Ectosomal PKM2 Promotes HCC by Inducing Macrophage Differentiation and Remodeling the Tumor Microenvironment.

Tumor-derived extracellular vesicles are important mediators of cell-to-cell communication during tumorigenesis. Here, we demonstrated that hepatocellular carcinoma (HCC)-derived ectosomes remodel the tumor microenvironment to facilitate HCC progression in an ectosomal PKM2-dependent manner. HCC-derived ectosomal PKM2 induced not only metabolic reprogramming in monocytes but also STAT3 phosphorylation in the nucleus to upregulate differentiation-associated transcription factors, leading to monocyte-to-macrophage differentiation and tumor microenvironment remodeling. In HCC cells, sumoylation of PKM2 induced its plasma membrane targeting and subsequent ectosomal excretion via interactions with ARRDC1. The PKM2-ARRDC1 association in HCC was reinforced by macrophage-secreted cytokines/chemokines in a CCL1-CCR8 axis-dependent manner, further facilitating PKM2 excretion from HCC cells to form a feedforward regulatory loop for tumorigenesis. In the clinic, ectosomal PKM2 was clearly detected in the plasma of HCC patients. This study highlights a mechanism by which ectosomal PKM2 remodels the tumor microenvironment and reveals ectosomal PKM2 as a potential diagnostic marker for HCC.

Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation.

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPß, a rate-limiting enzyme in FAO. Although TPß activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPß association results in Nur77 self-sacrifice to protect TPß from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPß interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

Chiroptical switching in the azobenzene-based self-locked [1]rotaxane by solvent and photoirradiation.

Because of its dynamic reversible nature and simple regulation properties, rotaxane systems provided a good route for the construction of responsive supramolecular chiral materials. Here, we covalently encapsulate the photo-responsive guest molecule azobenzene (Azo) in a chiral macrocycle ß-cyclodextrin (ß-CD) to prepare self-locked chiral [1]rotaxane [Azo-CD]. On this basis, the self-adaptive conformation of [Azo-CD] was manipulated by solvent and photoirradiation; meanwhile, dual orthogonal regulation of the [1]rotaxane chiroptical switching could also be realized.

Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression.

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.

Macroscopic homochiral helicoids self-assembled via screw dislocations.

Chirality is a fundamental property in nature and is widely observed at hierarchical scales from subatomic, molecular, supramolecular to macroscopic and even galaxy. However, the transmission of chirality across different length scales and the expression of homochiral nano/microstructures remain challenging. Herein, we report the formation of macroscopic homochiral helicoids with ten micrometers from enantiomeric pyromellitic diimide-based molecular triangle (PMDI-Δ) and achiral pyrene via a screw dislocation-driven co-self-assembly. Chiral transfer and expression from molecular and supramolecular levels, to the macroscopic helicoids, is continuous and follows the molecular chirality of PMDI-Δ. Furthermore, the screw dislocation and chirality transfer lead to a unidirectional curvature of the helicoids, which exhibit excellent circularly polarized luminescence with large |glum| values up to 0.05. Our results demonstrate the formation of a homochiral macroscopic organic helicoid and function emergence from small molecules via screw dislocations, which deepens our understanding of chiral transfer and expression across different length scales.