Engineered diets to improve cancer outcomes.

Cancer cells acquire a diverse range of metabolic adaptations that support their enhanced rates of growth and proliferation. While these adaptations help tune metabolism to support higher anabolic output and bolster antioxidant defenses, they can also decrease metabolic flexibility and increase dependence on nutrient uptake versus de novo synthesis. Diet is the major source of nutrients that ultimately support tumor growth, yet the potential impact of diet is currently underutilized during the treatment of cancer. Here, we review several forms of dietary augmentation therapy including those that alter the content of food, such as energy or macronutrient restriction, and those that alter the timing of food consumption, like intermittent fasting regimens. We discuss how these dietary strategies can be combined with pharmacologic therapies to exaggerate the metabolic liabilities of different cancer types.

Control of TSC2-Rheb signaling axis by arginine regulates mTORC1 activity.

The mammalian target of rapamycin complex 1 (mTORC1) is the key signaling hub that regulates cellular protein homeostasis, growth, and proliferation in health and disease. As a prerequisite for activation of mTORC1 by hormones and mitogens, there first has to be an available pool of intracellular amino acids. Arginine, an amino acid essential during mammalian embryogenesis and early development is one of the key activators of mTORC1. Herein, we demonstrate that arginine acts independently of its metabolism to allow maximal activation of mTORC1 by growth factors via a mechanism that does not involve regulation of mTORC1 localization to lysosomes. Instead, arginine specifically suppresses lysosomal localization of the TSC complex and interaction with its target small GTPase protein, Rheb. By interfering with TSC-Rheb complex, arginine relieves allosteric inhibition of Rheb by TSC. Arginine cooperates with growth factor signaling which further promotes dissociation of TSC2 from lysosomes and activation of mTORC1. Arginine is the main amino acid sensed by the mTORC1 pathway in several cell types including human embryonic stem cells (hESCs). Dependence on arginine is maintained once hESCs are differentiated to fibroblasts, neurons, and hepatocytes, highlighting the fundamental importance of arginine-sensing to mTORC1 signaling. Together, our data provide evidence that different growth promoting cues cooperate to a greater extent than previously recognized to achieve tight spatial and temporal regulation of mTORC1 signaling.

Cells need to be able to sense and respond to signals from their environment. A group (or complex) of conserved proteins called mTORC1 acts a key signaling hub that regulates cell growth and many other processes. This complex can be activated by many different signals from outside the cell. However, mTORC1 can only be activated by these signals if there is also a good supply of amino acids ­ which are needed to make new proteins ­ within the cell. The amino acids are thought to be presented to mTORC1 on the outer surface of cellular compartments known as lysosomes. A protein called Rheb on the surface of the lysosomes activates mTORC1, while a protein complex called TSC inhibits the activity of Rheb to regulate mTORC1 activity. Previous studies have shown that some amino acids influence whether mTORC1 can be activated by affecting whether it is localized to the lysosomes or not. Here, Carroll et al. explored how an amino acid called arginine regulates mTORC1. The experiments show that arginine is the major amino acid that influences whether mTORC1 can be activated in several different types of human cell. When cells were deprived of arginine, the activity of the complex was strongly suppressed. However, microscopy showed that arginine had no effect on whether mTORC1 was found at the lysosomes or not, which suggests that arginine might be acting in a different way to other amino acids. Further experiments found that a lack of arginine led to an increase in the number of TSC complexes at the lysosomes. This led to the inhibition of Rheb and therefore prevented mTORC1 from being activated. Together, Carroll et al.'s findings provide evidence that the different signals that regulate mTORC1 signaling cooperate to a greater extent than previously thought. A future challenge will be to understand the molecular details of how the arginine is detected.

iRFP is a sensitive marker for cell number and tumor growth in high-throughput systems.

GFP and luciferase are used extensively as markers both in vitro and in vivo although both have limitations. The utility of GFP fluorescence is restricted by high background signal and poor tissue penetrance. Luciferase throughput is limited in vitro by the requirement for cell lysis, while in vivo, luciferase readout is complicated by the need for substrate injection and the dependence on endogenous ATP. Here we show that near-infrared fluorescent protein in combination with widely available near-infrared scanners overcomes these obstacles and allows for the accurate determination of cell number in vitro and tumor growth in vivo in a high-throughput manner and at negligible per-well costs. This system represents a significant advance in tracking cell proliferation in tissue culture as well as in animals, with widespread applications in cell biology.