Abstract 994: Integrated embryonic transcriptome analyses identify key melanoma metastasis regulator
Authors: Mishra Pravin J. , Guo Theresa , Zaidi Raza , Davis Sean , Michalowski Aleksandra , Michael Helen , Reinhold William , Arnheiter Heinz , Meltzer Paul , Merlino Glenn 
Published: May 2015

The enhanced ability of melanoma cells to metastasize is reminiscent of the innate propensity of melanoblasts to migrate to distant sites during embryonic development - from the neural crest to their eventual niche in the skin. Once transformed, melanoma cells mimic migratory and growth capabilities similar to those of embryonic melanoblasts. This putative relationship between tumorigenesis and developmental processes was first suggested by Rudolf Virchow more than 150 years ago. While this theory is largely unproven, there are mechanistic links between the processes regulating development and malignancy. Here we investigate this age-old puzzle using a mouse model with melanocyte-specific GFP expression to capture and sequence embryonic melanoblasts. We have, for the first time, isolated and sequenced the transcriptomes of murine embryonic melanoblasts at several key representative developmental stages. To uncover the overall classes of gene expression and to identify and characterize genesets whose expression is common and equally important to melanomagenic and developmental processes, a heat-map of the top 1000 most variable developmental genes was generated, and then shortlisted based on compared levels of expression in human and mouse metastatic melanomas, and on the relationship with melanoma patient survival data. By integrating bioinformatics and functional data we have devised a new cross-species multi-dimensional embryonic-onco-genomics analyses (MEGA) approach and show that late stage melanomas reactivate genes used during embryonic development to achieve a more aggressive metastatic phenotype (which we refer to as metafetal genes). One such identified gene, a KDEL (Lys-Asp-Glu-Leu) endoplasmic reticulum (ER) protein retention receptor (KDELR) family member, was expressed in advanced mouse melanomas relative to normal skin or benign nevi. We confirmed this in human melanoma by showing that this metafetal gene was expressed at high levels in metastatic patient samples relative to benign lesions, and also predicted patient survival. Next, we determined the consequences of RNAi-based knockdown on experimental metastasis in mouse models. We validated the functional significance in human and mouse melanomas by showing that this KDELR plays a key role in melanoma metastasis through adaptation to chronic ER stress for survival by modulating the unfolded protein response (UPR), which can be targeted. We anticipate that this approach will identify a variety of key hardwired pathways associated with melanocyte development that can be co-opted by opportunistic metastatic melanoma cells. This approach also offers a novel perspective on melanoma therapeutics and intervention and offers both mechanistic as well as prognostic insights into our understanding of this fatal disease.

Citation Format: Pravin J. Mishra, Theresa Guo, Raza Zaidi, Sean Davis, Aleksandra Michalowski, Helen Michael, William Reinhold, Heinz Arnheiter, Paul Meltzer, Glenn Merlino. Integrated embryonic transcriptome analyses identify key melanoma metastasis regulator. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 994. doi:10.1158/1538-7445.AM2014-994