The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.

No abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

The long noncoding RNA HANR has been shown to be involved in the progression of hepatocellular carcinoma (HCC). However, the underlying mechanism of HCC‐associated long noncoding RNA (HANR)–regulated HCC metastasis and lymphangiogenesis has not been elucidated. RT‐qPCR and Western blot methods were utilized to detect the gene expressions. Interaction of HANR with miR‐296 was predicted by a bioinformatic program and validated by a dual‐luciferase reporter assay. For the functional experiment, a transwell invasion assay was utilized to examine the invasion abilities of HepG2 and Huh‐7 cells. The lymphatic vessel formation assay was used to show the HCC‐associated lymphatic vessel formation ability of human dermal lymphatic endothelial cells (HDLEC). HANR was shown to directly bind to miR‐296, and miR‐296 downregulated HANR expression in HepG2 cells. Then, we observed that miR‐296 inhibitor transfection in shHANR HCC cells could promote lymphatic vessel formation and invasion of HDLEC cells compared with shHANR HCC cells. EAG1 or VEGFA overexpression in HDLEC cells rescued lymphatic vessel formation and invasion in HDLEC cells coincubated with the medium of HepG2 cells expressing shHANR or miR‐296 mimic. Ultimately, HANR knockdown and miR‐296 mimic led to a significant decrease in the EAG1 and VEGFA expression levels in HepG2 cells. Here, we reveal a novel molecular mechanism in which the HANR/miR‐296/EAG1/VEGF axis is responsible for the lymphangiogenesis of HCC cells. Our findings provide more insights into developing therapeutical or diagnostic methods by targeting HANR.