Subj : Cancer's origin story features predictab To : All From : ScienceDaily Date : Fri Jul 07 2023 22:30:28 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. Facebook Twitter Pinterest LinkedIN Email ========================================================================== FULL STORY ========================================================================== 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. * RELATED_TOPICS o Health_&_Medicine # Cancer # Stem_Cells # Lymphoma # Brain_Tumor # Lung_Cancer # Colon_Cancer # Skin_Cancer # Diseases_and_Conditions * RELATED_TERMS o Prostate_cancer o Cervical_cancer o Colorectal_cancer o Breast_cancer o Chemotherapy o Carcinogen o Cancer o Metastasis ========================================================================== Print Email Share ========================================================================== ****** 1 ****** ***** 2 ***** **** 3 **** *** 4 *** ** 5 ** Breaking this hour ========================================================================== * Cystic_Fibrosis:_Lasting_Improvement * Artificial_Cells_Demonstrate_That_'Life_... * Advice_to_Limit_High-Fat_Dairy_Foods_Challenged * First_Snapshots_of_Fermion_Pairs * Why_No_Kangaroos_in_Bali;_No_Tigers_in_Australia * New_Route_for_Treating_Cancer:_Chromosomes * Giant_Stone_Artefacts_Found:_Prehistoric_Tools * Astonishing_Secrets_of_Tunicate_Origins * Most_Distant_Active_Supermassive_Black_Hole * Creative_People_Enjoy_Idle_Time_More_Than_Others Trending Topics this week ========================================================================== HEALTH_&_MEDICINE Birth_Defects Cholesterol Patient_Education_and_Counseling MIND_&_BRAIN Autism Creativity Depression LIVING_&_WELL Healthy_Aging Fitness Nutrition ========================================================================== Strange & Offbeat ========================================================================== HEALTH_&_MEDICINE Holograms_for_Life:_Improving_IVF_Success Grocery_Store_Carts_Set_to_Help_Diagnose_Common_Heart_Rhythm_Disorder_and Prevent_Stroke DNA_Can_Fold_Into_Complex_Shapes_to_Execute_New_Functions MIND_&_BRAIN AI_Tests_Into_Top_1%_for_Original_Creative_Thinking Everyone's_Brain_Has_a_Pain_Fingerprint_--_New_Research_Has_Revealed_for_the First_Time Scientists_Discover_Spiral-Shaped_Signals_That_Organize_Brain_Activity LIVING_&_WELL Illusions_Are_in_the_Eye,_Not_the_Mind Amputees_Feel_Warmth_in_Their_Missing_Hand Why_Do_Champagne_Bubbles_Rise_the_Way_They_Do?_Scientists'_New_Discovery_Is Worthy_of_a_Toast Story Source: Materials provided by Stanford_Medicine. Original written by Krista Conger. Note: Content may be edited for style and length. ========================================================================== 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 ========================================================================== Link to news story: https://www.sciencedaily.com/releases/2023/07/230707153834.htm --- up 1 year, 18 weeks, 4 days, 10 hours, 50 minutes * Origin: -=> Castle Rock BBS <=- Now Husky HPT Powered! (1:317/3) .