The Intratumoral Heterogeneity of Cancer Metabolism.

Cancer is one of the deadliest diseases in the world, causing over half a million deaths a year in the USA alone. Despite recent advances made in the field of cancer biology and the therapies that have been developed [1, 2], it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a complete cure eluded us? This chapter sheds light on one of cancer's most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest diseases is its ability to change and adapt. Cancer cells' rapid evolution, coupled with their irrepressible ability to divide, gives most of them the advantage over our immune systems. In this chapter, we delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity.

Uncovering the Role of N-Acetyl-Aspartyl-Glutamate as a Glutamate Reservoir in Cancer.

N-acetyl-aspartyl-glutamate (NAAG) is a peptide-based neurotransmitter that has been extensively studied in many neurological diseases. In this study, we show a specific role of NAAG in cancer. We found that NAAG is more abundant in higher grade cancers and is a source of glutamate in cancers expressing glutamate carboxypeptidase II (GCPII), the enzyme that hydrolyzes NAAG to glutamate and N-acetyl-aspartate (NAA). Knocking down GCPII expression through genetic alteration or pharmacological inhibition of GCPII results in a reduction of both glutamate concentrations and cancer growth. Moreover, targeting GCPII in combination with glutaminase inhibition accentuates these effects. These findings suggest that NAAG serves as an important reservoir to provide glutamate to cancer cells through GCPII when glutamate production from other sources is limited. Thus, GCPII is a viable target for cancer therapy, either alone or in combination with glutaminase inhibition.

The Intratumoral Heterogeneity of Cancer Metabolism.

KEY POINTS: Cancer is one of the deadliest diseases in the world, especially within the past few decades, causing over half a million deaths a year in the USA only [1]. Despite recent advances made in the field of cancer biology and the therapies that have been developed, it is clear that more advances are necessary for us to classify cancer as curable. The logical question that arises is simple: Why, despite all the technologies and medical innovations of our time, has a cure eluded us? This chapter will shed light on one of cancer's most impactful attributes: its heterogeneity and, more specifically, the intratumoral heterogeneity of cancer metabolism. Simply put, what makes cancer one of the deadliest known diseases is its ability to change and adapt. Cancer cells' rapid evolution, coupled with their irrepressible ability to divide, gives them the advantage over our immune systems. In this chapter, we will delve into the complexities of this adaptability and the vital role that metabolism plays in the rise and progression of this heterogeneity.