Non-small-cell lung cancer (NSCLC) is a common malignancy with a poor prognosis. Despite progress targeting oncogenic drivers, there are no therapies targeting tumor-suppressor loss. Smad4 is an established tumor suppressor in pancreatic and colon cancer; however, the consequences of Smad4 loss in lung cancer are largely unknown. We evaluated Smad4 expression in human NSCLC samples and examined Smad4 alterations in large NSCLC data sets and found that reduced Smad4 expression is common in human NSCLC and occurs through a variety of mechanisms, including mutation, homozygous deletion and heterozygous loss. We modeled Smad4 loss in lung cancer by deleting Smad4 in airway epithelial cells and found that Smad4 deletion both initiates and promotes lung tumor development. Interestingly, both Smad4(-/-) mouse tumors and human NSCLC samples with reduced Smad4 expression demonstrated increased DNA damage, whereas Smad4 knockdown in lung cancer cells reduced DNA repair and increased apoptosis after DNA damage. In addition, Smad4-deficient NSCLC cells demonstrated increased sensitivity to both chemotherapeutics that inhibit DNA topoisomerase and drugs that block double-strand DNA break repair by non-homologous end joining. In sum, these studies establish Smad4 as a lung tumor suppressor and suggest that the defective DNA repair phenotype of Smad4-deficient tumors can be exploited by specific therapeutic strategies.

Natural gas constitutes a growing share of global primary energy due to its abundant supply and lower CO₂ emission intensity compared to coal. For many natural gas reserves, CO₂ contamination must be removed at the wellhead to meet pipeline specifications. Here, we demonstrate the potential of the diamine-appended metal-organic framework ee-2-Mg₂(dobpdc) (ee-2 = N,N-diethylethylenediamine; dobpdc^4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) as a next-generation CO₂ capture material for high-pressure natural gas purification. Owing to a cooperative adsorption mechanism involving formation of ammonium carbamate chains, ee-2-Mg₂(dobpdc) can be readily regenerated with a minimal change in temperature or pressure and maintains its CO₂ capacity in the presence of water. Moreover, breakthrough experiments reveal that water enhances the CO₂ capture performance of ee-2-Mg₂(dobpdc) by eliminating "slip" of CO₂ before full breakthrough. Spectroscopic characterization and multicomponent adsorption isobars suggest that the enhanced performance under humid conditions arises from preferential stabilization of the CO₂-inserted phase in the presence of water. The favorable performance of ee-2-Mg₂(dobpdc) is further demonstrated through comparison with a benchmark material for this separation, zeolite 13X, as well as extended pressure cycling. Overall, these results support continued development of ee-2-Mg₂(dobpdc) as a promising adsorbent for natural gas purification.