Abstract 1990: Aberrant cell surface expression of GRP78 in breast cancer cells marks a stem-like population that has increased metastatic potential in vivo

Abstract

Abstract Reliable approaches to identify and target stem-cell mechanisms that mediate aggressive cancer could have great therapeutic value, based on the growing evidence of embryonic signatures in metastatic cancers. However, how to best identify and target stem-like mechanisms aberrantly utilized by cancer cells has been challenging. We harnessed the power of induced pluripotent stem cells (iPSCs) to identify embryonic mechanisms exploited by cancer. A screen comparing the cell surface proteome of iPSCs and breast cancer cells identified GRP78, a heat shock protein that is normally ER-restricted, but has been shown to be aberrantly expressed on the cell surface of several cancers, where it can act as a signaling molecule by poorly understood mechanisms. Although cell surface GRP78 (sGRP78) has emerged as an attractive chemotherapeutic target, understanding how sGRP78 is functioning in cancer has been complicated by the fact that GRP78 can function to regulate a variety of cellular responses, using a diverse array of reported binding partners, which can vary by cell type. Therefore, without insight into the specific GRP78-dependent mechanisms that are responsible for mediating aggressive cancer, it will be difficult to determine how to best target GRP78. We have discovered that (1) sGRP78 is expressed on iPSCs (but not their somatic parental populations) and plays an important role in reprogramming, (2) sGRP78 promotes cellular functions such as proliferation/survival and migration in both stem cells and breast cancer cells (3) overexpression of GRP78 in breast cancer cells leads to an induction of a previously established CD24-/CD44+ 'cancer stem cell' (CSC) population (4) sGRP78+ breast cancer cell populations are enriched for genes involved in stemness and appear to be a subset of previously established CSCs (5) sGRP78+ breast cancer cell populations show a significantly enhanced ability to seed metastatic organ sites in vivo (6) GRP78 interacts with Dermcidin (DCD) at the cell surface of cancer cells and iPSCs, where it is important in regulating stem cell and cancer cell migration and survival/proliferation. These collective findings suggest that sGRP78 marks a stem-like population in breast cancer cells that has increased metastatic potential in vivo, and that sGRP78 and DCD cooperate to regulate key cellular functions important in mediating tumorigenesis. Overall, this work has implications for understanding how cancer cells exploit embryonic-like mechanisms, which could provide novel strategies for chemotherapeutic targeting of aggressive breast cancer cell populations. Citation Format: Tyson W. Lager, Henry C. Conner, Ian H. Guldner, Michael Z. Wu, Yuriko Hishida, Tomoaki Hishida, Sergio Ruiz, Amanda E. Yamasaki, Juan Carlos Izpisua Belmonte, Peter C. Gray, Jonathan A. Kelber, Siyuan Zhang, Athanasia D. Panopoulos. Aberrant cell surface expression of GRP78 in breast cancer cells marks a stem-like population that has increased metastatic potential in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1990.