The degree of metastatic disease varies widely amongst cancer patients and impacts clinical outcomes. However, the biological and functional differences that drive the extent of metastasis are poorly understood. We analyzed primary tumors and paired metastases using a multifluorescent lineage-labeled mouse model of pancreatic ductal adenocarcinoma (PDAC) -a tumor type where most patients present with metastases. Genomic and transcriptomic analysis revealed an association between metastatic burden and gene amplification or transcriptional upregulation of MYC and its downstream targets. Functional experiments showed that MYC promotes metastasis by recruiting tumor associated macrophages (TAMs), leading to greater bloodstream intravasation. Consistent with these findings, metastatic progression in human PDAC was associated with activation of MYC signaling pathways and enrichment for MYC amplifications specifically in metastatic patients. Collectively, these results implicate MYC activity as a major determinant of metastatic burden in advanced PDAC. Statement of SignificanceHere, we investigate metastatic variation seen clinically in PDAC patients and murine PDAC tumors and identify MYC as a major driver of this heterogeneity.Research.

Context: Osteogenesis imperfecta (OI) is a genetic disorder of the extracellular matrix of bone characterized by low bone mass manifesting as frequent fractures, delayed motor development, pain, and impaired quality of life. The intravenous bisphosphonate, pamidronate is an established treatment for OI. Recently, zoledronic acid (ZA) has been used for the management of OI. Aim: To assess the efficacy and safety of ZA in children below five years of age with OI. Settings and Design: A hospital-based prospective observational study. Methods and Material: Patients with OI aged less than five years attending our centre were treated with intravenous ZA at a dose of 0.05 mg/kg every six months. Subjects were closely monitored for clinical and biochemical variables, adverse events, and new-onset fractures. The response to therapy was assessed by monitoring clinical variables including the degree of bony pains, number of fractures, height/length standard deviation score (SDS), and motor developmental milestones. All patients were analysed at baseline and at the end of two years for biochemical parameters and clinical severity score (CSS) as proposed by Aglan et al . with modifications. Results: After two years of treatment, OI patients showed a significant decline in the rate of fractures ( p < 0.001), improvement in ambulation ( p = 0.005), alleviation of pain ( p < 0.001), and improvement in height SDS ( p < 0.05). There was a significant improvement in CSS after two years of therapy. Apart from mild flu-like symptoms and mild asymptomatic hypocalcaemia immediately post-infusion, no other adverse effect was noted. Conclusion: ZA therapy in infants and children below five years of age with OI was effective and safe and a more convenient alternative to pamidronate.

Supplementary Figure from <i>MYC</i> Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma

Supplementary Data from <i>MYC</i> Levels Regulate Metastatic Heterogeneity in Pancreatic Adenocarcinoma