Researchers from the Institute of Science Tokyo have found that tongue cancer (TC) cells can enter a state resistant to chemotherapy by activating pathways linked to autophagy and cholesterol synthesis. By creating a large library of TC organoids, they conducted thorough analyses comparing chemotherapy-sensitive and resistant cells, revealing new potential treatment strategies for tongue cancer.
Oral cancer is becoming increasingly common globally, with over 300,000 new diagnoses each year. Among these, tongue cancer (TC) is the most frequently occurring type and is often associated with a poor prognosis. For high-risk TC cases, surgery combined with chemoradiotherapy is a primary treatment option. However, the likelihood of recurrence is significant, as tumors can regenerate from a small number of surviving cells, termed minimal residual disease (MRD).
Gaining insight into how MRD occurs is crucial for enhancing treatment efficacy in TC and various other cancers. To investigate this, scientists typically use cancer cell lines as preclinical models, which are helpful for testing drugs and analyzing gene and protein functions. However, establishing these cell lines from primary cancer tissues is often challenging, and they may not accurately replicate cancer characteristics, making it hard to compare tumor traits across patients.
In light of this, a research group led by Professor Toshiaki Ohteki from Institute of Science Tokyo took a novel approach to investigate MRD in TC. Instead of developing cancer cell lines, they created a comprehensive library of tongue cancer organoids (TCOs) derived from surgical samples of 28 patients. Organoids are three-dimensional models that imitate the biology of organs. Their study, published in Developmental Cell on November 5, 2024, aimed to ensure that this library would reflect the diversity found in TC among patients and utilize it for discovering new treatment options.
These organoids enable researchers to closely replicate cancer biology in a controlled laboratory environment. The team developed the TCO library using tissue samples from 28 untreated TC patients of varying ages and disease stages. They employed these organoids to conduct extensive and comparative analyses, including functional, genetic/epigenetic, histopathological characterizations, and drug-sensitivity evaluations.
Through their experiments, the researchers gained significant insights into the mechanisms driving chemoresistance, particularly concerning MRD formation. When they treated the TCOs with cisplatin, a key chemotherapy drug, it was observed that the chemotherapy-resistant organoids displayed a dormant-like state akin to embryonic diapause—a temporary cessation in embryo development.
Delving deeper, the research team discovered that chemo-resistant TCOs depend on the activation of autophagy (internal recycling) and cholesterol biosynthesis pathways for their survival. Professor Ohteki pointed out, “By inhibiting these pathways with specific inhibitors, we were able to transform chemo-resistant TCOs into chemo-sensitive ones. Conversely, enhancing autophagy with appropriate inhibitors made the chemo-sensitive TCOs resistant to chemotherapy.” He concluded, “As our unique TCO library provided deeper insights into the molecular foundation of MRD formation, it holds significant potential as a resource for identifying effective drug targets and biomarkers for chemotherapy-resistant TC cells, aiding in the development of personalized treatment strategies.”