An NFATc1/SMAD3/cJUN Complex Restricted to SMAD4-Deficient Pancreatic Cancer Guides Rational Therapies.

BACKGROUND & AIMS: The highly heterogeneous cellular and molecular makeup of pancreatic ductal adenocarcinoma (PDAC) not only fosters exceptionally aggressive tumor biology, but contradicts the current concept of one-size-fits-all therapeutic strategies to combat PDAC. Therefore, we aimed to exploit the tumor biological implication and therapeutic vulnerabilities of a clinically relevant molecular PDAC subgroup characterized by SMAD4 deficiency and high expression of the nuclear factor of activated T cells (SMAD4-/-/NFATc1High). METHODS: Transcriptomic and clinical data were analyzed to determine the prognostic relevance of SMAD4-/-/NFATc1High cancers. In vitro and in vivo oncogenic transcription factor complex formation was studied by immunoprecipitation, proximity ligation assays, and validated cross model and species. The impact of SMAD4 status on therapeutically targeting canonical KRAS signaling was mechanistically deciphered and corroborated by genome-wide gene expression analysis and genetic perturbation experiments, respectively. Validation of a novel tailored therapeutic option was conducted in patient-derived organoids and cells and transgenic as well as orthotopic PDAC models. RESULTS: Our findings determined the tumor biology of an aggressive and chemotherapy-resistant SMAD4-/-/NFATc1High subgroup. Mechanistically, we identify SMAD4 deficiency as a molecular prerequisite for the formation of an oncogenic NFATc1/SMAD3/cJUN transcription factor complex, which drives the expression of RRM1/2. RRM1/2 replenishes nucleoside pools that directly compete with metabolized gemcitabine for DNA strand incorporation. Disassembly of the NFATc1/SMAD3/cJUN complex by mitogen-activated protein kinase signaling inhibition normalizes RRM1/2 expression and synergizes with gemcitabine treatment in vivo to reduce the proliferative index. CONCLUSIONS: Our results suggest that PDAC characterized by SMAD4 deficiency and oncogenic NFATc1/SMAD3/cJUN complex formation exposes sensitivity to a mitogen-activated protein kinase signaling inhibition and gemcitabine combination therapy.

Aggregation kinetics of diesel soot nanoparticles in artificial and human sweat solutions: Effects of sweat constituents, pH, and temperature.

Soot nanoparticles (SNPs) are airborne contaminants that could potentially penetrate skin, but their aggregation after contact with sweat may lower their health risks. This study investigated SNP aggregation kinetics in 4 artificial sweat standards and 21 human sweat samples. Effects of sweat inorganic (NaCl, Na2HPO4, and NaH2PO4) and organic (L-histidine, lactic acid, and urea) constituents, pH, temperature, and concentrations were examined. Results showed that SNP aggregation rates in 4 standards followed American Association of Textile Chemists and Colorists (AATCC) > British Standard (EN) > International Standard Organization (ISO) pH 5.5 > ISO pH 8.0, and could be described by the Derjaguin-Landau-Verwey-Overbeek (DLVO) theory. The aggregation rates increased with concentrations of SNPs, inorganic salts, L-histidine, and lactic acid, decreased with increasing pH and concentration of urea, and were weakly influenced by temperature. Systematic characterizations revealed SNP adsorption for organic sweat constituents. SNPs aggregated rapidly to ∼1000 nm in AATCC, but remained stable in ISO pH 8.0 and > 14/21 human sweat fluids over 20 min. The SNP aggregation rates correlated negatively with pH (r = -0.531*) and |ζ potential| (r = -0.464*) of human sweat samples. Sweat evaporation could promote aggregation of SNPs, hence lowering their potential harm via dermal exposure.