Bio380 Cancer Phylogenomics


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Bio380 lecture on cancer as an evolutionary process, showing descent with modification, branching evolution and natural selection; focus on genome evolution

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Bio380 Cancer Phylogenomics

  1. 1. <ul><li>PROFESSOR MARK PALLEN </li></ul>The Phylogenomics of Cancer
  2. 2. Charles Darwin 1809-1882 <ul><li>Shrewsbury; Edinburgh; Cambridge (1809-31) </li></ul><ul><li>Beagle voyage (1831-36) </li></ul><ul><li>London (1836-42) </li></ul><ul><li>Down House (1842-1882) </li></ul><ul><ul><li>Geology; Zoology; Barnacles </li></ul></ul><ul><ul><li>Voyage of the Beagle, 1839 </li></ul></ul><ul><li>Evolution </li></ul><ul><ul><li>Origin of Species, 1859 (“one long argument”). </li></ul></ul><ul><ul><li>Descent of Man, 1871 </li></ul></ul>
  3. 3. Natural Selection Fecundity of Nature Struggle for Existence Mutability of Species Vestigial features Non-Progressive Branching Evolution Evolutionary Gradualism Evolution of complex organs Nature rich in variety, poor in innovation Population Thinking Blurred boundaries between species and varieties Extinction Imperfection of fossil record Variation Reproduction Selection Sexual Selection Principle of divergence Taxonomy as Genealogy Tree of Life: Common Descent Homology equals similarity from common ancestry Biogeography Geography reflects genealogy Dispersal and Adaptive Radiation Darwin’s Theory of Evolution Newton’s law-governed universe Hutton and Lyell’s deep time and uniformitarianism The Beagle voyage Fossils and biogeography Family tradition of religious dissent and r/evolutionary ideas Paley’s Natural Theology Humboldt’s adventures in natural history Malthus Essay on Population Scottish enlightenment Smith’s Invisible Hand Wallace’s letter
  4. 4. Natural Selection Non-Progressive Branching Evolution Evolutionary Gradualism
  5. 5. Natural Selection… “ Owing to this struggle for life, any variation , however slight and from whatever cause proceeding, if it be in any degree profitable to an individual of any species, in its infinitely complex relations to other organic beings and to external nature, will tend to the preservation of that individual , and will generally be inherited by its offspring. The offspring, also, will thus have a better chance of surviving, for, of the many individuals of any species which are periodically born, but a small number can survive . I have called this principle, by which each slight variation, if useful, is preserved, by the term of Natural Selection , in order to mark its relation to man's power of selection. We have seen that man by selection can certainly produce great results, and can adapt organic beings to his own uses, through the accumulation of slight but useful variations, given to him by the hand of Nature. But Natural Selection, as we shall hereafter see, is a power incessantly ready for action, and is as immeasurably superior to man's feeble efforts, as the works of Nature are to those of Art .” On the Origin of Species, 1859
  6. 6. Natural Selection… without genetics “ Our ignorance of the laws of variation is profound. Not in one case out of a hundred can we pretend to assign any reason why this or that part differs, more or less, from the same part in the parents.”
