Evolving Cancer

Evolving Cancer

By Mel Greaves

(for details see this article published online in Nature Dec 15, 2010

Cancer clone evolution has long been regarded as a ‘Darwinian’ process driven by somatic cell mutation coupled with natural, clonal selection within tissues or ‘artificial’ selection via drug therapy ¹.  Despite this accepted paradigm, a common perception has been that the process works in a rather simple or linear way by clonal succession and dominance as mutations accumulate sequentially in a cell lineage.  Similarly, current cancer genomics, though technically a tour de force, portrays cancer genomes as one dimensional or uniform (but very complex) landscapes ².  Molecular pathology of cancer has however for some years now provided evidence for substantial sub-clonal complexity and likely non-linear dynamics ^3,4.  A recent paper by Anderson et al ⁵ provides new insight into cancer clone development at the single cell level.  By multi-plexing mutation detection by multi-colour fluorescence in situ hybridization (FISH), Anderson et al were able to identify genetically distinct sub-clones of acute lymphoblastic leukaemia and their likely evolutionary relationships.  The outcome was, perhaps not surprisingly, that the clonal architecture had a complex branching structure, very reminiscent of Charles Darwin’s iconic 1837 ‘I think’ image.  Perhaps more significantly, Anderson et al analysed the genetics of the likely units of selection in cancer clone evolution – the so-called cancer stem or propagating cells.  These were also found to be genetically variegated, as would be expected if they provide the substrate for selection.  These new data very much endorse the Darwinian view of cancer clone evolution.  More importantly, they have implications for cancer therapeutics particularly in the context of so-called ‘targeted’ therapy ⁶.  If the cancer stem cell pool is genetically variegated, then directing therapy at specific mutations will simply provide selective pressure for the emergence and dominance of mutation negative sub-clones – except if the ‘founder’ or initiating mutation, present in all clonal progeny, is the selected target.
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References

1. Nowell PC (1976)  The clonal evolution of tumor cell populations.  Science, 194: 23-28.
2. Stratton MR, Campbell PJ, Futreal PA (2009)  The cancer genome.  Nature, 458: 719-724.
3. Merlo LMF, Pepper JW, Reid BJ, Maley CC (2006)  Cancer as an evolutionary and ecological process.  Nature Rev Cancer, 6: 924-935.
4. Marusyk A, Polyak K (2010)  Tumor heterogeneity: causes and consequences.  Biochim Biophys Acta, 1805: 105-117.
5. Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M (2010)  Genetic variegation of clonal architecture and propagating cells in leukaemia.  Nature, doi:10.1038/nature09650.
6. Greaves M (2010)  Cancer stem cells: back to Darwin?  Sem Cancer Biol, 20: 65-70.

Genetic variegation of clonal architecture
and propagating cells in leukaemia

Kristina Anderson1, Christoph Lutz2, Frederik W. van Delft1, Caroline M. Bateman1, Yanping Guo2, Susan M. Colman1,
Helena Kempski3, Anthony V. Moorman4, Ian Titley1, John Swansbury1, Lyndal Kearney1, Tariq Enver2{ & Mel Greaves1
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Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for
cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia
in which the ETV6–RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or
‘driver’ copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight
genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of
subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated
genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and
reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is
subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation
in NOD/SCID IL2Rcnull mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive
regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer.