How nearby nutrients shape tumor growth

Abstract

Studying the nutrient composition immediately surrounding pancreatic cancer cells provides new insights into their metabolic properties and how they can evade the immune system to promote disease progression.

Keywords: amino acid homeostasis; biochemistry; cancer; cancer biology; chemical biology; human; immunotherapy; metabolism; mouse; nutrient stress; tumor microenvironment.

Figure 1.. Depletion of arginine in the tumor microenvironment shapes how pancreatic cancer cells behave and respond to drug treatment in the laboratory.

(A) The microenvironment surrounding pancreatic ductal adenocarcinoma cells (PDA, green) contains myeloid cells (pink) that secrete an enzyme called arginase 1 (ARG1, yellow trimers): this enzyme breaks down arginine (dark blue circles), which leads to depleted levels of this amino acid. The nutrient composition of the PDA microenvironment was used to formulate a new medium for pancreatic cancer cells called TIFM. PDA cells grown in TIFM, but not standard culture media, display an active urea cycle (shown in circle inset), similar to when they are grown within the body. By taking up citrulline, a key ingredient of the TIFM but not standard media, the cancer cells can short circuit the urea cycle to synthesize their own arginine. The amino acid can then be degraded into other molecules (ornithine and urea) that help to dispose of excess nitrogen, or used to synthesize metabolic products that may promote tumor growth, such as proteins (P), nitric oxide (N) and creatine (C). (B) Treating mice bearing PDA tumors with the arginase inhibitor CB-1158 (small orange pentagons) raises arginine levels in the tumor microenvironment and promotes infiltration of anti-tumor CD8⁺ T cells (light blue). However, many of these immune cells are ‘exhausted’ or inactive due to their programmed cell death protein (PD1, green) binding to its ligand on the surface of tumor cells (PD-L1, red). Adding a drug that blocks this interaction called Anti-PD1 (Y-shaped red protein) helps to reactivate the CD8⁺ T cells, leading to the death of PDA cancer cells and reduced tumor growth.