A groundbreaking study from researchers at Tokyo Institute of Science sheds light on how certain tongue cancer (TC) cells resist chemotherapy.
This research emphasizes the critical involvement of autophagy and cholesterol synthesis pathways in developing chemotherapy resistance.
By leveraging an extensive collection of tongue cancer organoids derived from surgical samples, the team conducted detailed comparisons between chemotherapy-sensitive and resistant cells, potentially paving the way for new treatment strategies in tongue cancer.
Prevalence and Challenges of Tongue Cancer
Oral cancers are becoming increasingly prevalent worldwide, with over 300,000 new cases diagnosed annually.
Among these, tongue cancer stands out as the most common type, often carrying a poor prognosis.
Typically, high-risk cases are treated through a combination of surgery and chemoradiotherapy.
However, many patients experience high recurrence rates, largely due to the survival of minimal residual disease (MRD)—the few cells that withstand treatment.
Innovative Research Approach
To improve the outcomes of tongue cancer treatments, understanding how MRD develops is essential.
Researchers often utilize preclinical models like cancer cell lines to test drug effects and investigate the roles of various genes and proteins.
Yet, these models frequently fall short, as they do not fully reflect the complexity of primary tumors, making it challenging to derive meaningful conclusions relevant to different patient profiles.
To overcome these limitations, scientists are exploring more advanced models that better mimic the tumor microenvironment and disease progression.
Recent studies suggest that the mical2 enzyme and pancreatic cancer may share molecular pathways relevant to tumor resistance, highlighting potential targets for therapy.
Integrating such insights into tongue cancer research could lead to more precise and effective treatment strategies.
In light of these challenges, Professor Toshiaki Ohteki and his team took an innovative route by establishing a robust library of tongue cancer organoids (TCOs).
These organoids, created from surgical specimens obtained from 28 patients, aimed to authentically replicate the diversity found in tongue cancer.
Their findings, published in *Developmental Cell*, offer new insights into potential treatment options.
Mechanisms of Chemoresistance
The TCO library included samples from untreated individuals across various ages and stages of disease, effectively mirroring cancer biology within a controlled setting.
Researchers performed comprehensive analyses, including functional, genetic, epigenetic, and histopathological assessments, alongside evaluations of drug sensitivity.
Their results shed new light on the mechanisms underlying chemoresistance and the ensuing development of MRD.
When the team exposed TCOs to cisplatin—a standard chemotherapy drug—they noted that the chemo-resistant organoids entered a dormant phase, akin to embryonic diapause, whereby development is temporarily paused.
Further investigations revealed that the survival of these chemo-resistant TCOs hinged on the activation of autophagy and cholesterol biosynthesis pathways.
By employing specific inhibitors to disrupt these pathways, the team successfully reverted the chemo-resistant TCOs to a state sensitive to chemotherapy.
Interestingly, when they enhanced autophagy in the chemotherapy-sensitive organoids, these cells then exhibited chemoresistance.
Ohteki noted that the comparative analysis of their TCO library has unearthed significant molecular discoveries regarding MRD formation.
These insights could prove invaluable for pinpointing effective drug targets and identifying biomarkers in resistant TC cells, ultimately paving the way for progress in personalized medicine.
Source: ScienceDaily