A research team at the Institute of Science in Tokyo, Japan, has developed a novel library of patient-derived tongue cancer organoids (TCOs) that could help drug developers understand the development of drug resistance in tongue cancer (TC). The organoids could suggest new drugs targeting autophagy and cholesterol synthesis pathways to treat the most common oral cancer, and one that often carries a poor prognosis. Details of the organoid development are published in the journal Developmental Cell.
“Given that a comparative analysis of our unique TCO library provided insights into the molecular basis of (minimal residual disease) 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,” said professor Toshiaki Ohteki from Institute of Science Tokyo, Japan.
There are more than 300,000 new cases of tongue cancer diagnosed each year. The most common treatment strategy for high-risk cases involves surgery followed by chemoradiotherapy. But recurrence rates are high, often due to the presence of a small population of cancer cells that survive these treatments that then go on to reestablish the tumor. Understanding MRD is crucial for developing treatments that prevent relapse and improve survival rates.
To explore the mechanisms behind MRD, the research team turned to an alternative to traditional cancer cell lines: patient-derived organoids. These three-dimensional models can better replicate the biology of a tumor compared to conventional two-dimensional cell cultures. The team created a large-scale library of TCOs from 28 surgery samples from 28 patients with tongue cancer.
The organoids allowed the researchers to examine cancer characteristics and responses to chemotherapy in a more accurate, patient-specific context. They discovered that some organoids displayed resistance to cisplatin, a standard chemotherapy drug used in TC treatment.
One of the most surprising findings was that chemotherapy-resistant TCOs exhibited dormant-like characteristics similar to embryonic diapause, a temporary pause in development that occurs during embryogenesis. This state of dormancy helped the treatment-resistant cancer cells to survive chemotherapy. Further study into why this was happening identified two key biological processes responsible for this resistance: autophagy, a cellular recycling mechanism, and cholesterol biosynthesis.
“We found that inhibiting these pathways with specific inhibitors converted the chemo-resistant TCOs into chemo-sensitive TCOs,” Ohteki said. “Conversely, autophagy activation with appropriate inhibitors conferred chemo-resistance on the chemo-sensitive TCOs.”
The ability to more accurately predict and manipulate treatment-resistance in tongue cancer could eventually lead to more personalized treatment strategies. For instance, the identification of biomarkers that predict which patients will develop MRD could allow doctors to tailor therapies to the individual, potentially reducing recurrence rates and improving survival.
The research also addresses a critical gap in the study of chemotherapy resistance. While previous studies have explored drug-tolerant persister (DTP) cells—quiescent or slow-cycling tumor cells that evade chemotherapy—few have examined how these cells contribute to MRD in a tumor environment. The TCOs enable the researchers to study these phenomena in what is closer to a real-world setting, offering deeper insights into the biology of tongue cancer. Further, the organoids can be an important tool in drug screening to get more accurate readings on the interactions between potential new drugs and mutations in tongue cancer.
“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,” Ohteki concluded.
