Oral cancer is a growing global health concern, with over 300,000 new cases diagnosed annually. Among various types, tongue cancer (TC) stands out as the most common and deadliest form, often marked by high recurrence rates and poor prognoses. Despite the advancements in surgery and chemoradiotherapy, treatment outcomes remain grim due to the persistence of minimal residual disease (MRD)—a few surviving cancer cells that often lead to relapse. In a groundbreaking effort to address this challenge, a research team led by Professor Toshiaki Ohteki at the Institute of Science Tokyo has developed a novel approach using tongue cancer organoids (TCOs) to study MRD and identify new therapeutic targets.

To understand why recurrence is common, researchers have long used cancer cell lines as preclinical models to study cancer behavior and test potential treatments. While these cell lines are convenient for drug testing, they come with significant limitations. Cell lines are difficult to establish from primary cancer tissues and often fail to accurately represent the diversity and complexity of real tumors, making patient-specific comparisons unreliable.

Against this backdrop, Professor Ohteki’s team opted for a more advanced and reliable model: organoids. Unlike conventional cell lines, organoids are three-dimensional tissue models that closely mimic the biological characteristics of tumors. The researchers aimed to use these organoids to gain deeper insights into MRD formation and drug resistance mechanisms in TC.

The research team collected tissue samples from 28 untreated TC patients, representing various ages and stages of the disease. These samples were then used to create a large-scale library of TCOs. According to their paper, published in Developmental Cell on November 5, 2024, this organoid library allowed the team to perform comprehensive analyses, including functional, genetic, epigenetic, and histopathological assessments, alongside drug-sensitivity tests.

“Given that a comparative analysis of our unique TCO library provided insights into the molecular basis of MRD formation, this library may offer an important resource for discovering effective drug targets and biomarkers for chemo-resistant TC cells, thereby helping in the development of personalized medicine,” stated Professor Ohteki.

One of the most significant findings from the study involved the mechanisms by which TC cells develop resistance to chemotherapy. Using cisplatin, a commonly used chemotherapeutic drug, the researchers observed that chemo-resistant organoids exhibited a dormant-like state similar to embryonic diapause—a developmental pause seen in embryos under certain conditions.

Upon further investigation, the team discovered that these chemo-resistant cells survived by activating two key pathways: autophagy, a cellular recycling process, and cholesterol biosynthesis. “Inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs,” noted Ohteki. Conversely, inducing autophagy in chemo-sensitive organoids conferred resistance, underscoring the central role these pathways play in MRD formation.

These findings open up promising avenues for developing new treatment strategies aimed at overcoming drug resistance in TC. By targeting autophagy and cholesterol biosynthesis pathways, it may be possible to prevent MRD formation and improve patient outcomes. The TCO library, with its diverse representation of patient tumors, provides a valuable platform for identifying potential drug targets and biomarkers, paving the way for personalized medicine in oral cancer treatment.

“With any luck, further efforts down this path will lead to more reliable treatment strategies for challenging oral cancers,” added Professor Ohteki.

The study marks a significant milestone for the newly established Institute of Science Tokyo (Science Tokyo), which was formed on October 1, 2024, through the merger of Tokyo Medical and Dental University (TMDU) and Tokyo Institute of Technology (Tokyo Tech). With a mission to advance science and promote human wellbeing, the institute is poised to become a leading hub for cutting-edge research in cancer and other critical health issues.

By leveraging advanced models like organoids and focusing on personalized medicine, the research team at Science Tokyo exemplifies the institute’s commitment to creating value for society through innovative science. Their work not only sheds light on the underlying mechanisms of chemoresistance in TC but also offers hope for more effective and individualized treatments in the near future.