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  • Cancer Metastasis: A Deep Dive into Cellular Plasticity

    Cancer's lethal spread, or metastasis, is responsible for approximately 90% of cancer-related deaths. This process is facilitated by cancer cells' remarkable ability to hijack and utilize various genetic programs, some of which are typically reserved for early human development stages. Researchers at Memorial Sloan Kettering Cancer Center (MSK) are at the forefront of investigating this phenomenon, utilizing cutting-edge single-cell sequencing and computational tools to understand the complexities of cancer cell adaptation.

    The Mechanism of Plasticity in Cancer
    Dr. Dana Pe’er, Chair of the Computational and Systems Biology Program at MSK, shared promising insights into this process in a plenary presentation at the 2024 American Association for Cancer Research (AACR) Annual Meeting. "It’s not genetic mutations that are critical here, but the ability to access gene programs that normally are associated with other cell types," Pe’er explained. This capability, referred to as 'plasticity,' allows cancer cells to exploit existing gene programs for malignant purposes, a phenomenon that is important for metastasis.

    Colorectal and Pancreatic Cancer Studies
    Pe’er's team, in collaboration with MSK physician-scientist Karuna Ganesh, M.D., Ph.D., conducted a study on advanced colorectal cancer, highlighting significant differences in gene programs between primary and metastatic tumors. After analyzing samples from 31 patients and employing organoid technology to mimic human tissue, the research demonstrated that metastatic tumors often abandon their original cellular characteristics in favor of more versatile identities, enhancing their survival in new environments.

    A separate study focused on pancreatic cancer metastases from a patient who participated in MSK's Last Wish Program. This research highlighted the adaptability of cancer cell clones to various body environments, thanks to their ability to switch between different gene programs. Such plasticity enables these cells to thrive in diverse organs, demonstrating the environment's pivotal role in dictating advantageous cancer cell traits.

    Turning Plasticity Against Cancer
    A promising aspect of Pe’er's research involves focusing on the concept of plasticity to combat cancer. In collaboration with neuro-oncologist Adrienne Boire, M.D., Ph.D., the team discovered a way to challenge cancer cells' survival strategies in the leptomeningeal metastasis context. A clinical trial is currently underway for the drug deferoxamine, showing promising early results by targeting the unique biology of cancer cells that enables them to monopolize iron resources.

    Future Treatment
    These studies exemplify the potential of targeting cellular plasticity to develop novel cancer therapies. Pe’er emphasized MSK's unique position in advancing this field, thanks to its integration of laboratory and clinical research, access to advanced sequencing technologies, and a wealth of patient samples.

    “Not every cancer center would see enough patients with leptomeningeal metastasis to set up a clinical trial like this,” Pe’er stated. “Or have someone like Dr. Boire, who not only cares for patients with metastasis to the central nervous system but who also runs a lab dedicated to studying the underlying molecular mechanisms.”



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