Tongue cancer (TC) cells can enter a chemoresistant state by activating pathways related to autophagy and cholesterol synthesis, report researchers from the Tokyo Institute of Science. Using a large-scale library of TC organoids they developed, the researchers performed comprehensive comparative analyzes of chemosensitive and chemoresistant cells. Their efforts shed light on promising avenues toward new treatments for tongue cancer.
Oral cancer is an increasingly prevalent disease worldwide, with more than 300,000 new cases diagnosed each year. Among oral cancers, tongue cancer (TC) is the most common type and often carries a poor prognosis. Surgery combined with chemoradiotherapy is one of the main lines of treatment for high-risk TC cases. However, recurrence rates are high as tumors can reestablish themselves from only a few surviving cells. A few surviving cells are called minimal residual disease (MRD).
Understanding the mechanisms behind MRD formation is critical to improving treatment outcomes in TC and many other forms of cancer. To study it, scientists often rely on cancer cell lines as preclinical models, which serve as a convenient tool for testing drugs and analyzing the functions of genes and proteins. However, cancer cell lines are quite difficult to establish from primary cancer tissues and do not accurately reflect the characteristics of cancer. This makes comparisons of tumor characteristics between patients challenging.
In this context, a research team led by Professor Toshiaki Ohteki from the Tokyo Institute of Science, Japan, took a different approach to shed light on MRE in CT. Instead of trying to establish cancer cell lines, they built a large-scale library of tongue cancer organoids (TCOs) from surgical samples from 28 patients. Organoids are three-dimensional tissue models that mimic organs. As explained in his article, which was published in development cell On November 5, 2024, the team sought to have this library accurately represent the diversity that exists in CT from patient to patient and use it to identify promising treatment avenues.
Organoids allow scientists to replicate cancer biology in a controlled laboratory. The team built the TCO library by obtaining tissue samples from 28 untreated TC patients of different ages and stages of the disease. They used these organoids to perform comprehensive and comparative analyses, including functional, genetic/epigenetic, histopathological characterization, and drug sensitivity testing.
Their experiments revealed new insights into the mechanisms of chemoresistance, specifically MRD formation. By treating OCTs with cisplatin, a key drug in chemotherapy, the researchers found that chemoresistant OCTs displayed a dormancy-like state that resembled embryonic diapause, a temporary pause that sometimes occurs during embryo development.
Digging deeper, the research team discovered that chemoresistant OCTs rely on activation of autophagy (or “internal recycling”) and cholesterol biosynthesis pathways to survive. “Inhibition of these pathways with specific inhibitors converted chemoresistant OCTs into chemosensitive OCTs. In contrast, activation of autophagy with appropriate inhibitors conferred chemoresistance to chemosensitive OCTs,” highlights Ohteki, “since a comparative analysis of our unique La TCO library provided insights into the molecular basis of MRD formation; this library may provide an important resource for discovering effective drug targets and biomarkers for TC cells. chemoresistant, thus helping the development of personalized medicine,” concludes Ohteki.