Summary Breast cancer bone micrometastases can remain asymptomatic for years before progressing into overt lesions. The biology of this process, including the microenvironment niche and supporting pathways, is unclear. We find that bone micrometastases predominantly reside in a niche that exhibits features of osteogenesis. Niche interactions are mediated by heterotypic adherens junctions (hAJs) involving cancer-derived E-cadherin and osteogenic N-cadherin, the disruption of which abolishes niche-conferred advantages. We further elucidate that hAJ activates the mTOR pathway in cancer cells, which drives the progression from single cells to micrometastases. Human datasets analyses support the roles of AJ and the mTOR pathway in bone colonization. Our study illuminates the initiation of bone colonization, and provides potential therapeutic targets to block progression toward osteolytic metastases. Significance In advanced stages, breast cancer bone metastases are driven by paracrine crosstalk among cancer cells, osteoblasts, and osteoclasts, which constitute a vicious osteolytic cycle. Current therapies targeting this process limit tumor progression, but do not improve patient survival. On the other hand, bone micrometastases may remain indolent for years before activating the vicious cycle, providing a therapeutic opportunity to prevent macrometastases. Here, we show that bone colonization is initiated in a microenvironment niche exhibiting active osteogenesis. Cancer and osteogenic cells form heterotypic adherens junctions, which enhance mTOR activity and drive early-stage bone colonization prior to osteolysis. These results reveal a strong connection between osteogenesis and micrometastasis and suggest potential therapeutic targets to prevent bone macrometastases.

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SUMMARY The fate of disseminated tumor cells is largely determined by microenvironment (ME) niche. The osteogenic niche promotes cancer cell proliferation and bone metastasis progression. We investigated the underlying mechanisms using pre-clinical models and analyses of clinical data. We discovered that the osteogenic niche serves as a calcium (Ca) reservoir for cancer cells through gap junction (GJs). Cancer cells cannot efficiently absorb Ca from ME, but depend on osteogenic cells to increase intracellular Ca concentration. The Ca signaling, together with previously identified mTOR signaling, promotes bone metastasis progression. Interestingly, effective inhibition of these pathways can be achieved by danusertib, or combination of everolimus and arsenic trioxide, which provide possibilities of eliminating bone micrometastases (BMM) using clinically established drugs.

The development of gastritis is associated with an increased risk of gastric cancer. Current invasive gastritis diagnostic methods are not suitable for monitoring progress. In this work based on 78 gastritis patients and 50 healthy individuals, we observed that the variation of tongue-coating microbiota was associated with the occurrence and development of gastritis. Twenty-one microbial species were identified for differentiating tongue-coating microbiomes of gastritis and healthy individuals. Pathways such as microbial metabolism in diverse environments, biosynthesis of antibiotics and bacterial chemotaxis were up-regulated in gastritis patients. The abundance of Campylobacter concisus was found associated with the gastric precancerous cascade. Furthermore, Campylobacter concisus could be detected in tongue coating and gastric fluid in a validation cohort containing 38 gastritis patients. These observations provided biological evidence of tongue diagnosis in traditional Chinese medicine, and indicated that tongue-coating microbiome could be a potential non-invasive biomarker, which might be suitable for long-term monitoring of gastritis. Electronic supplementary material The online version of this article (10.1007/s13238-018-0596-6) contains supplementary material, which is available to authorized users.

Background/Aims: Lipid accumulation, inflammatory responses and oxidative stress have been implicated in the pathology of alcoholic liver disease (ALD). Targeting inhibition of these features may provide a promising therapeutic strategy for ALD. Baicalin, a flavonoid isolated from Scutellaria baicalensis Georgi, has been shown to exert a hepatoprotective effect. However, its effects on ALD remain obscure. This study was aimed to investigate the effects of baicalin on alcohol-induced liver injury and its related mechanisms. Methods: For in vivo experiments, rats were supplied intragastrical administration of alcohol continuously for 4 or 8 weeks, and then received baicalin treatment in the latter 4 weeks in the presence / absence of alcohol intake. Liver histology and function, inflammatory cytokines, oxidative mediators, and the components of the Sonic hedgehog pathway were evaluated. For in vitro experiments, alcohol-stimulated human normal liver cells LO2 were used. Results: Baicalin treatment significantly alleviated alcoholic liver injury, improved liver function impaired by alcohol, and inhibited hepatocytes apoptosis. In addition, baicalin decreased the expression levels of proinflammatory cytokines TNF-α, IL-1β, IL-6) and malonyldialdehyde (MDA), and increased the activities of antioxidant enzymes SOD and GSH-Px. Furthermore, baicalin modulated the activation of Sonic hedgehog (Shh) pathway. Administration of baicalin upregulated the expression of sonic hedgehog (Shh), patched (Ptc), Smoothened (Smo), and Glioblastoma-1(Gli-1). Blockade of the Shh pathway in cyclopamine abolished the effects of baicalin in vitro. Conclusion:Both in vivo and in vitro experimental results indicate that baicalin exerts hepatoprotective roles in alcohol-induced liver injury through inhibiting oxidative stress, inflammatory response, and the regulation of the Shh pathway.