Summary We leveraged IDH wild-type glioblastomas, derivative neurospheres, and single cell gene expression profiles to define three tumor-intrinsic transcriptional subtypes designated as proneural, mesenchymal, and classical. Transcriptomic subtype multiplicity correlated with increased intratumoral heterogeneity and presence of tumor microenvironment. In silico cell sorting identified macrophages/microglia, CD4+ T lymphocytes, and neutrophils in the glioma microenvironment. NF1 deficiency resulted in increased tumor-associated macrophages/microglia infiltration. Longitudinal transcriptome analysis showed that expression subtype is retained in 55% of cases. Gene signature-based tumor microenvironment inference revealed a decrease in invading monocytes and a subtype-dependent increase in macrophages/microglia cells upon disease recurrence. Hypermutation at diagnosis or at recurrence associated with CD8+ T cell enrichment. Frequency of M2 macrophages detection associated with short-term relapse after radiation therapy.

Cancer cells survive cellular crisis through telomere maintenance mechanisms. We report telomere lengths in 18,430 samples, including tumors and non-neoplastic samples, across 31 cancer types. Tumor telomeres were shorter compared to normal tissues, and longer in sarcomas and gliomas compared to other cancers. Amongst 6,835 cancers, 73% expressed telomerase reverse transcriptase (TERT), which was associated with TERT point mutations, rearrangements, DNA amplifications, and transcript fusions, and predicted telomerase activity. TERT promoter methylation provided an additional deregulatory TERT expression mechanism. Five percent of cases, mostly with undetectable TERT, harbored ATRX or DAXX alterations, demonstrated elongated telomeres and increased telomeric repeat containing RNA (TERRA). The remaining 22% of tumors neither expressed TERT, nor harbored alterations in ATRX/DAXX. In this group, telomere length positively correlated with TP53 and RB1 mutations. Our analysis integrates TERT abnormalities, telomerase activity and genomic alterations with telomere length in cancer.

the effects they observed could be influenced by inhibition of other types of Trk receptors or signaling molecules downstream of Trk. We have recently started a series of experiments aiming to verify whether specific TrkB inhibition reduces glioma cell proliferation using ANA-12, a small-molecule selective TrkB antagonist. Our first results showed that ANA-12 effectively and dose-dependently reduces the viability of a human glioblastoma cell line with almost complete disappearance of cultured cells 72 hours after treatment (Fig. 1). Therefore, selective TrkB inhibition might prove to be an effective experimental therapeutic strategy, possibly with fewer off-target toxicities compared with multitarget drugs in patients with astrocytomas harboring oncogenic TrkB.