Pancreatic ductal adenocarcinoma (PDAC) is notorious for a dense fibrotic stroma that is interlaced with a collagen-based extracellular matrix (ECM) that plays an important role in tumor biology. Traditionally thought to only provide a physical barrier from host responses and systemic chemotherapy, new studies have demonstrated that the ECM maintains biomechanical and biochemical properties of the tumor microenvironment (TME) and restrains tumor growth. Recent studies have shown that the ECM augments tumor stiffness, interstitial fluid pressure, cell-to-cell junctions, and microvascularity using a mix of biomechanical and biochemical signals to influence tumor fate for better or worse. In addition, PDAC tumors have been shown to use ECM-derived peptide fragments as a nutrient source in nutrient-poor conditions. While collagens are the most abundant proteins found in the ECM, several studies have identified growth factors, integrins, glycoproteins, and proteoglycans in the ECM. This review focuses on the dichotomous nature of the PDAC ECM, the types of collagens and other proteins found in the ECM, and therapeutic strategies targeting the PDAC ECM.

Fatty acid transport protein 2 (FATP2) is highly expressed in the liver, small intestine, and kidney, where it functions in both the transport of exogenous long-chain fatty acids and the activation of very-long-chain fatty acids. Here, using a murine model, we investigated the phenotypic impacts of deleting FATP2, followed by a transcriptomic analysis using unbiased RNA-Seq to identify concomitant changes in the liver transcriptome. WT and FATP2-null (Fatp2−/−) mice (5 weeks) were maintained on a standard chow diet for 6 weeks. The Fatp2−/− mice had reduced weight gain, lowered serum triglyceride, and increased serum cholesterol levels and attenuated dietary fatty acid absorption. Transcriptomic analysis of the liver revealed 258 differentially expressed genes in male Fatp2−/− mice and a total of 91 in female Fatp2−/− mice. These genes mapped to the following gene ontology categories: fatty acid degradation, peroxisome biogenesis, fatty acid synthesis, and retinol and arachidonic acid metabolism. Targeted RT-quantitative PCR verified the altered expression of selected genes. Of note, most of the genes with increased expression were known to be regulated by peroxisome proliferator–activated receptor α (PPARα), suggesting that FATP2 activity is linked to a PPARα-specific proximal ligand. Targeted metabolomic experiments in the Fatp2−/− liver revealed increases of total C16:0, C16:1, and C18:1 fatty acids; increases in lipoxin A4 and prostaglandin J2; and a decrease in 20-hydroxyeicosatetraenoic acid. We conclude that the expression of FATP2 in the liver broadly affects the metabolic landscape through PPARα, indicating that FATP2 provides an important role in liver lipid metabolism through its transport or activation activities.

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Fatty acid transport protein 2 (FATP2) is highly expressed in liver, small intestine and kidney where it functions in both the uptake of exogenous long chain fatty acids and in the activation of very long chain fatty acids. Previous studies from this lab have found that when the fatty acid uptake is attenuated using the FATP2‐specific inhibitor Lipofermata, cells that express this protein are protected from lipotoxicity. These observations support the notion that FATP2 functions as a gate in regulating the uptake of exogenous fatty acids, which are linked to downstream lipid metabolic events. In the present study, we completed a comprehensive RNA seq analysis to address the impact of deleting FATP2 in the liver on the transcriptome. Wild type (C57BL/6NJ) and FATP null (FATP2−/−) mice (5 weeks old) were maintained on standard chow diet for 6 weeks. Over this period of time, the FATP2−/− mice had reduced weight gain and lowered blood triglyceride levels compared with control mice. A number of lipid metabolic genes in the liver were increased in the FATP2−/− mice that mapped to the gene ontology categories beta‐oxidation, peroxisome biogenesis, fatty acid trafficking and arachidonic fatty acid/eicosanoid metabolism. These metabolic systems are linked through activity of the transcription factor PPARa suggesting endogenous expression was elevated possibly through increases in a proximal ligand when FATP2 is absent. This correlated with increased expression of phospholipase A2. To address these changes further, we employed untargeted (NMR) and targeted (LC‐MS/MS) metabolomics experiments, which showed there were no major differences in the abundance of substrates in central carbon metabolism between the wild type and FATP2−/− livers, but there was a significant increase in the eicosanoids LXA4 and PGJ2 in the FATP2−/− livers. Taken together, the expression of FATP2 appears to have a broad impact on the expression of key lipid metabolic genes that may be linked through increased levels of bioactive lipid mediators.Support or Funding InformationThis work has been supported by the Agricultural Research Division of the University of Nebraska.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Fatty Acid Transport Protein 2 (FATP2) is highly expressed in the small intestine, liver, kidney, pancreas, and placenta. FATP2 has two activities: [1] it facilitates the uptake of long chain fatty acids into the cell and [2] it activates very long chain fatty acids destined for incorporation into cellular lipids or β‐oxidation. Previous work from this laboratory implicates FATP2 activity in the promotion of lipotoxicity that may lead to cell death. The present studies employ mice lacking the FATP2 gene (FATP2−/−) to more fully understand the function and effects of FATP2‐dependent fatty acid uptake on liver metabolism and lipotoxic disease. We hypothesize a reduction in uptake and metabolism of fatty acids dependent upon FATP2 may lead to alterations in expression of genes that are responsive to exogenous fatty acids. Gene expression was measured in wild type and FATP2−/− livers using quantitative PCR and validated using western blots to assess the impact of genotype, diet, and fasting period. Preliminary data shows that expression of FABP1, CD36, Cyp4A10, and ACOX are elevated in livers of FATP2−/− mice independent of dietary fat levels. In contrast, expression of NPC1L1 was decreased. Differences between diets alone resulted in an increase in FABP2 and FABP4, FAS, Serpinb6 and ApoB expression, while FABP1, CD36, and ACOX expression was dependent on both genotype and diet. These results further suggest deletion of FATP2 increases PPARa signaling, perhaps through increases in a native fatty acid ligand. Overall, these studies further demonstrate an important role for FATP2 in liver lipid homeostasis during high fat dietary challenge.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.