Intra‐tumour heterogeneity – going beyond genetics

Abstract

Cancer patients die primarily due to disease recurrence after transient treatment responses. The emergence of therapy-resistant escape variants is fuelled by intra-tumour heterogeneity, underpinned by interference and Darwinian evolution among continuously developing sub-clones in the mutating tumour. Novel cancer cell variants build upon the pre-existing genetic landscape and tumour heterogeneity is often ascribed largely to genetic variability. While mutations are required for cancer development and studies of genetic evolution of tumours have improved our understanding of cancer biology, genetics only represents one dimension of the fitness of each cancer cell. Beyond the mutations, several non-genetic factors also add significant variability, resulting in a complex and highly dynamic tumour cell population that can drive disease under almost any condition. This viewpoint article summarizes the genetic basis of intra-tumour heterogeneity, before dissecting four major interdependent non-genetic factors we think critically contribute to the overall variability of tumour cells in all types of cancer: epigenetic regulation, cellular differentiation hierarchies, gene expression stochasticity and tumour microenvironment. We finally present the relevant technological approaches to address the combined contribution of both genetic and non-genetic factors to intra-tumour heterogeneity, focusing on genomic profiling, cellular lineage tracing and single-cell RNA sequencing technologies. This strategy will ultimately allow dissection of the full range and depth of intra-tumour heterogeneity. We thus believe that understanding how cancer genetics synergize with the emerging non-genetic factors will be key for development of therapies able to tackle tumour escape and thereby improve cancer patient survival. Cancer clonal evolution and its clinical implicationsThe existence of intra-tumour heterogeneity was first described in the 1800s by the pathologist Rudolf Virchow [1]. Identification of heterogeneity in cancer cell morphology and histology within tumours was followed by observations of variation in cell surface markers [2][3][4][5], genetic abnormalities [6,7], growth rates [2,8,9] and response to therapies [2,10]. The formulation of the chromosomal theory in the 1950s [11], supported by the observation of increasing chromosomal changes during tumour progression, provided the genetic basis for the observed tumour cell heterogeneity and was key for the formulation of Peter Nowell's theory in his seminal 1976 paper, 'Clonal evolution of tumor cell populations' [12].

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

“…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.…”

Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression

“…Genetic divergence is a well-known driver for heterogeneity. However, non-genetic factors such as epigenetic regulation and the TME also add significant variability [148]. First, alterations in histone markers, DNA methylation, and noncoding RNA contribute to tumor heterogeneity [149–152].…”

Targeting dynamics of subclones of GI, liver and pancreatic cancers

“…A medium-term perspective for spatiotemporal identification of intratumor heterogeneity (ITH) raises exciting new therapeutic horizons [2]. In contrast to simple ITH, an intrapatient heterogeneity (IPH) of both structural and functional genome variation, as well as ITH and circulating genomic clones diversity (cGCD), represents the most rational longterm perspective to reach precision cancer medicine [8].…”

“…However, there has been no breakthrough study to reveal IPH by comparing ITH [31] with cGCD yet [2,32]. Such a comparison is required in large-scale studies.…”

“…In this editorial, we summarize potential and challenges of latest developments in next-generation sequencing (NGS) platforms and technological genome systems to explore genomic clonal diversity and tumor heterogeneity. The spatiotemporal identification of genomic heterogeneity shapes new predictive and therapeutic avenues to improve personalized tumor responsiveness [2].…”