Intratumoral Heterogeneity of the Epigenome

Mazor, Tali; Pankov, Aleksandr; Song, Jun S.; Costello, J

doi:10.1016/j.ccell.2016.03.009

Cited by 185 publications

(162 citation statements)

References 126 publications

(172 reference statements)

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“…While the complex genetics of untreated GBM are being investigated with next-generation sequencing technologies (Brennan et al 2013), it is now understood that the genetics and epigenetics of gliomas are also impacted by therapy and tumor progression (Johnson et al 2014;Mazor et al 2015;Wang et al 2016). In addition to genetics, a central aspect of the pathogenesis of GBM is its heterogeneity, which is reflected in the various histological subtypes, epigenetic and gene expression landscapes, and different cells of origin and tumor microenvironment constituents, all contributing to the therapeutically recalcitrant nature of this tumor type (Alcantara Llaguno et al 2015;Archetti et al 2015;Furnari et al 2015;Caiado et al 2016;Mazor et al 2016). To achieve treatment success for GBM patients, it is critical to understand the contribution of each one of these tumor features.…”

Section: Discussionmentioning

confidence: 99%

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Zanca

Villa

Benítez³

et al. 2017

Genes Dev.

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In glioblastoma (GBM), heterogeneous expression of amplified and mutated epidermal growth factor receptor (EGFR) presents a substantial challenge for the effective use of EGFR-directed therapeutics. Here we demonstrate that heterogeneous expression of the wild-type receptor and its constitutively active mutant form, EGFRvIII, limits sensitivity to these therapies through an interclonal communication mechanism mediated by interleukin-6 (IL-6) cytokine secreted from EGFRvIII-positive tumor cells. IL-6 activates a NF-κB signaling axis in a paracrine and autocrine manner, leading to bromodomain protein 4 (BRD4)-dependent expression of the prosurvival protein survivin (BIRC5) and attenuation of sensitivity to EGFR tyrosine kinase inhibitors (TKIs). NF-κB and survivin are coordinately up-regulated in GBM patient tumors, and functional inhibition of either protein or BRD4 in in vitro and in vivo models restores sensitivity to EGFR TKIs. These results provide a rationale for improving anti-EGFR therapeutic efficacy through pharmacological uncoupling of a convergence point of NF-κB-mediated survival that is leveraged by an interclonal circuitry mechanism established by intratumoral mutational heterogeneity.

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Section: Discussionmentioning

confidence: 99%

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Zanca

Villa

Benítez³

et al. 2017

Genes Dev.

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“…Intra-tumoral heterogeneity at multiple levels (DNA, RNA, epigenetics, protein) provides the fuel for tumor evolution, which forms the basis of disease progression, treatment response, relapse, and metastasis (Burrell et al 2013;Mazor et al 2016;Turajlic and Swanton 2016). Distinct genetic or epigenetic subclones may compete or collaborate for better fitness in response to microenvironmental or developmental changes (Tirosh et al 2016b).…”

Section: Discussionmentioning

confidence: 99%

Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

et al. 2017

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Intra-tumoral genetic heterogeneity has been characterized across cancers by genome sequencing of bulk tumors, including chronic lymphocytic leukemia (CLL). In order to more accurately identify subclones, define phylogenetic relationships, and probe genotype-phenotype relationships, we developed methods for targeted mutation detection in DNA and RNA isolated from thousands of single cells from five CLL samples. By clearly resolving phylogenic relationships, we uncovered mutated LCP1 and WNK1 as novel CLL drivers, supported by functional evidence demonstrating their impact on CLL pathways. Integrative analysis of somatic mutations with transcriptional states prompts the idea that convergent evolution generates phenotypically similar cells in distinct genetic branches, thus creating a cohesive expression profile in each CLL sample despite the presence of genetic heterogeneity. Our study highlights the potential for single-cell RNA-based targeted analysis to sensitively determine transcriptional and mutational profiles of individual cancer cells, leading to increased understanding of driving events in malignancy.

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“…Importantly, heterogeneity does not simply affect coding mutations. A multitude of epigenetic mechanisms, including DNA methylation, chromatin remodeling and post-translational modification of histones, can contribute to diversity within tumors (for a review see (Mazor et al, 2016)). …”

Section: How Much Heterogeneity Is There?mentioning

confidence: 99%

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

McGranahan

Swanton

2017

Cell

2,102

1,694

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Intratumor heterogeneity, which fosters tumor evolution, is a key challenge in cancer medicine. Here we review data and technologies that have revealed intra-tumor heterogeneity across cancer types, and the dynamics, constraints and contingencies inherent to tumor evolution. We emphasize the importance of macro-evolutionary leaps, often involving large-scale chromosomal alterations, in driving tumor evolution and metastasis, and consider the role of the tumor microenvironment in engendering heterogeneity and drug-resistance. We suggest that bold approaches to drug development, harnessing the adaptive properties of the immunemicroenvironment whilst limiting those of the tumor, combined with advances in clinical trial-design, will improve patient outcome.

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Intratumoral Heterogeneity of the Epigenome

Cited by 185 publications

References 126 publications

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Glioblastoma cellular cross-talk converges on NF-κB to attenuate EGFR inhibitor sensitivity

Integrated single-cell genetic and transcriptional analysis suggests novel drivers of chronic lymphocytic leukemia

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future

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