental cells. We were able to uncover metabolic signatures of the metastatic cancer cells. Currently we are investigating how these metabolic reprogramming events promote cell proliferation and survival during metastasis.





Project 3:

How is mTORC1 activity regulated by metabolic stress?

The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of protein translation, cell growth and metabolism, which are key determinants of cellular and organismal homeostasis.  The dysregulation of mTORC1 activity is commonly associated with diseases including diabetes and cancer.  During nutrient-replete conditions, mTORC1 promotes cell growth and proliferation by initiating a biosynthetic program including protein translation and lipogenesis. However, during microenvironmental stresses such as hypoxia or nutrient deprivation, mTORC1 activity is inhibited to maintain energy and nutrient homeostasis, which is critical for cell survival. 

Recently, we have conducted experiments to study the relationship between the integrated stress response and mTORC1 signaling. We were able to show that amino acid starvation activates GCN2, while glucose starvation or hypoxia induces the unfolded protein response to activate PERK; these integrated stress response signals converge to phosphorylate eIF2α, leading to upregulation of the transcription factor ATF4 and its target genes, which inhibits mTORC1 and block its lysosomal localization. This established a critical link between these stress and nutrient regulatory pathways, by which the integrated stress response antagonizes mTORC1-dependent anabolic activities. In the future, we will a) elucidate the regulatory mechanism of these target genes of ATF4 under hypoxia and nutrient starvation; b) study the role of mTORC1 inhibition in autophagy induction and cell survival during stress.