Pancreatic tumors activate arginine biosynthesis to adapt to myeloid-driven amino acid stress

Abstract

Nutrient stress in the tumor microenvironment requires cancer cells to adopt adaptive metabolic programs to maintain 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 (Sullivan et al., 2019a). Here, we develop Tumor Interstitial Fluid Medium (TIFM), a cell culture medium that contains nutrient levels representative of the PDAC microenvironment, enabling study of PDAC metabolism under physiological nutrition. We show that PDAC cells cultured in TIFM, compared to standard laboratory models, adopt a cellular state more similar to PDAC cells in tumors. Further, using the TIFM model we identified arginine biosynthesis as a metabolic adaptation PDAC cells engage to cope with microenvironmental arginine starvation driven by myeloid cells in PDAC tumors. Altogether, these data show 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 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).…”

SLC7A5 is required for citrulline-dependent growth in arginine limited conditions

“…Inhibition of SLC7A5 may sensitize tumors to an arginine depletion agent such as ADI-PEG20 and improve therapeutic efficacy. Beyond co-treatment with arginine depleting agents, the efficacy of SLC7A5 agents may reveal tumors with limited arginine availability in the TME 65,66 . Numerous studies have shown that JPH203 treatment slows tumor growth in xenograft models [67][68][69][70] .…”

Modelling cancer metabolism in vitro: current improvements and future challenges

“…Those include a dramatic drop in arginine and tryptophan [26]. The same group recently suggested in a preprint study, that cultivating PDAC cells in a TIF‐based culture medium better recapitulated the transcriptomic in vivo gene signature of PDAC xenografts, which supports a chronic starvation state of these tumours associated with a constitutive activation of the amino‐acid response pathway [27]. These findings advocate for the use of TIF‐based media to understand tumour cell metabolism, particularly in this new era dedicated to developing alternative models to animals.…”