Metabolic reprogramming of tumor-associated macrophages by collagen turnover promotes fibrosis in pancreatic cancer.

A hallmark of pancreatic tumors is their highly desmoplastic stroma composed of fibroblasts, immune cells, and a dense network of collagen fibers. Tumor-associated macrophages are one of the most abundant immune cell populations in the pancreatic tumor stroma. Their protumorigenic function has been attributed predominantly to their capacity to promote immune evasion and metastasis. Tumor-assoc iated macrophages are also well known for their role in the remodeling of the stroma via collagen production and degradation, with the latter being mediated by mannose receptor (MRC1)-dependent endocytosis of collagen. Here we show that MRC1-mediated collagen internalization and subsequent lysosomal degradation by macrophages harboring a tumor-associated phenotype are accompanied by the accumulation of collagen-derived intracellular free amino acids and increased arginine biosynthesis. The resulting increase in intracellular arginine levels leads to the up-regulation of inducible nitric oxide synthase and the production of reactive nitrogen species. Furthermore, reactive nitrogen species derived from internalized and degraded collagen promotes a profibrotic phenotype in pancreatic stellate cells resulting in enhanced intratumoral collagen deposition. Overall, our findings identify a role for extracellular matrix remodeling in the functional modulation of tumor-associated macrophages via metabolic rewiring.

Evidence for key enzymatic controls on metabolism of Arctic river organic matter.

Permafrost thaw in the Arctic driven by climate change is mobilizing ancient terrigenous organic carbon (OC) into fluvial networks. Understanding the controls on metabolism of this OC is imperative for assessing its role with respect to climate feedbacks. In this study, we examined the effect of inorganic nutrient supply and dissolved organic matter (DOM) composition on aquatic extracellular enzyme activities (EEAs) in waters draining the Kolyma River Basin (Siberia), including permafrost-derived OC. Reducing the phenolic content of the DOM pool resulted in dramatic increases in hydrolase EEAs (e.g., phosphatase activity increased >28-fold) supporting the idea that high concentrations of polyphenolic compounds in DOM (e.g., plant structural tissues) inhibit enzyme synthesis or activity, limiting OC degradation. EEAs were significantly more responsive to inorganic nutrient additions only after phenolic inhibition was experimentally removed. In controlled mixtures of modern OC and thawed permafrost endmember OC sources, respiration rates per unit dissolved OC were 1.3-1.6 times higher in waters containing ancient carbon, suggesting that permafrost-derived OC was more available for microbial mineralization. In addition, waters containing ancient permafrost-derived OC supported elevated phosphatase and glucosidase activities. Based on these combined results, we propose that both composition and nutrient availability regulate DOM metabolism in Arctic aquatic ecosystems. Our empirical findings are incorporated into a mechanistic conceptual model highlighting two key enzymatic processes in the mineralization of riverine OM: (i) the role of phenol oxidase activity in reducing inhibitory phenolic compounds and (ii) the role of phosphatase in mobilizing organic P. Permafrost-derived DOM degradation was less constrained by this initial 'phenolic-OM' inhibition; thus, informing reports of high biological availability of ancient, permafrost-derived DOM with clear ramifications for its metabolism in fluvial networks and feedbacks to climate.

Route of self-amplifying mRNA vaccination modulates the establishment of pulmonary resident memory CD8 and CD4 T cells.

Respiratory tract resident memory T cells (TRM), typically generated by local vaccination or infection, can accelerate control of pulmonary infections that evade neutralizing antibody. It is unknown whether mRNA vaccination establishes respiratory TRM. We generated a self-amplifying mRNA vaccine encoding the influenza A virus nucleoprotein that is encapsulated in modified dendron-based nanoparticles. Here, we report how routes of immunization in mice, including contralateral versus ipsilateral intramuscular boosts, or intravenous and intranasal routes, influenced influenza-specific cell-mediated and humoral immunity. Parabiotic surgeries revealed that intramuscular immunization was sufficient to establish CD8 TRM in the lung and draining lymph nodes. Contralateral, compared with ipsilateral, intramuscular boosting broadened the distribution of lymph node TRM and T follicular helper cells but slightly diminished resulting levels of serum antibody. Intranasal mRNA delivery established modest circulating CD8 and CD4 T cell memory but augmented distribution to the respiratory mucosa. Combining intramuscular immunizations with an intranasal mRNA boost achieved high levels of both circulating T cell memory and lung TRM. Thus, routes of mRNA vaccination influence humoral and cell-mediated immunity, and intramuscular prime-boosting establishes lung TRM that can be further expanded by an additional intranasal immunization.

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

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 cross-talk between PSCs and PDAC is orchestrated by the utilization of specific 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 identifies critical neutral amino acid transporters involved in channeling alanine between pancreatic stellate and PDAC cells. Targeting PDAC-specific alanine uptake results in a metabolic crisis impairing metabolism, proliferation, and tumor growth. PDAC cells specifically activate and require SLC38A2 to fuel their alanine demands that may be exploited therapeutically.This article is highlighted in the In This Issue feature, p. 890.

Plastic bronchitis in patients with fontan physiology: review of the literature and preliminary experience with fontan conversion and cardiac transplantation.

Plastic bronchitis is a rare, life-threatening condition characterized by the formation of mucofibrinous casts within the pulmonary bronchi. In patients with congenital heart disease, it is most frequently observed in single ventricular anatomies after Fontan palliation. The pathophysiology of plastic bronchitis remains unknown, and a consistently effective treatment strategy has yet to be identified. We report two cases of plastic bronchitis in patients with Fontan physiology. The first was treated with Fontan conversion and, despite encouraging short-term results, experienced recurrence of cast formation seven months postoperatively. The second underwent cardiac transplantation and has been free of bronchial casts for over one year. In addition, we explore the similarities between plastic bronchitis and protein-losing enteropathy, considering theories of their pathophysiologic mechanisms and reports of mutually effective treatment strategies. We propose that bronchial cast formation may result from the confluence of genetic makeup, inflammation, and the Fontan physiology and conclude that further investigation into therapies directed at these factors is merited.