Pancreatic tumors exhibit myeloid-driven amino acid stress and upregulate arginine biosynthesis

Abstract

Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs for survival and proliferation. Therefore, knowledge of microenvironmental nutrient levels and how cancer cells cope with such nutrition is critical to understand the metabolism underpinning cancer cell biology. Previously, we performed quantitative metabolomics of the interstitial fluid (the local perfusate) of murine pancreatic ductal adenocarcinoma (PDAC) tumors to comprehensively characterize nutrient availability in the microenvironment of these tumors (M. R. Sullivan, Danai, et al., 2019). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling us to study PDAC metabolism ex vivo under physiological nutrient conditions. We show that PDAC cells cultured in TIFM adopt a cellular state closer to that of PDAC cells present in tumors compared to standard culture models. Further, using the TIFM model, we found arginine biosynthesis is active in PDAC and allows PDAC cells to maintain levels of this amino acid despite microenvironmental arginine depletion. We also show that myeloid derived arginase activity is largely responsible for the low levels of arginine in PDAC tumors. Altogether, these data indicate that nutrient availability in tumors is an important determinant of cancer cell metabolism and behavior, and cell culture models that incorporate physiological nutrient availability have improved fidelity to in vivo systems and enable the discovery of novel cancer metabolic phenotypes.

Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability

“…Nevertheless, it is provocative to consider that general tissue homeostatic nutrient maintenance mechanisms are preserved in tumors, and that cancer cells may retain some dependence on nutrients defined by the adjacent origin tissue. To this end, it is notable that the metabolites found in RCC TIF differ from those reported in mouse pancreatic ductal adenocarcinoma (PDAC) TIF 14,49 , and from those found in interstitial fluid derived from mouse brain and mammary fat pad tissue 8 . Findings from analysis of PDAC TIF from tumors implanted in different tissue sites also noted differences in metabolite levels 14 , supporting the notion that cancer must adapt to a specific tissue nutrient environment rather than determine the majority of nutrients present.…”

“…Recent studies have found that arginine is depleted to very low levels in murine pancreatic cancer TIF 14,49,50 , a phenomenon facilitated by myeloid-derived arginase activity 49 . Of note, arginine is not significantly depleted in KIF or TIF from RCC patients compared to plasma, although levels of related urea cycle metabolites are reduced in TIF and KIF compared to plasma (Figure 2E) .…”

Evaluating Metabolite-Based Biomarkers for Early Diagnosis of Pancreatic Cancer: A Systematic Review

“…Arginine is a non-essential or semi-essential amino acid involved in several biological functions such as cell proliferation, survival and protein synthesis, and it also acts as a precursor for the synthesis of molecules involved in tumorigenesis and tumor progression in PDAC, such as nitric oxide and polyamines, among others [ 57 , 58 ]. Arginine biosynthesis upregulation has been reported in pancreatic tumors [ 59 ]. Arginine metabolism facilitates PDAC progression, and its depletion has been associated with the suppression of cell invasion, migration and proliferation and the promotion of autophagy and apoptosis.…”

Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer

“…This consumption also has effects on tumor cells. A recent study showed that pancreatic tumors must upregulate arginine biosynthesis to compensate for this competition for local arginine ( 115 ).…”