  7. 7. From Mendel to the Modern Synthesis <ul><li>Mendel’s experiments on peas in 1860s </li></ul><ul><ul><li>Rediscovered in 1900s </li></ul></ul><ul><li>Soma/germ-line distinction (Weismann) </li></ul><ul><li>Chromosomes; mutations </li></ul><ul><li>Twilight of Darwinism; persistence of “Lamarckianism” </li></ul><ul><li>1940s: </li></ul><ul><ul><li>“ Modern Synthesis” of Evolution and Genetics </li></ul></ul><ul><ul><li>‘ Mendel meets Darwin’ </li></ul></ul>
  8. 9. Spectrum of genome evolution Homo neanderthalensis Extinct hominins Living primates Homo sapiens
  9. 10. Cancer evolution
  10. 11. What is Cancer? <ul><li>Cancers or malignant neoplasms occur in multicellular organisms when a group of cells displays </li></ul><ul><ul><li>uncontrolled growth, </li></ul></ul><ul><ul><li>invasion ± metastasis </li></ul></ul><ul><li>By contrast benign tumours are self-limited and do not invade or metastasize </li></ul><ul><li>Cancer cells are cheaters on the contract between genomically identical cells to create multicellular bodies to propagate the germ line </li></ul>
  11. 12. Six hallmarks of cancer <ul><li>self-sufficiency of cells in signals controlling growth </li></ul><ul><li>loss of sensitivity to antigrowth signals </li></ul><ul><li>evasion of apoptosis via mutation or loss of gatekeeper genes </li></ul><ul><li>development of limitless replicative potential, usually via the expression of telomerase </li></ul><ul><li>sustained angiogenesis, whereby the blood supply to a tumor is augmented </li></ul><ul><li>tissue invasion and metastasis </li></ul>
  12. 13. <ul><li>Simple views of cancer </li></ul>
  13. 14. Nowell, 1976
  14. 15. Nowell, 1976
  15. 16. Cancer as an evolutionary process
  16. 17. Descent with Modification
  17. 18. Branching Evolution
  18. 20. Natural Selection in Cancer <ul><li>Three prerequisites are necessary and sufficient for evolution by natural selection : </li></ul><ul><ul><li>Individual variations exist in the population </li></ul></ul><ul><ul><li>These variations are heritable </li></ul></ul><ul><ul><li>Variations in individuals lead to differential survival and reproduction </li></ul></ul>
  19. 21. Natural Selection in Cancer <ul><li>Cancer composed of billions of malignant cells descended from single progenitor </li></ul><ul><ul><li>all carry somatic mutations present in founder cell </li></ul></ul><ul><ul><li>additional mutations acquired by generations of daughter cells during tumour progression </li></ul></ul><ul><ul><li>genomic instability fuels genetic intra-tumour heterogeneity </li></ul></ul><ul><li>Diversification into subclones, which compete for resources, such as oxygen, vascular supply, growth signals and vary in growth rate, invasiveness etc </li></ul><ul><li>Natural selection drives selective sweeps and adaptation to local micro-environments </li></ul>
  20. 22. Artificial Selection in Cancer <ul><ul><li>Development of resistance to cancer chemotherapeutics governed by Darwinian natural selection, an inevitable consequence of genetic diversity and selective pressure. </li></ul></ul>
  21. 23. Artificial Selection in Cancer Cancer stem cells with genetic instability: the best vehicle with the best engine for cancer E Lagasse
  22. 24. Evolution of the Cancer Genome ~1% of our coding genes, >350 genes, can, as mutants, contribute to cancer clone evolution
  23. 25. <ul><li>Driver mutations </li></ul><ul><li>Passenger mutations </li></ul><ul><li>Contribute to oncogenesis; provide growth advantage; selected for in micro-niche </li></ul><ul><li>Occur in </li></ul><ul><ul><li>oncogenes (gain of function mutations) or </li></ul></ul><ul><ul><li>tumour-suppressor genes (loss of function mutations) </li></ul></ul><ul><li>Neutral mutations </li></ul><ul><li>Carried along for the ride </li></ul><ul><ul><li>somatic mutations without functional consequences often occur during cell division </li></ul></ul><ul><li>PLUS huge increase in mutation rate with loss of genome repair mechanisms </li></ul>Passengers and Drivers
