Differentiation Stage Predicts Radiosensitivity in Mesenchymal-Like Pancreatic Cancer.

Area of Science:

• Genomics
• Radiation Oncology
• Cancer Biology

Background:

• Pancreatic cancer exhibits variable radiosensitivity.
• Predicting treatment response is crucial for effective radiation therapy.

Purpose of the Study:

• Develop a genomic classifier to predict pancreatic cancer radiosensitivity.
• Enable genomic-guided radiation therapy for pancreatic cancer patients.

Main Methods:

• Analyzed clonogenic survival curves of 45 pancreatic cancer cell lines.
• Derived epithelial-mesenchymal and differentiation stage classifiers using single-cell RNA-sequencing.
• Correlated differentiation stage with radiosensitivity in cell lines and patient data (The Cancer Genome Atlas).

Main Results:

• Radiosensitivity varied widely among cell lines to photon and proton beams.
• Differentiation stage predicted radiosensitivity in mesenchymal, but not epithelial, cell lines.
• Undifferentiated mesenchymal cells were radioresistant with compact chromatin; differentiated cells were radiosensitive.
• More differentiated tumors correlated with better patient survival.

Conclusions:

• Mesenchymal-like undifferentiated pancreatic cancer cells are more radioresistant than differentiated ones.
• Patients with undifferentiated tumors treated with radiation therapy had lower overall survival.
• Differentiation stage is a feasible predictor of tumor-specific radiosensitivity in mesenchymal pancreatic cancer.