Selective Alanine Transporter Utilization Creates a Targetable Metabolic Niche in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) evolves a complex microenvironment comprised of multiple cell types, including pancreatic stellate cells (PSC). Previous studies have demonstrated that stromal supply of alanine, lipids, and nucleotides supports the metabolism, growth, and therapeutic resistance of PDAC. Here we demonstrate that alanine crosstalk between PSCs and PDAC is orchestrated by the utilization of specifi c transporters. PSCs utilize SLC1A4 and other transporters to rapidly exchange and maintain environmental alanine concentrations. Moreover, PDAC cells upregulate SLC38A2 to supply their increased alanine demand. Cells lacking SLC38A2 fail to concentrate intracellular alanine and undergo a profound metabolic crisis resulting in markedly impaired tumor growth. Our results demonstrate that stromal-cancer metabolic niches can form through differential transporter expression, creating unique therapeutic opportunities to target metabolic demands of cancer. SIGnIFICAnCE: This work identifi es critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specifi c alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifi cally activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.

Increased expression of glutamine transporter SNAT2/SLC38A2 promotes glutamine dependence and oxidative stress resistance, and is associated with worse prognosis in triple-negative breast cancer

“…In pancreatic cancer, SLC38A2 represents the major AAT for alanine, which is then deaminated to pyruvate (which can maintain the tricarboxylic acid cycle) in the presence of pyruvate carboxylase. 56 Finally, our analysis of clinical data from a large breast cancer cohort suggests that high baseline SLC38A2 protein expression correlates with poor BCSS survival in patients with breast cancer and with TNBC. Moreover, tumours with high SLC38A2 expression were also commonly represented in the poor prognostic high SLC cluster (SLC1A5+/SLC7A5+/SLC3A2+).…”

Regulation of metabolic reprogramming by tumor suppressor genes in pancreatic cancer

“…And as mentioned before, p53 can promote the adaption to glutamine deprivation by increasing arginine uptake through upregulating SLC7A3 in MEFs [37]. Parker et al found that PDAC cells lacking of SLC38A2 were unable to concentrate intracellular alanine and occurred a profound metabolic crisis which lead to markedly impaired tumor growth [117]. In addition, LKB1 can activate AMP-activated protein kinase (AMPK) and inhibit Acetyl-CoA carboxylase (ACC), which is a product in the first step of fatty acid (FA) synthesis, thus inhibiting FA synthesis and tumor growth in lung cancer mouse models [118,119].…”

CRISPR screens in physiologic medium reveal conditionally essential genes in human cells

“…While glutamate levels between the two media are comparable, HPLM contains the three remaining components at concentrations at least 5-(aKG), 15-(pyruvate), and 200-fold (alanine) greater than those quantified in RPMI +dS ( Figure 3G). Studies in human cancer cells over the past decade have highlighted a role for GPT2 in facilitating glutamine anaplerosis via the production of aKG (Hao et al, 2016;Kim et al, 2019;Smith et al, 2016;Weinberg et al, 2010), and further, others have reported that GPT can serve to fuel the TCA cycle in certain cancers by catabolizing alanine to pyruvate (Parker et al, 2020;Sousa et al, 2016). Therefore, we considered whether the differential availability of either aKG or pyruvate could explain the RPMI-essential phenotype of GPT2 deletion.…”