报告题目: Regulation of nutrient uptake controls cancer cell growth and metabolism

报告人: Jeff Holst, Associate Professor/Faculty, Centenary Institute and the University of Sydney

主持人: 李大力 研究员

报告时间: 2016-4-28  13:30-15:00 （周四下午）

报告地点: 闵行校区天美娱乐534小会议室

主办单位: 天美娱乐 科技处

 

报告人简介👩🏿‍🍼：Associate Professor Jeff Holst obtained his PhD from the University of New South Wales in 2003, before moving to the USA to undertake a postdoc at St Jude Children’s Research Hospital (2003-2006). This work examined T cell receptor signalling and resulted in first author Nature Immunology (2008), Nature Methods and Nature Protocols (2006) publications. These publications have combined for over 200 citations and resulted in his receipt of the Research Australia Discovery Award in 2008.

 

After returning to Australia, he discovered a new signalling pathway critical for ex vivo expansion of haemopoietic stem cells (Nature Biotechnology, 2010). His laboratory was also involved in the novel discovery that intron retention is a conserved mechanism of gene regulation involved in cellular differentiation (Cell, 2013). He currently leads the Origins of Cancer Laboratory (2008), as a member of Faculty (Centenary Institute) and Associate Professor (University of Sydney). His laboratory aims to dissect how nutrient uptake regulates cancer cell growth and downstream metabolic pathways.

 

 

 

报告简介：Solid tumours activate angiogenic signals to ensure an adequate blood supply. In parallel, amino acid transporters on the cell surface are also increased so as to provide nutrients for the higher metabolic and growth demands of cancers. We are studying a number of amino acid transporters, including L-type amino acid transporters (LAT1 and LAT3) and alanine-serine-cysteine transporter 2 (ASCT2) that are increased in prostate and breast cancer and mediate uptake of essential amino acids including leucine and glutamine. Leucine and glutamine are critical for cellular metabolism, cell growth, and proliferation. Therefore, targeting leucine and glutamine transport in cancer cells may provide a novel strategy for “starving” cancer cells.

 

We have used a variety of cell and molecular biology techniques (chemical and shRNA-mediated inhibition) to examine the role of amino acid transporters in prostate and breast cancer in vitro and in vivo models. Our results have demonstrated that prostate cancer cells coordinate the expression of LAT1 and LAT3 during disease progression, thereby maintaining sufficient leucine to promote mTORC1 signaling and cell growth. Similarly, we have shown that both LAT1 and ASCT2 are highly upregulated in ER+ and triple-negative breast cancer. Unlike prostate cancer cells, however, triple-negative breast cancer cells are tolerant to leucine deprivation, while exhibiting exquisite sensitivity to glutamine deprivation through ASCT2 chemical or shRNA mediated inhibition. Interestingly, our data also show that prostate cancer cells are sensitive to both leucine and glutamine deprivation.

 

In summary, cancer cells respond to the demand for amino acids through integrated pathways that lead to increased amino acid transporter expression and cell growth. Furthermore, ASCT2, LAT3 and LAT1 may provide novel therapeutic targets in early and late stage prostate cancer as well as triple-negative breast cancer.