Adipocyte-driven unfolded protein response is a shared transcriptomic signature of metastatic prostate carcinoma cells

A critical unknown in the field of skeletal metastases is how Cancer cells find a way to thrive under harsh conditions, as exemplified by metastatic colonization of adipocyte-rich bone marrow by prostate carcinoma cells. To begin understanding molecular processes that enable tumor cells to survive and progress in difficult microenvironments such as bone, we performed unbiased examination of the transcriptome of two different prostate Cancer cell lines in the absence or presence of bone marrow adipocytes. Our RNAseq analyses and subsequent quantitative PCR and protein-based assays reveal that upregulation of endoplasmic reticulum (ER) stress and unfolded protein response (UPR) genes is a shared signature between metastatic prostate carcinoma cell lines of different origin. Pathway analyses and pharmacological examinations highlight the ER chaperone BIP as an upstream coordinator of this transcriptomic signature. Additional patient-based data support our overall conclusion that ER stress and UPR induction are shared, important factors in the response and adaptation of metastatic tumor cells to their micro-environment. Our studies pave the way for additional mechanistic investigations and offer new clues towards effective therapeutic interventions in metastatic disease.