Elitsa Ananieva-Stoyanova, Ph.D.

My long term research interest is to study the cellular metabolism of proliferating cells such as cancer and immune cells. There are fundamental differences in central metabolic pathways operating in proliferating cells as opposed to normal cells and deciphering the molecular mechanisms that trigger those differences will provide basis for the discovery of novel (metabolic) approaches for cancer treatment and cancer immunotherapy.

More specifically, my research focuses on the branched chain amino acid (BCAA) metabolic pathway and our current aims are:

• Characterize the role of BCAA metabolism in immunity and inflammation
• Study the molecular mechanisms of gene and protein regulation of BCAA enzymes in cancer and immune cells with the ultimate goal to improve the performance of the immune system to fight cancer
• Characterize BCAA metabolism in bone cancer and explore new (metabolic or nutritional) approaches to fight bone cancer
• Engage high schoolers through outreach activities in community projects to increase awareness of cancer

Overview of Branched Chain Amino Acid Metabolism

The essential BCAAs comprise around 40% of the free amino acids in the blood plasma and act as nutrient signals regulating protein synthesis and degradation (Hutson et al., 2005, J Nutr, 135: 1557S). To ensure adequate supply of BCAAs for protein synthesis and to prevent buildup of toxic metabolites, the concentrations of BCAAs are regulated during the first two steps of their degradation pathway (transamination and oxidative decarboxylation), catalyzed by the branched chain aminotransferase isozymes (mitochondrial BCATm and cytosolic BCATc) and the branched chain α-keto acid dehydrogenase enzyme complex (BCKDC), respectively (Sweatt et al., 2004, Am. J Physiol, 286: E64).

Genetic disorders, such as maple syrup urine disorder (MSUD), methylmalonic acidaemia, and propionic acidaemia result from defects in the BCAA catabolic enzymes and mainly affect the central nervous system (Chuang et al., 2006,  J Nutr, 136: 243S).

Apart from genetic disorders, dysregulations in BCAA catabolism may impact both the immune system and cancer growth, as BCAAs are necessary to fuel immune and cancer cells, supporting efficient immune function and sustaining cancer growth (Calder PC, 2006, J Nutr 136, 288S; Zhou et al., 2013, Mol Cancer ,12: 53). This implies that both immune and cancer cells share similar metabiotic requirements for BCAAs.

Most important findings about BCAA metabolism in immune and cancer cells

T lymphocytes:

1. Upon pathogen or cancer encounter, T lymphocytes (T cells) become activated which triggers their rapid growth and proliferation
2. Leucine uptake increases upon T cell activation via Slc7a5 (leucine transporter) (Sinclair et al., 2013, Nature Immunol, 14: 500)
3. The activated T cells use leucine to stimulate the complex I of the mammalian target of rapamycin (mTORC1), the latter is an activator of protein translation, glycolysis, and cell growth (Fig.1)
4. The gene for BCATc (called BCAT1) is selectively induced upon T cell activation
5. By transaminating leucine, BCATc controls the leucine supply to mTORC1 thus providing negative feedback regulation of T cell activation (Fig. 1A)
6. T cells from a global BCATc knockout (BCATc^-/-) mouse have up-regulated mTORC1 signaling, experience higher glycolytic rate and produce more interferon gamma (IFNƴ)
7. Refer to Ananieva et al (2014, J Biol Chem, 289: 18793) and Ananieva et al (2016 Advances in Nutrition 7: 798S-805S) for more information

Cancer:

• BCAT1 gene was proposed as a prognostic cancer marker in:
  • Lung cancer (Diaz-Lagares A et al., Clin Cancer Res. 2016 Jul 1;22(13):3361-71)
  • Lymphoblastic leukemia (Safavi S et al., Haematologica. 2015 Jan;100(1):55-61.)
  • Ovarian cancer (Wang ZQ et al., 2015 Oct 13;6(31):31522-43)
  • Colorectal cancer (Mitchell SM et al., BMC Cancer. 2014 Jan 31;14:54)
  • Glioblastoma (Tönjes M et al., Nat Med. 2013 Jul;19(7):901-8)
  • Breast cancer (Zhang EYJet al., Proteome Res. 2013 Jun 7;12(6):2805-17)
  • Nasopharyngeal carcinoma (Zhou W et al., Mol Cancer. 2013 Jun 8;12:53)
• BCAT1 gene expression in cancer is regulated by:
  • The oncogene c-Myc
  • Methylation (epigenetic modification)
• BCAT2 gene was proposed as a prognostic cancer marker in:
  • Glioma cancer (Conway ME et al.,Brain Pathol. 2016 Apr 12. doi: 10.1111/bpa.12385)