Project description:Tumor metastasis remains one of the major causes of cancer-related deaths in patients with solid tumors. Mechanisms by which metabolic alterations regarding pro-survival lipid signaling activation in inducing cancer cell migration and metastasis are largely unknown. Here, we demonstrate that S1P metabolism activates endogenous complement signaling for inducing tumor metastasis via inducing inflammasome-mediated pro-inflammation. Our studies using molecular, pharmacologic and genetic tools showed that activation of sphingosine 1-phosphate (S1P) and S1P receptor 1 (S1P/S1PR1) induces tumor metastasis via enhanced intracellular complement signaling by the regulation of the C3-PPIL1 complex and subsequent inflammasome activation in cancer cells and in vivo xenograft-derived tumors.
Project description:Preoperative prediction of lymph node (LN) metastasis is accepted as an important independent risk factor for treatment decision-making for esophageal squamous cell carcinoma (ESCC) patients. This study aimed to develop a non-invasive biomarker to identify LN metastasis preoperatively in ESCC patients with serum exosomal RNA-seq.
Project description:Development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic, but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP+ exosomes. Moreover, uptake of CEMIP+ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating Ptgs2, Tnf, and Ccl/Cxcl 86 cytokines, known to promote brain vascular remodeling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting of exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.
Project description:Recent evidence suggests that sphingosine-1-phosphate receptor 1 (S1PR1) modulates the intracellular complement system or the complosome to induce NLRP3 inflammasome formation and the release of IL-1β through caspase-1, thereby promoting tumor metastasis. Here, we examined the transcriptomic effects of S1PR1 and complement C3 conditional knockouts on lung metastasis in MMTV-PyMT Mice, a widely used model for studying mammary tumor progression and metastasis.