Differentiation stage predicts radiosensitivity in mesenchymal-like pancreatic cancer.

Purpose: To derive a genomic classifier to predict radiosensitivity of pancreatic cancer cell lines and pancreatic cancer patients to allow genomic-guided radiotherapy.

Methods and materials: We collected a comprehensive dataset of full clonogenic cell survival curves of 45 pancreatic cancer cell lines irradiated with clinical photon and proton beams. We derived classifiers based on data from human embryonic and fetal pancreas single-cell RNA-sequencing (scRNA-seq) to distinguish between epithelial and mesenchymal cells and to predict pancreas cell-line differentiation stage. Independent testing was done with an embryonic mouse pancreas scRNA-seq dataset. We then used bulk RNA-seq profiles from the Cancer Cell Line Encyclopedia (CCLE) to classify our pancreatic cancer cell lines using our epithelial-mesenchymal and differentiation stage classifiers. We then correlated the differentiation stage classifier with the radiosensitivity of the pancreatic cancer cell lines as well as with pancreatic cancer patient data from The Cancer Genome Atlas.

Results: We found wide variability in radiosensitivity to both photons and protons among pancreatic cancer cell lines. We showed that the differentiation stage is predictive of radiosensitivity of mesenchymal pancreatic cancer cell lines but not epithelial pancreatic cancer cell lines. We found that chromatin compaction is associated with the differentiation stage and showed that the less differentiated mesenchymal pancreatic cancer cell lines tend to be radioresistant and with more compact chromatin than the radiosensitive differentiated cell lines. Patients with more differentiated tumors exhibit better overall survival.

Conclusions: We found that mesenchymal-like undifferentiated pancreatic cancer cell lines are more radioresistant than mesenchymal-like differentiated ones and that pancreatic cancer patients with mesenchymal-like undifferentiated tumors treated with radiotherapy tend to have lower overall survival compared to patients with mesenchymal-like differentiated tumors. We show that it is feasibility to use the differentiation stage of mesenchymal pancreatic cancer cells to predict tumor specific radiosensitivity.