LGI4 blocking peptide

Intratumoral heterogeneity (ITH) represents an obstacle for cancer diagnosis and treatment, but little is known about its functional role in cancer progression. The A Desintegrin And Metalloproteinase 23 (ADAM23) gene is epigenetically silenced in different types of tumors, and silencing is often associated with advanced disease and metastasis. Here, we show that invasive breast tumors exhibit significant ADAM23-ITH and that this heterogeneity is critical for tumor growth and metastasis. We demonstrate that while loss of ADAM23 expression enhances invasion, it causes a severe proliferative deficiency and is not itself sufficient to trigger metastasis. Rather, we observed that, in ADAM23-heterotypic environments, ADAM23-negative cells promote tumor growth and metastasis by enhancing the proliferation and invasion of adjacent A23-positive cells through the production of LGI4 (Leucine-rich Glioma Inactivated 4) and nitric oxide (NO). Ablation of LGI4 and NO in A23-negative cells significantly attenuates A23-positive cell proliferation and invasion. Our work denotes a driving role of ADAM23-ITH during disease progression, shifting the malignant phenotype from the cellular to the tissue level. Our findings also provide insights for therapeutic intervention, enforcing the need to ascertain ITH to improve cancer diagnosis and therapy.

The mechanisms that regulate peripheral nervous system (PNS) gliogenesis are incompletely understood. For example, gut neural crest stem cells (NCSCs) do not respond to known gliogenic factors, suggesting that yet-unidentified factors regulate gut gliogenesis. To identify new mechanisms, we performed gene expression profiling to identify factors secreted by gut NCSCs during the gliogenic phase of development. These cells highly expressed leucine-rich glioma inactivated 4 (Lgi4) despite the fact that Lgi4 has never been implicated in stem cell function or enteric nervous system development. Lgi4 is known to regulate peripheral nerve myelination (having been identified as the mutated gene in spontaneously arising claw paw mutant mice), but Lgi4 is not known to play any role in PNS development outside of peripheral nerves. To systematically analyze Lgi4 function, we generated gene-targeted mice. Lgi4-deficient mice exhibited a more severe phenotype than claw paw mice and had gliogenic defects in sensory, sympathetic, and enteric ganglia. We found that Lgi4 is required for the proliferation and differentiation of glial-restricted progenitors throughout the PNS. Analysis of compound-mutant mice revealed that the mechanism by which Lgi4 promotes enteric gliogenesis involves binding the ADAM22 receptor. Our results identify a new mechanism regulating enteric gliogenesis as well as novel functions for Lgi4 regulating the proliferation and maturation of glial lineage cells throughout the PNS.