Charles Swanton: Projects

Despite progress in our understanding of somatic aberrations that occur within and between different cancer types, the majority of metastatic solid tumours remain incurable.

The Translational Cancer Therapeutics (TCT) Group is developing a deeper understanding into the basis of this clinical problem by deciphering the causes and consequences of intratumour heterogeneity upon drug resistance and patient outcome (Swanton, 2012; Cancer Res. 2(19): 4875-82). Intratumour heterogeneity results in cancer cell population-level diversity providing a substrate for selection under different environmental contexts, such as drug treatment.

Darwin's central hypotheses of evolution, based on diversity and selection, are immediately applicable to tumour development and therapeutic failure (Nowell, 1976; Science. 194(4260): 23-8). The TCT Group aims to develop novel insights into tumour evolution through both space and time, deciphering how cancer evolution is influenced by established and novel genomic instability mechanisms and DNA damaging therapies used in the clinical setting.

Intratumour heterogeneity: tumour diversity in space and time

Deep sequencing, ploidy profiling and DNA copy number analyses from our group and others indicate that branched evolution occurs in both haematologic and solid tumours, resulting in both spatial and temporal intratumour heterogeneity (Swanton, 2012). We and others have demonstrated that chromosomal instability (CIN), a common mechanism generating intratumour heterogeneity, is implicated in cancer multidrug resistance and adverse clinical outcomes (Swanton et al., 2009; Proc Natl Acad Sci USA. 106(21): 8671-6; Lee et al., 2011; Cancer Res. 71(5): 1858-70).

Our work suggests that intratumour heterogeneity is likely to be a major impediment to improving cancer outcome, both in terms of reliable biomarker identification (Gerlinger et al., 2012; Engl J Med. 366(10): 883-92) and due to the relationship between heterogeneity and resistance to therapy. Defining 'actionable mutations' for therapeutic targeting based on a single biopsy without consideration of clonal dominance may be ineffective (Gerlinger et al., 2012), due to spatial separation or subclonality of tumour driver events, resulting in sampling bias (Martinez et al., 2013; J Pathol. 230(4): 356-64).

Despite heterogeneity, we have revealed evidence for the same gene being subject to loss of function through somatic mutations in spatially separated regions of the same tumour, or for the same signal transduction pathway being activated through mutations in different signal transduction components (Gerlinger et al., 2012). These observations suggest that in depth analysis of tumour evolution through space and time may help define routes through which tumours must progress and reveal the impact of therapy upon tumour evolution.

However, there are major limitations to enhancing knowledge of tumour evolution and therapeutic strategies to attenuate tumour adaptation. These limitations result from modest insight into mechanisms that generate genomic instability and diversity witnessed in human tumours, and as a consequence, a restricted number of animal tumour models re-capitulating tumour heterogeneity in which tumour evolution can be studied in vivo.

The TCT Group is utilising new genetic mechanisms, discovered in our laboratory that contribute to genomic instability in human tumours, to develop novel mouse models of human cancer (Burrell et al., 2013; Nature. 494(7438): 492-6). Intratumour heterogeneity will be extensively evaluated in these new models, in order to gain deeper insights into the impact of different selection pressures, such as growth at metastatic sites or the application of DNA damaging agents and the impact of the host immune response (Gerlinger et al., 2013; J Pathol. 231(4):424-32) upon tumour genomic evolution. It is hoped that this approach may enable the development and evaluation of therapeutic strategies aimed at limiting the two fundamental Darwinian principles of evolution: diversity and selection.

TRAcking Cancer Evolution through therapy/Rx (TRACERx) clinical study

Our group, together with the UCL Cancer Trials Centre, has initiated the TRACERx 850 patient clinical study that aims to decipher tumour evolutionary trajectories in early non-small cell lung cancer (Figure 1).

Through multi-region sequencing analysis of primary tumours and recurrent metastatic biopsies we will attempt to address the origins of the lethal tumour subclone, distinguish the changing patterns of tumour evolution over time, the associations of intratumour heterogeneity with disease outcome and the host immune response, and the impact of cancer cytotoxics upon the emergent subclonal genetic landscape at relapse.

Figure 1

Figure 1. Overview of TRACERx (Tracking Lung Cancer Evolution through Therapy/Rx). (Click to view larger image)

Identification of CIN suppressors: emerging role of DNA replication stress

Chromosomal instability (CIN) contributes to intratumour heterogeneity in the majority of epithelial carcinomas. We and others have demonstrated the association of CIN with poor prognosis and drug resistance (Lee et al., 2011; McGranahan et al., 2012; EMBO Rep. 13(6): 528-38).

Both structural and numerical CIN frequently occur together in tumours, however a mechanistic basis explaining this phenomenon in tumours is the subject of active investigation.

Our group has been deciphering a mechanistic basis for structural and numerical CIN in colorectal cancer (CRC), revealing that many chromosome segregation errors in these cells are caused by structural chromosome defects (Burrell et al., 2013). Hallmarks of DNA replication stress were elevated in CIN CRC cell lines relative to diploid controls, and segregation errors could be attenuated through exposure to exogenous nucleosides, previously shown to alleviate replication stress, suggesting that replication contributes to CIN in CRC.

In attempting to characterise a genetic basis for the generation of CIN in CRC, we used a bioinformatics analysis of CRC datasets to define a region on chromosome 18q that was consistently lost in aneuploid CRC compared to diploid chromosomally stable CRC. Chromosome 18q was lost during the adenoma-adenocarcinoma transition in tumours, and was temporally associated with the onset of aneuploidy. Furthermore, 18q is subject to copy number loss in a range of solid tumours including pancreatic and upper gastrointestinal malignancies.

18q-encoded genes were examined in an RNA interference screen for chromosome segregation error induction, revealing three genes, ZNF516, MEX3C and PIGN, the silencing of which increased the chromosome segregation error rate in diploid cells. Silencing these three candidate 'CIN Suppressors' in diploid cells resulted in an increase in the hallmarks of replication stress. Similar to CIN cells with 18q loss, exogenous nucleoside addition resulted in the attenuation of segregation errors in diploid cells following loss of the three CIN suppressors.

These data implicate replication stress in the generation of structural and numerical CIN and intratumour heterogeneity, and provide evidence that combining tumour bioinformatics approaches with intricate functional genomics analysis can reveal novel mechanisms contributing to intratumour heterogeneity.

The TCT Group is building on the experimental frameworks established through this approach to identify novel mechanisms generating genomic instability in other tumour types.

Charles Swanton

charles.swanton@crick.ac.uk
+44 (0)20 379 62047

  • Qualifications and history
  • 1995 PhD, Imperial Cancer Research Fund, UK (this became Cancer Research UK in 2002)
  • 2002 Membership Royal College of Physicians
  • 2004 Established lab at the London Research Institute, Cancer Research UK
  • 2015 Group Leader, the Francis Crick Institute, London, UK