  24. 27. Why Cancer? <ul><li>Different types of causation within a causal chain </li></ul><ul><ul><li>Epidemiologists say cigarette tar causes lung cancer </li></ul></ul><ul><ul><li>Molecular biologists say gene mutations cause lung cancer </li></ul></ul><ul><li>Mechanistic versus evolutionary causation </li></ul><ul><ul><li>Evolutionary or Darwinian medicine </li></ul></ul><ul><li>Why is cancer common especially in humans? </li></ul><ul><ul><li>one in three lifetime risk </li></ul></ul>
  25. 28. Why Cancer? <ul><li>cancer as reversion to unicellular selfishness </li></ul><ul><ul><li>multicellularity requires the social cohesion of cells and the severe prohibition of clonal escape </li></ul></ul><ul><li>cancer as intrinsic fallibility that escalates with increasing complexity and longevity </li></ul><ul><ul><li>intrinsic mutability and recombination capacity of DNA </li></ul></ul><ul><ul><li>incomplete fidelity of repair </li></ul></ul>
  26. 29. Why Cancer? <ul><li>Disposable soma </li></ul><ul><ul><li>flaws or trade-offs apparent only in old age tolerated so long as they do not impact deleteriously on reproductive fitness </li></ul></ul><ul><li>Cellular attributes required for cell cycle, viviparity and embryogenesis available for co-option by malignant cells </li></ul><ul><ul><li>e.g. immunological tolerance; motility, chemotaxis, migration and invasiveness </li></ul></ul><ul><li>Stem cells retain intrinsic competence for transient, selfish replication </li></ul>
  27. 30. Why Cancer? <ul><li>Stone age genome versus 21st century lifestyle </li></ul><ul><ul><li>pale skin provides more vitamin D, but leads to cancer in e.g. white Australians with sun exposure </li></ul></ul><ul><ul><li>breast and ovarian cancer arise from mismatch between hunter-gatherer reproductive physiology and modern reproductive and breast-feeding choices </li></ul></ul><ul><ul><li>prostate cancer as sides effect of large prostate driven by need for sperm production matched to non-seasonal oestrus </li></ul></ul>
  28. 31. Why Cancer? <ul><li>No eyes to the future… </li></ul><ul><li>Darwinian natural selection operates on a “what works best today” basis. </li></ul><ul><li>selects genetic variants from the limited options available that best fit the prevailing conditions. </li></ul><ul><li>winners today can become losers tomorrow: cancer cells kill their host! </li></ul>
  29. 34. Genome evolution in Chimps, Humans, Cancers…
  30. 36. Genome evolution in Chimps, Humans, Cancers… <ul><li>Structural alterations linked to single-nucleotide changes across different time scales in somatic- and germ-cell lineages </li></ul><ul><ul><li>at species level </li></ul></ul><ul><ul><li>in personal genomes </li></ul></ul><ul><ul><li>in human cancer cell populations </li></ul></ul><ul><li>Proposed explanation </li></ul><ul><ul><li>low fidelity of non-replicative error-prone repair polymerases, used during insertion or deletion, results in break-repair-induced single-nucleotide mutations in the vicinity of structural alteration </li></ul></ul>
  31. 37. Cancer and the birth and death of species
  32. 38. Henrietta Lacks 1920 -1951 <ul><li>African–American woman </li></ul><ul><li>Born in Roanoke, Virginia </li></ul><ul><li>married her first cousin, David &quot;Day&quot; Lacks </li></ul><ul><li>Moved to Baltimore County, Maryland when David started working in shipyard </li></ul><ul><li>Five children: Lawrence, Elsie, David &quot;Sonny&quot; Jr., Deborah, and Joseph (born 1950; later changed name to Zakariyya Bari Abdul Rahman). </li></ul>
  33. 39. Henrietta Lacks 1920 -1951 <ul><li>Feb 1951, Lacks visits Johns Hopkins with painful lump in her cervix and bloody vaginal discharge </li></ul><ul><ul><li>After biopsy, diagnosed with unusually aggressive cervical cancer </li></ul></ul><ul><ul><li>Eight days later, Dr. George Gey takes second sample from her tumour </li></ul></ul><ul><ul><li>Lacks treated with radium but condition worsens </li></ul></ul><ul><li>Re-admitted on Aug 8, dies Oct 4, aged 31 </li></ul><ul><li>autopsy shows widespread metastases </li></ul><ul><li>buried without tombstone in family cemetery in Lackstown, Virginia. </li></ul>
