MSGID: 1:317/3 64a8e675   
   PID: hpt/lnx 1.9.0-cur 2019-01-08   
   TID: hpt/lnx 1.9.0-cur 2019-01-08   
    Cancer's origin story features predictable plot line, researchers find   
    Predictable mutations chart cancer's path    
      
     Date:   
         July 7, 2023   
     Source:   
         Stanford Medicine   
     Summary:   
         Human cells evolving in the laboratory undergo a series   
         of predictable, sequential genetic changes that lead to   
         pre-cancer. Blocking these changes may allow intervention before   
         cancer occurs.   
      
      
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   Cancer cells-to-be accumulate a series of specific genetic changes in   
   a predictable and sequential way years before they are identifiable as   
   pre- malignancies, researchers at Stanford Medicine have found. Many of   
   these changes affect pathways that control cell division, structure and   
   internal messaging -- leaving the cells poised to go bad long before   
   any visible signs or symptoms occur.   
      
   The study is the first to exhaustively observe the natural evolution of   
   the earliest stages of human cancers, starting with cells that have a   
   single cancer-priming mutation and culminating with a panel of descendants   
   harboring a galaxy of genetic abnormalities.   
      
   Identifying the first steps associated with future cancer development   
   could not only facilitate earlier-than-ever diagnosis -- when a deadly   
   outcome is but a twinkle in a rogue cell's eye -- but may also highlight   
   novel interventions that could stop the disease in its tracks, the   
   researchers say.   
      
   "Ideally, we would find ways to intercept this progression before the   
   cells become truly cancerous," said Christina Curtis, PhD, professor of   
   medicine, of genetics and of biomedical data science. "Can we identify   
   a minimal constellation of genetic alterations that imply the cell will   
   progress? And, if so, can we intervene? The striking reproducibility   
   in the genetic changes we observed from multiple donors suggests it's   
   possible."  Curtis is the senior author of the research, which was   
   published on May 31 in Nature. The lead authors of the study are former   
   postdoctoral scholar Kasper Karlsson, PhD, and visiting graduate student   
   Moritz Przybilla.   
      
   Cells of nefarious beginnings The research builds on previous work in   
   Curtis's laboratory indicating that some colon cancer cells are seemingly   
   born to be bad -- they acquire the ability to metastasize long before   
   the disease is detectable.   
      
   "Our studies of established tumors showed us that early genomic   
   alterations seem to dictate what happens later, and that many of these   
   changes seem to happen before tumor formation," Curtis said. "We wanted   
   to know what happens at the very earliest stages. How does a cancer   
   cell evolve, and is this evolutionary path repeatable? If we start with   
   a given set of conditions, will we get the same result in every case?"   
   The researchers studied tiny, three-dimensional clumps of human stomach   
   cells called gastric organoids. The cells were obtained from patients   
   undergoing gastric bypass surgery to treat obesity. At the beginning   
   of the study, the researchers nudged the cells toward cancers by   
   disabling the production of a key cancer-associated protein called p53   
   that regulates when and how often a cell divides. Mutations in p53 are   
   known to be an early event in many human cancers, and they trigger the   
   accumulation of additional genetic changes including mutations and copy   
   number alterations -- in which repetitive regions of the genome are lost   
   or gained during cell division.   
      
   Then they waited.   
      
   Every two weeks, for two years, Karlsson cataloged the genetic changes   
   occurring in the dividing cells. When Karlsson and Przybilla analyzed   
   the data they found that, although changes occurred randomly, those that   
   conferred greater fitness gave their host cells an evolutionary advantage   
   over other cells in the organoid. As the cells continued to divide and   
   the cycle of mutation and competition repeated over many iterations,   
   the researchers saw some common themes.   
      
   Predictable pathways "There are reproducible patterns," Curtis   
   said. "Certain regions of the genome are consistently lost very early   
   after the initial inactivation of p53. This was repeatedly seen in cells   
   from independent experiments with the same donor and across donors. This   
   indicates that these changes are cell-intrinsic, that they are hardwired   
   into tumor evolution. At the same time, these cells and organoids appear   
   mostly normal under the microscope. They have not yet progressed to a   
   cancer."  The researchers found that these early changes usually occur in   
   biological pathways that control when and how often a cell divides, that   
   interfere with a cell's intricate internal signaling network coordinating   
   the thousands of steps necessary to keep it running smoothly, or that   
   control cell structure and polarity -- its ability to know what is "up"   
   and "down" and to situate itself with respect to neighboring cells to   
   form a functioning tissue.   
      
   The researchers saw similar patterns occur again and again in cells   
   from different donors. Like water flowing downhill into dry creek beds,   
   the cells traced tried-and-true paths, gaining momentum with each new   
   genetic change.   
      
   Several of these changes mirror mutations previously observed in stomach   
   cancer and in Barrett's esophagus, a pre-cancerous condition arising   
   from cells that line the colon and stomach.   
      
   "These changes occur in a stereotyped manner that suggest constraints   
   in the system," Curtis said. "There's a degree of predictability at the   
   genomic level and even more so at the transcriptomic level -- in the   
   biological pathways that are affected -- that gives insights into how   
   these cancers arise."  Curtis and her colleagues plan to repeat the study   
   in different cell types and initiating events other than p53 mutation.   
      
   "We're trying to understand exactly what malignant transformation is,"   
   Curtis said. "What does it mean to catch these cells in the act, about   
   to topple over the edge? We'd like to repeat this study with other   
   tissue types and initiating mutations so we can understand the early   
   genetic events that occur in different organs. And we'd like to study   
   the interplay between the host and the environment. Do inflammatory   
   factors play a role in promoting progression? We know that it matters   
   that the cells in these organoids are communicating with each other, and   
   that is important to understanding progression and treatment response."   
   Researchers from Karolinska Institutet, the University College London   
   and the Chan Zuckerberg Biohub also contributed to the study.   
      
   The research was supported by the National Institutes of Health (grants   
   DP1- CA238296 and U01-CA217851) and the Swedish Research Council.   
      
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   Journal Reference:   
      1. Karlsson, K., Przybilla, M.J., Kotler, E. et al. Deterministic   
      evolution   
         and stringent selection during preneoplasia. Nature, 2023 DOI:   
         10.1038/ s41586-023-06102-8   
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   Link to news story:   
   https://www.sciencedaily.com/releases/2023/07/230707153834.htm   
      
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