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January 6, 2015

Novel p53 Biomarker Discovery May Improve Cancer Surgery Outcomes

  • Scientists at Cold Spring Harbor Laboratory (CSHL) say they have discovered a novel cellular biomarker that could better help cancer surgeons determine if a patient has a potentially lethal mutation in the tumor suppressor protein p53. Knowing the p53 status of cells in a tumor being treated surgically can help pathologists determine where to remove tissue and where to spare it.
    This, and the fact that the new biomarker can be used to assess p53 status in as little as 15 minutes, makes it especially valuable, noted the researchers adding that in contrast, performing genetic sequencing on tissue samples would take days, and at least for now is not an option for a team in the middle of a surgical procedure.

    The biomarker's identity surprised the team, which was led by Lloyd Trotman, Ph.D., and Darryl Pappin, Ph.D., associate professors at CSHO. The key insight in their study “P53 Mutations Change Phosphatidylinositol Acyl Chain Composition”, which they describe in Cell Reports, is the length of an anchoring chain that holds the PI (phosphatidylinositide) signaling molecule in position in the inner membrane of cells.

    The anchoring chain becomes slightly shorter than normal when p53 is mutated. The difference (of either 2 or 4 carbon atoms) can be detected via mass spectrometry. Many large hospitals have the ability to perform mass spec analysis on samples delivered directly from operating rooms while procedures are in progress.

    “We [applied] a mass-spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition,” wrote the investigators. “Using this approach, we find that PI lipid chains represent a cell-specific fingerprint and are unperturbed by serum-mediated signaling in contrast to the inositol head group.

    Like most other scientists interested in cancers controlled by PI molecules, Dr. Trotman originally set out to closely study not its anchoring tail but rather the head of the molecule, which was discovered 15 years ago to be the cellular equivalent of an important traffic signal. When large molecules like growth hormone or insulin  dock at receptors on the cell surface, they set off a cascade of events inside the cell membrane, beginning with signaling devices like the PI molecule. Dr. Trotman compares it to a traffic light, in part because it has three open positions at which other signaling molecules can dock, leading to further signal propagation inside the cell. Much attention has been focused on the 3rd position, the spot on the head of PI, which is dysregulated in most if not all cancers and a common point from which abnormal growth signals are sent in many diseases.

    The unexpected insight for the multidisciplinary team was that the length of the fatty-acid "lamp-post" that supports the traffic light-like head of the PI molecule varied in cells that were cancerous.

    Experiments demonstrated that the PI lamp-posts were normal in some cancers; that they were also of normal length in cells in which p53 was deleted entirely; but that they were consistently shorter, by 2 or 4 carbon atoms, in pancreatic cancer cells from a mouse model in which p53 was mutated. It is possible that other cancer-causing mutations might affect the length as well. This will be explored in future research.

    "What we would like to find out now," says Dr. Trotman, "is whether the p53-induced changes in the PI molecule are important in either making or maintaining the cancer state. If so, then in addition to p53 mutations, there may be other ways for cancer cells to generate the same or related changes. We will be looking for this in tissue samples from cancer patients.”

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