As a result of aberrant signaling, cancer cells undergo metabolic reprogramming, which enables persistent growth and proliferation despite nutrient scarcity. Metabolic changes include the activation of various mechanisms for nutrient assimilation, such as the expression of high- affinity amino acid transporters. Accordingly, most studies of nutrient uptake in cancer have focused on monomeric nutrients (e.g. glucose and glutamine), ignoring intact macromolecules as a potential fuel source. Recently, we discovered that Ras-transformed cells use macropinocytosis of intact protein as an alternative means for amino acid acquisition. This process enables Ras-driven cells to grow in low glutamine environments, and its inhibition selectively blocks the growth of Ras-activated human pancreatic cancer xenografts. Thus, uptake and catabolism of intact protein is an important nutrient uptake mechanism for Ras- driven cancers, including pancreatic cancer. The overall goal of my Ph.D. thesis is to expand basic science knowledge about this mode of eating in pancreatic cancer.
In Aim 1, I will develop both cell biological and isotope-tracer methods to quantitate the extent to which macropinocytosis of protein can substitute for free amino acids in cultured cells.
In Aim 2, I will develop related isotope tracer methods for xenografts. Finally, in Aim 3, I will conduct a RNAi screen for genes essential to effective amino acid acquisition via protein degradation. Collectively, these aims will better define the significance of and molecular machinery for tumor cell eating of intact extracellular protein, a novel nutrient acquisition mechanism.
Understanding the differences between cancer cells and benign cells is crucial to the development of anti-cancer therapies. Many such differences involve the altered metabolic program of cancer cells, which must adapt to low nutrient levels to maintain aggressive growth. We recently identified macropinocytosis of protein as an alternative mechanism for amino acid acquisition in Ras-driven cancer cells. This proposal aims to develop a more complete understanding of this process.
|Nofal, Michel; Zhang, Kevin; Han, Seunghun et al. (2017) mTOR Inhibition Restores Amino Acid Balance in Cells Dependent on Catabolism of Extracellular Protein. Mol Cell 67:936-946.e5|
|Kamphorst, Jurre J; Nofal, Michel; Commisso, Cosimo et al. (2015) Human pancreatic cancer tumors are nutrient poor and tumor cells actively scavenge extracellular protein. Cancer Res 75:544-53|