Cancers

Review on the future of epigenetic therapies for glioblastoma. We specifically focus on epidrugs and other approaches that target epigenetic and chromatin factors in cancer stem cells. We also discuss some experimental challenges and the importance of appropriate patient-derived models for preclinical studies.

CSH Molecular Case Studies

Hi-C provides information on 3D genome conformation, but it can also be used to detect genetic structural variants. Here, we describe how we used Hi-C to detect structural variants of clinical significance in peripheral blood of pediatric leukemia patients.

eLife

Lineage transformation between lung cancer subtypes is a poorly understood phenomenon associated with resistance to treatment and poor patient outcomes. Here, we aimed to model this transition to define underlying biological mechanisms and identify potential avenues for therapeutic intervention.

eLife

Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumours, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention.

Science

Several species of intestinal bacteria have been associated with enhanced efficacy of checkpoint blockade immunotherapy, but the underlying mechanisms by which the microbiome enhances antitumor immunity are unclear. In this study, we isolated three bacterial species-Bifidobacterium pseudolongum, Lactobacillus johnsonii, and Olsenella species-that significantly enhanced efficacy of immune checkpoint inhibitors in four mouse models of cancer. 

Genome Research

We investigated the role of 3D genome architecture in instructing functional properties of glioblastoma stem cells (GSCs) by generating sub-5-kb resolution 3D genome maps by in situ Hi-C. Contact maps at sub-5-kb resolution allow identification of individual DNA loops, domain organization, and large-scale genome compartmentalization.

Journal of Clinical Investigation

Replicative immortality is a hallmark of cancer cells governed by telomere maintenance. Approximately 90% of human cancers maintain their telomeres by activating telomerase, driven by the transcriptional upregulation of telomerase reverse transcriptase (TERT). Although TERT promoter mutations (TPMs) are a major cancer-associated genetic mechanism of TERT upregulation, many cancers exhibit TERT upregulation without TPMs. I

bioRχiv

Pediatric glioblastoma (pGBM) is a lethal cancer with no effective therapies. Intratumoral genetic heterogeneity and mode of tumour evolution have not been systematically addressed for this cancer. Whole-genome sequencing of germline-tumour pairs showed that pGBM is characterized by intratumoral genetic heterogeneity and consequent subclonal architecture.

Cancer Cell

Mutations in the histone 3 variant H3.3 have been identified in one-third of pediatric glioblastomas (GBMs), but not in adult tumours. Here we show that H3.3 is a dynamic determinant of functional properties in adult GBM. H3.3 is repressed by mixed-lineage leukemia 5 (MLL5) in self-renewing GBM cells. MLL5 is a global epigenetic repressor that orchestrates reorganization of chromatin structure by punctuating chromosomes with foci of compacted chromatin, favouring tumorigenic and self-renewing properties.

Nature

Ependymomas are common childhood brain tumours that occur throughout the nervous system but are most common in the pediatric hindbrain. Current standard therapy comprises surgery and radiation, but not cytotoxic chemotherapy as it does not further increase survival.

Cancer Research

Glioblastoma growth is driven by cancer cells that have stem cell properties, but molecular determinants of their tumorigenic behaviour are poorly defined. In cancer, altered activity of the epigenetic modifiers Polycomb and Trithorax complexes may contribute to the neoplastic phenotype. Here, we provide the first mechanistic insights into the role of the Trithorax protein mixed-lineage leukemia (MLL) in maintaining cancer stem cell characteristics in human glioblastoma.