Search bioRxiv⌕ Search

Biology subjects

Reese, T.

Publications and source records attributed to Reese, T..

2 recordsLinked to original sources

Programming the Internal Architecture of Synthetic Compartments by Coassembling Filamentous and Liquid DNA Phases

Living cells rely on filaments and condensates as key organizers of their interior. Developing these structural primitives together inside synthetic compartments using programmable components is a step toward building functional synthetic cells, composite biomaterials, and synthetic tissues. Here, we demonstrate that DNA nanotubes and DNA condensates can be co-assembled within cell-sized compartments, including water-in-oil droplets and giant unilamellar vesicles (GUVs). The two nanostructures form as expected, producing a single condensate surrounded by nanotubes in diverse morphologies that depend on DNA and salt concentration, as well as compartment size. By incorporating photoactivatable DNA linkers, we can control the order of assembly and trigger reconfiguration of nanotube networks into ring-shaped bundles enclosing a condensate, architectures reminiscent of a cellular nucleus within a cytoskeletal ring. An isothermal assembly protocol based on monovalent salts further extends this approach to GUVs. Together, these results establish DNA filaments and condensates as programmable, composable organizers of synthetic cell interiors.

synthetic biology↗

AXL-TBK1 driven nuclear AKT3 promotes metastasis

Epithelial-to-mesenchymal transition (EMT) contributes to tumor cell survival, immune evasion, migration, invasion, and therapy resistance. Across human cancer, tumors that are high grade, poorly differentiated, and have undergone EMT carry a worse prognosis with a higher likelihood of metastasis. AXL, a receptor tyrosine kinase, drives EMT and is implicated in tumor progression, metastasis, and therapy resistance in multiple cancer types including pancreatic cancer and breast cancer. TANK-binding kinase 1 (TBK1) is central to AXL-driven EMT yet, the mechanism of how TBK1 induces EMT remains unclear. Here, we report that AXL activation stimulates TBK1 binding and phosphorylation of AKT3. TBK1 activation of AKT3 drives binding and phosphorylation of slug/snail resulting in protection from proteasomal degradation and translocation of the complex into the nucleus. We show that nuclear translocation of AKT3 is required for AXL-driven EMT and metastasis. Congruently, nuclear AKT3 expression correlates with worse outcome in aggressive breast cancer. To advance AKT3 as a therapeutic target, an AKT3-isoform selective allosteric small molecule inhibitor, BGB214, was developed. BGB214 inhibits AKT3 nuclear translocation, EMT-TF stability, AKT3-mediated invasion of breast cancer cells and reduces tumor initiation in vivo. Our results suggest that AKT3 nuclear activity is an important feature of AXL-driven epithelial plasticity and that selective AKT3 inhibition represents a novel therapeutic avenue for treating aggressive cancer. SignificanceNuclear AKT3 activity is an important feature of AXL-TBK1 driven EMT and metastasis, thus selective AKT3 targeting represents a novel approach to treat aggressive cancer.

cancer biology↗