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.

骨骼转移领域的一个关键未知数是癌细胞如何找到在恶劣条件下茁壮成长的方法，例如前列腺癌细胞对富含脂肪细胞的骨髓的转移定植。为了开始了解使肿瘤细胞在骨骼等困难微环境中存活和发展的分子过程，我们在不存在或存在骨髓脂肪细胞的情况下对两种不同前列腺癌细胞系的转录组进行了公正的检查。我们的 RNAseq 分析和随后的定量 PCR 和基于蛋白质的分析表明，内质网 (ER) 应激和未折叠蛋白反应 (UPR) 基因的上调是不同来源的转移性前列腺癌细胞系之间的共同特征。通路分析和药理学检查突出了 ER 伴侣 BIP 作为该转录组特征的上游协调者。其他基于患者的数据支持我们的总体结论，即 ER 应激和 UPR 诱导是共享的，这是转移性肿瘤细胞对其微环境的反应和适应的重要因素。我们的研究为额外的机制研究铺平了道路，并为转移性疾病的有效治疗干预提供了新线索。