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Chromobox 4 (CBX4) is a core component of polycomb-repressive complex 1 with important roles in cancer biology and tissue homeostasis. Aberrant expression of CBX4 has been implicated in several human malignancies. However, its role and underlying mechanisms in the tumorigenesis of lung adenocarcinoma (LUAD) have not been defined in vivo. Here, we found that expression of CBX4 was frequently up-regulated in human LUAD samples and correlated with poor patient survival. Importantly, genetic ablation of CBX4 greatly dampened lung tumor formation and improved survival in the KrasG12D/P53L/L (KP) autochthonous mouse model of LUAD. In addition, CBX4 depletion significantly inhibited proliferation and anchorage-independent growth of KP mouse embryonic fibroblasts. Moreover, ectopic CBX4 expression clearly promoted proliferation and anchorage-independent growth in both human and mouse LUAD cells, whereas silencing of CBX4 exerted opposite effects. Mechanistically, CBX4 promoted growth of LUAD cells through activation of the Wnt/β-catenin pathway. Furthermore, expression levels of CBX4 were positively correlated with β-catenin in human LUAD samples. In conclusion, our data suggest that CBX4 plays an oncogenic role via the Wnt/β-catenin pathway and could serve as a potential therapeutic target in LUAD. [ABSTRACT FROM AUTHOR]

Abstract: Phosphate signaling allows unicellular organisms and higher plants to respond and adapt to phosphate starvation efficiently. Four major adaptive processes include root system development, phosphate mobilization, phosphate transport and metabolism. Phosphite, a non-metabolic analog of phosphate, specifically attenuates several phosphate starvation responses, supporting the hypothesis that plants have a phosphate-sensing machinery comparable to that of unicellular organisms. Biochemical and molecular approaches have characterized acid phosphatases, RNases, high-affinity phosphate transporters, and metabolic enzymes as executive proteins in phosphate signaling. Mutant screening in Arabidopsis thaliana have identified several phosphate signaling regulators, such as PHR1, PHO2 and PHF1. PHO2, microRNA399 family and AtIPS1/At4 family represent a novel circuit in phosphate signaling. Microarray studies in A. thaliana and Oryza sativa suggest regulation at the mRNA level can be an important mechanism of phosphate signaling, and that the leaf and the root may occupy two separate phosphate signaling programs. In addition, phosphate signaling is suggested to interact with hormone and sugar signaling pathways. Finally, an integrated model summarizing the contemporary understanding of phosphate signaling, mainly in A. thaliana and O. sativa, is presented. [Copyright &y& Elsevier]

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRAS G12C -mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRAS G12C and STK11 / LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1 -deficient KRAS G12C and Kras G12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer. [Display omitted] • High SCC signature at baseline correlates with poor adagrasib response in KL NSCLC • AST drives resistance to KRAS inhibition in GEMMs and organoid models • ELF5-ΔNp63 axis governs AST process and drug response • AST plasticity signature and KRT6A enrichment predict poor adagrasib responses Tong et al. show that high squamous cell carcinoma (SCC) signature at baseline correlates with poor adagrasib response in patients with KRAS / LKB1 -mutant NSCLC. Integrative GEMM and organoid studies demonstrate that adeno-to-squamous transition (AST) drives KRAS inhibitor resistance involving ELF5-mediated epigenetic regulation of ΔNp63. AST plasticity signature and KRT6A predict poor adagrasib response. [ABSTRACT FROM AUTHOR]