  34. 40. HeLa cells <ul><li>Lacks’ cells propagated by George Gey </li></ul><ul><li>No permission or consent as, by US law, tissues or cells taken from patients do not belong to them </li></ul><ul><li>First human cell line, named HeLa, supposedly after Helen Lane or Helen Larson to preserve anonymity </li></ul><ul><li>Gey freely donated cells to scientific community: </li></ul><ul><ul><li>used to test first polio vaccine in the 1950s </li></ul></ul><ul><ul><li>widely used for research on cancer, infection, cell biology, toxicology etc in > 60,000 scientific papers (>300 new papers per month) </li></ul></ul>
  35. 41. HeLa cells <ul><li>Original HeLa cells were mixed population from biopsy, subsequently cloned in several labs </li></ul><ul><ul><li>strains of HeLa cells continue to evolve while grown in cell culture </li></ul></ul><ul><ul><li>total number of HeLa cells now far exceeds total number of cells in Lacks' body </li></ul></ul><ul><ul><li>HeLa cells grow like weed to contaminate many other cell lines: coomon cause of scientific error and embarrassment </li></ul></ul><ul><li>HeLa Genome is different from Lacks Genome </li></ul><ul><ul><li>HPV18 integration </li></ul></ul><ul><ul><li>HeLa cells have modal chromosome number of 82, with four copies of chromosome 12 and three copies of chromosomes 6, 8, and 17 </li></ul></ul><ul><li>American evolutionary biologist Leigh Van Valen claimed HeLa represents new species, Helacyton gartleri , based on : </li></ul><ul><ul><li>Chromosomal incompatibility of HeLa cells with humans </li></ul></ul><ul><ul><li>Adaptation to novel ecological niche (cell culture) </li></ul></ul><ul><ul><li>Immortal and expand beyond desire of human cultivators </li></ul></ul>
  36. 42. Infectious cancers <ul><li>Canine transmissible venereal tumor </li></ul><ul><ul><li>infectious cancer in dogs and other canids caused by an immortal cell line </li></ul></ul><ul><ul><li>Tolerated by immune system because does not express MHC </li></ul></ul><ul><li>Devil facial tumour disease </li></ul><ul><ul><li>infectious cancer in the Tasmanian devil caused by an immortal cell line </li></ul></ul><ul><ul><li>Tolerated by immune system because Devils all have functionally identical MHC </li></ul></ul><ul><ul><li>Likely to cause extinction of Tasmanian Devils in the wild </li></ul></ul>
  37. 43. Summary <ul><li>Cancers present a microcosm of evolution, illustrating: </li></ul><ul><ul><li>Descent with modification </li></ul></ul><ul><ul><li>Branching Evolution </li></ul></ul><ul><ul><li>Natural Selection </li></ul></ul><ul><ul><li>Artificial Selection </li></ul></ul><ul><li>Various answers to Why Cancer? </li></ul><ul><li>Similar principles may govern genome evolution at species, population and cellular level </li></ul><ul><li>Cancers and the birth and death of the soma and the species </li></ul>
  38. 44. <ul><li>W hen we no longer look at an organic being as a savage looks at a ship, as something wholly beyond his comprehension; when we regard every production of nature as one which has had a long history; when we contemplate every complex structure and instinct as the summing up of many contrivances, each useful to the possessor, in the same way as any great mechanical invention is the summing up of the labour, the experience, the reason, and even the blunders of numerous workmen; when we thus view each organic being, how far more interesting—I speak from experience—does the study of natural history become! </li></ul><ul><li>Charles Darwin, Origin of Species, 1859 </li></ul>
  39. 45.,16701433,20615949,19956175,19360079,17989699,20877357,18723673,20359535,959840,15613288