BackgroundThe concept of tumour heterogeneity is not novel but is fast becoming a paradigm by which to explain part of the highly recalcitrant nature of aggressive malignant tumours. Glioblastoma is a prime example of such difficult‐to‐treat, invasive, and incurable malignancies. With the advent of the post‐genomic age and increased access to next‐generation sequencing technologies, numerous publications have described the presence and extent of intratumoural and intertumoural heterogeneity present in glioblastoma. Moreover, there have been numerous reports more directly correlating the heterogeneity of glioblastoma to its refractory, reoccurring, and inevitably terminal nature. It is therefore prudent to consider the different forms of heterogeneity seen in glioblastoma and how to harness this understanding to better strategize novel therapeutic approaches. One of the most central questions of tumour heterogeneity is how these numerous different cell types (both tumour and non‐tumour) in the tumour mass communicate.Recent findingsThis chapter provides a brief review on the variable heterogeneity of glioblastoma, with a focus on cellular heterogeneity and on modalities of communication that can induce further molecular diversity within the complex and ever‐evolving tumour microenvironment. We provide particular emphasis on the emerging role of actin‐based cellular conduits called tunnelling nanotubes (TNTs) and tumour microtubes (TMs) and outline the perceived current problems in the field that need to be resolved before pharmacological targeting of TNTs can become a reality.ConclusionsWe conclude that TNTs and TMs provide a new and exciting avenue for the therapeutic targeting of glioblastoma and that numerous inroads have already made into TNT and TM biology. However, to target TMs and TNTs, several advances must be made before this aim can become a reality.

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Sexual dimorphism in gene regulation, including DNA methylation, is the main driver of sexual dimorphism in phenotypes. However, the questions of how and when sex shapes DNA methylation remain unresolved. Recently, using mice with different combinations of genetic and phenotypic sex, we identified sex-associated differentially methylated regions (sDMRs) that depended on the sex phenotype. Focusing on a panel of validated sex-phenotype dependent male- and female-biased sDMRs, we tested the developmental dynamics of sex bias in liver methylation and the impacts of mutations in the androgen receptor, estrogen receptor alpha, or the transcriptional repressor Bcl6 gene. True hermaphrodites that carry both unilateral ovaries and contralateral testes were also tested. Our data show that sex bias in methylation either coincides with or follows sex bias in the expression of sDMR-proximal genes, suggesting that sex bias in gene expression may be required for demethylation at certain sDMRs. Global ablation of AR, ESR1, or a liver-specific loss of BCL6, all alter sDMR methylation, whereas presence of both an ovary and a testis delays the establishment of male-type methylation levels in hermaphrodites. Moreover, the Bcl6-LKO shows dissociation between expression and methylation, suggesting a distinct role of BCL6 in demethylation of intragenic sDMRs.