RESUMEN
The biology of metastatic pancreatic ductal adenocarcinoma (PDAC) is distinct from that of the primary tumor due to changes in cell plasticity governed by a distinct transcriptome. Therapeutic strategies that target this distinct biology are needed. We detect an upregulation of the neuronal axon guidance molecule Netrin-1 in PDAC liver metastases that signals through its dependence receptor (DR), uncoordinated-5b (Unc5b), to facilitate metastasis in vitro and in vivo. The mechanism of Netrin-1 induction involves a feedforward loop whereby Netrin-1 on the surface of PDAC-secreted extracellular vesicles prepares the metastatic niche by inducing hepatic stellate cell activation and retinoic acid secretion that in turn upregulates Netrin-1 in disseminated tumor cells via RAR/RXR and Elf3 signaling. While this mechanism promotes PDAC liver metastasis, it also identifies a therapeutic vulnerability, as it can be targeted using anti-Netrin-1 therapy to inhibit metastasis using the Unc5b DR cell death mechanism.
Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Hepáticas , Neoplasias Pancreáticas , Humanos , Netrina-1 , Retinoides , Células Estrelladas Hepáticas/metabolismo , Línea Celular Tumoral , Neoplasias Pancreáticas/patología , Carcinoma Ductal Pancreático/patología , Neoplasias Hepáticas/metabolismo , Receptores de Netrina , Proteínas de Unión al ADN , Factores de Transcripción , Proteínas Proto-Oncogénicas c-etsRESUMEN
A large percentage of transcription factors require zinc to bind DNA. In this review, we discuss what makes p53 unique among zinc-dependent transcription factors. The conformation of p53 is unusually malleable: p53 binds zinc extremely tightly when folded, but is intrinsically unstable in the absence of zinc at 37°C. Whether the wild-type protein folds in the cell is largely determined by the concentration of available zinc. Consequently, zinc dysregulation in the cell as well as a large percentage of tumorigenic p53 mutations can cause p53 to lose zinc, misfold, and forfeit its tumor suppressing activity. We highlight p53's noteworthy biophysical properties that give rise to its malleability and how proper zinc binding can be restored by synthetic metallochaperones to reactivate mutant p53. The activity and mechanism of metallochaperones are compared to those of other mutant p53-targeted drugs with an emphasis on those that have reached the clinical trial stage.
