p38MAPK builds a hyaluronan cancer niche to drive lung tumorigenesis.

Expansion of neoplastic lesions generates the initial signal that instigates the creation of a tumor niche. Nontransformed cell types within the microenvironment continuously coevolve with tumor cells to promote tumorigenesis. Here, we identify p38MAPK as a key component of human lung cancer, and specifically stromal interactomes, which provides an early, protumorigenic signal in the tissue microenvironment. We found that lung cancer growth depends on short-distance cues produced by the cancer niche in a p38-dependent manner. We identified fibroblast-specific hyaluronan synthesis at the center of p38-driven tumorigenesis, which regulates early stromal fibroblast activation, the conversion to carcinoma-associated fibroblasts (CAFs), and cancer cell proliferation. Systemic down-regulation of p38MAPK signaling in a knock-in model with substitution of activating Tyr182 to phenylalanine or conditional ablation of p38 in fibroblasts has a significant tumor-suppressive effect on K-ras lung tumorigenesis. Furthermore, both Kras-driven mouse lung tumors and orthotopically grown primary human lung cancers show a significant sensitivity to both a chemical p38 inhibitor and an over-the-counter inhibitor of hyaluronan synthesis. We propose that p38MAPK-hyaluronan-dependent reprogramming of the tumor microenvironment plays a critical role in driving lung tumorigenesis, while blocking this process could have far-reaching therapeutic implications.

The KRAB-zinc-finger protein ZFP708 mediates epigenetic repression at RMER19B retrotransposons.

Global epigenetic reprogramming is vital to purge germ cell-specific epigenetic features to establish the totipotent state of the embryo. This process transpires to be carefully regulated and is not an undirected, radical erasure of parental epigenomes. The TRIM28 complex has been shown to be crucial in embryonic epigenetic reprogramming by regionally opposing DNA demethylation to preserve vital parental information to be inherited from germline to soma. Yet the DNA-binding factors guiding this complex to specific targets are largely unknown. Here, we uncover and characterize a novel, maternally expressed, TRIM28-interacting KRAB zinc-finger protein: ZFP708. It recruits the repressive TRIM28 complex to RMER19B retrotransposons to evoke regional heterochromatin formation. ZFP708 binding to these hitherto unknown TRIM28 targets is DNA methylation and H3K9me3 independent. ZFP708 mutant mice are viable and fertile, yet embryos fail to inherit and maintain DNA methylation at ZFP708 target sites. This can result in activation of RMER19B-adjacent genes, while ectopic expression of ZFP708 results in transcriptional repression. Finally, we describe the evolutionary conservation of ZFP708 in mice and rats, which is linked to the conserved presence of the targeted RMER19B retrotransposons in these species.

Biodegradable Polymeric Multilayer Capsules for Therapy of Lung Cancer.

Formulated forms of cancer therapeutics enhance the efficacy of treatment by more precise targeting, increased bioavailability of drugs, and an aptitude of some delivery systems to overcome multiple drug resistance of tumors. Drug carriers acquire importance for anti-cancer interventions via targeting tumor-associated macrophages with active molecules capable to either eliminate them or change their polarity. Although several packaged drug forms have reached the market, there is still a high demand for novel carrier systems to hurdle limitations of existing drugs on active molecules, toxicity, bioeffect, and stability. Here, we report a facile assembly and delivery methodology for biodegradable polymeric multilayer capsules (PMC) with the purpose of further use in injectable drug formulations for lung cancer therapy via direct erosion of tumors and suppression of the tumor-promoting function of macrophages in the tumor microenvironment. We demonstrate delivery of low-molecular-weight drug molecules to lung cancer cells and macrophages and provide details on in vivo distribution, cellular uptake, and disintegration of the developed PMC. Poly-l-arginine and dextran sulfate alternately adsorb on a ∼500 nm CaCO3 sacrificial template followed by removal of the inorganic core to obtain hollow capsules for consequent loading with drug molecules, gemcitabine or clodronate. The capsules further compacted upon loading down to ∼250 nm in diameter via heat treatment. A comparative study of the capsule internalization rate in vitro and in vivo reveals the benefits of a diminished carrier size. We show that macrophages and epithelial cells of the lungs and liver internalize capsules with efficacy higher than 75%. Using an in vivo mouse model of lung cancer, we also confirm that tumor lungs better retain smaller capsules than the healthy lung tissue. The pronounced cytotoxic effect of the encapsulated gemcitabine on lung cancer cells and the ability of the encapsulated clodronate to block the tumor-promoting function of macrophages prove the efficacy of the developed capsule loading method in vitro. Our study taken as a whole demonstrates the great potential of the developed PMC for in vivo treatment of cancer via transporting active molecules, including those that are water-soluble with low molecular weight, to both cancer cells and macrophages through the bloodstream.