The Ye Lab is currently investigated three areas of cancer metabolism resarch:
How does serine and one-carbon unit metabolism regulate chromatin remodeling and cancer cell differentiation?
Neuroblastoma is the most common and deadliest solid tumor in childhood. Both MYCNamplification and hypoxia promote dedifferentiation and aggressiveness of neuroblastoma, though the mechanism remains unclear. Our preliminary studies demonstrate that the mitochondrial enzyme serine hydroxymethyltransferase 2 (SHMT2) is a prognostic marker that is highly expressed in poorly differentiated/undifferentiated neuroblastoma samples. Given that hypoxia induces SHMT2 through HIF-1 solely in MYCN-amplified neuroblastoma cells, and one-carbon unit flux through SHMT2 provides methyl group for histone/DNA methylation, we propose that one-carbon unit flux from SHMT2 is critical for cellular methyltransferase activity, which causes histone/DNA hypermethylation that correlate with the inability of neuroblastoma cells to activate lineage-specific genes involved in cellular differentiation. Through these proposed studies we hope to broaden the understanding of the metabolic regulation of chromatin remodeling in neuroblastoma, and develop new therapeutic approaches targeting neuroblastoma adaptation to Myc amplification and hypoxia.
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.
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.