The brain microenvironment mediates resistance in luminal breast cancer to PI3K inhibition through HER3 activation

Although targeted therapies are often effective systemically, they fail to adequately control brain metastases. In preclinical models of breast cancer that faithfully recapitulate the disparate clinical responses in these microenvironments, we observed that brain metastases evade phosphatidylinositide 3-kinase (PI3K) inhibition despite drug accumulation in the brain lesions. In comparison to extracranial disease, we observed increased HER3 expression and phosphorylation in brain lesions. HER3 blockade overcame the resistance of HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases to PI3K inhibitors, resulting in marked tumor growth delay and improvement in mouse survival. These data provide a mechanistic basis for therapeutic resistance in the brain microenvironment and identify translatable treatment strategies for HER2-amplified and/or PIK3CA-mutant breast cancer brain metastases

Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models

Cytotoxic chemotherapy is an effective treatment for invasive breast cancer. However, experimental studies in mice also suggest that chemotherapy has pro-metastatic effects. Primary tumours release extracellular vesicles (EVs), including exosomes, that can facilitate the seeding and growth of metastatic cancer cells in distant organs, but the effects of chemotherapy on tumour-derived EVs remain unclear. Here we show that two classes of cytotoxic drugs broadly employed in pre-operative (neoadjuvant) breast cancer therapy, taxanes and anthracyclines, elicit tumour-derived EVs with enhanced pro-metastatic capacity. Chemotherapy-elicited EVs are enriched in annexin A6 (ANXA6), a Ca2+-dependent protein that promotes NF-κB-dependent endothelial cell activation, Ccl2 induction and Ly6C+CCR2+ monocyte expansion in the pulmonary pre-metastatic niche to facilitate the establishment of lung metastasis. Genetic inactivation of Anxa6 in cancer cells or Ccr2 in host cells blunts the prometastatic effects of chemotherapy-elicited EVs. ANXA6 is detected, and potentially enriched, in the circulating EVs of breast cancer patients undergoing neoadjuvant chemotherapy

Myelin-associated inhibitors regulate cofilin phosphorylation and neuronal inhibition through LIM kinase and slingshot phosphatase

Myelin-associated inhibitors (MAIs) signal through a tripartate receptor complex on neurons to limit axon regeneration in the CNS.Inhibitory influences ultimately converge on the cytoskeleton to mediate growth cone collapse and neurite outgrowth inhibition. RhoGTPase and its downstream effector Rho kinase are key signaling intermediates in responseto MAIs; however,the links between Rho andthe actin cytoskeleton have not been fully defined. We found that Nogo-66, a potent inhibitory fragment of Nogo-A, signals through LIM(LIM is an acronym of the three gene products Lin-11, Isl-1, and Mec-3) kinase and Slingshot (SSH) phosphatase to regulate the phosphorylationprofile of the actin depolymerization factor cofilin. Blockade of LIMK1 activation and subsequent cofilin phosphorylationcircumvents myelin-dependent inhibition in chick dorsal root ganglion neurons, suggesting that phosphorylation and inactivation ofcofilin is critical for neuronal inhibitory responses. Subsequent activation of SSH1 phosphatase mediates cofilin dephosphorylation andreactivation. Overexpression of SSH1 does not mimic the neurite outgrowth inhibitory effects of myelin, suggesting an alternative role inMAI inhibition. We speculate that SSH-mediated persistent cofilin activation may be responsible for maintaining an inhibited neuronalphenotype in response to myelin inhibitors

LGI1 is a Nogo receptor 1 ligand that antagonizes myelin-based growth inhibition

Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditory features. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion and growth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth cone collapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitory substrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specific Nogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 and ADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22L\u2019\ue9pilepsie autosomique dominante du lobe temporal, pr\ue9c\ue9d\ue9e d\u2019une aura auditive, peut \ueatre attribuable \ue0 des mutations dans le g\ue8ne LGI1 (leucine-rich glioma inactivated 1). La LGI1 est une prot\ue9ine s\ue9cr\ue9t\ue9e qui pr\ue9sente une homologie avec des membres de la famille SLIT, des ligands qui guident la r\ue9pulsion axonale et le collapsus des c\uf4nes de croissance. Nous avons donc consid\ue9r\ue9 la possibilit\ue9 que LGI1 puisse r\ue9guler le processus d\u2019\ue9longation axonale ou le collapsus des c\uf4nes de croissance. Nous avons constat\ue9 que LGI1 n\u2019affecte pas directement la croissance, mais stimule plut\uf4t la croissance neuronale sur des substrats inhibiteurs associ\ue9s \ue0 la my\ue9line et est l\u2019antagoniste du collapsus des c\uf4nes de croissance induit par la my\ue9line. Nous montrons que LGI1 m\ue9die cet effet en agissant comme un ligand sp\ue9cifique au r\ue9cepteur Nogo 1 (NgR1) qui s\u2019oppose \ue0 l\u2019action des signaux inhibiteurs associ\ue9s \ue0 la my\ue9line. Enfin, nous d\ue9montrons que le NgR1 et ADAM22 se lient physiquement pour former un complexe r\ue9cepteur dans lequel le NgR1 facilite la liaison de LGI1 \ue0 ADAM22.Peer reviewed: YesNRC publication: Ye

LGI1 is a nogo receptor 1 ligand that antagonizes myelin-based growth inhibition

Mutations in leucine-rich glioma inactivated (LGI1) are a genetic cause of autosomal dominant temporal lobe epilepsy with auditoryfeatures. LGI1 is a secreted protein that shares homology with members of the SLIT family, ligands that direct axonal repulsion andgrowth cone collapse, and we therefore considered the possibility that LGI1 may regulate neuronal process extension or growth conecollapse. Here we report that LGI1 does not affect growth directly but instead enhances neuronal growth on myelin-based inhibitorysubstrates and antagonizes myelin-induced growth cone collapse. We show that LGI1 mediates this effect by functioning as a specificNogo receptor 1 (NgR1) ligand that antagonizes the action of myelin-based inhibitory cues. Finally, we demonstrate that NgR1 andADAM22 physically associate to form a receptor complex in which NgR1 facilitates LGI1 binding to ADAM22