Abstract 1932: Parallel functions of the endoplasmic reticulum chaperone protein GRP78 in tumorigenesis and the induction of pluripotency
Authors: Panopoulos Athanasia D. , Hishida Yuriko , Wu Min-Zu , Ruiz Sergio , Batchelder Erika , Hishida Tomoaki , Kelber Jonathan A. , Gray Peter C. , Belmonte Juan Carlos Izpisua 
Published: May 2015

Abstract
Increasing evidence supports the concept that instances of cancer recurrence may be due to a subpopulation of cells within a tumor that behave as stem cells. Previous studies have demonstrated that pathways critical in oncogenesis parallel those necessary for the induction of pluripotency, suggesting that similar mechanisms regulate both processes. By therefore understanding the mechanisms that govern reprogramming, we may gain insight into the methods by which cancer cells acquire and exploit stem cell properties, and enable more strategic targeting of these cell populations to prevent malignant relapse. Members of the TGF-beta superfamily (e.g. activin/Nodal), which regulate many important normal cellular responses including cell growth and differentiation, have also been shown to promote tumorigenesis. Cripto, a regulator of TGF-beta superfamily ligand signaling expressed on human embryonic stem cells, is overexpressed in many types of cancer, and has also been shown to promote tumor growth and metastasis. Previous work has demonstrated that Cripto regulates TGF-beta function in tumor cell lines by forming a complex with GRP78, a protein generally restricted to the endoplasmic reticulum in normal tissues, but expressed at the cell surface in many types of tumors. Targeting GRP78 in mouse models suppresses tumor growth, and cell surface GRP78 has been shown to be a molecular target on human tumor samples. Although these studies have suggested an important role for GRP78 in promoting tumorigenesis, the mechanisms are not yet fully understood. We have discovered that GRP78 expression is induced during reprogramming, and becomes localized to the cell surface in pluripotent cells, where it co-localizes with Cripto. Overexpression of GRP78 in somatic cells induced their reprogramming efficiency. We further found that a GRP78 antibody, that disrupts cell surface GRP78/Cripto binding and Cripto-mediated TGF-beta superfamily signaling, inhibited reprogramming. Treatment of pluripotent stem cell populations with this GRP78 antibody also decreased proliferation, but did not impact pluripotency. These combined findings suggest that GRP78 may be localized to the cell surface during reprogramming where it functions to inhibit TGF-beta signaling and promote stem cell proliferation and/or survival. Interestingly, overexpression of GRP78 in human breast cancer cell lines caused an increased resistance to cisplatin. Furthermore, inhibiting cell surface function of GRP78 in these breast cancer lines resulted in a higher susceptibility to cisplatin treatment, demonstrating a specific function for cell surface GRP78 in cisplatin resistance. These combined stem cell functions of GRP78 therefore parallel many of the functions of GRP78 for cancer cells, and thus provide insight into understanding how cancer cells acquire and exploit stem cell properties.
Citation Format: Athanasia D. Panopoulos, Yuriko Hishida, Min-Zu Wu, Sergio Ruiz, Erika Batchelder, Tomoaki Hishida, Jonathan A. Kelber, Peter C. Gray, Juan Carlos Izpisua Belmonte. Parallel functions of the endoplasmic reticulum chaperone protein GRP78 in tumorigenesis and the induction of pluripotency. [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 1932. doi:10.1158/1538-7445.AM2014-1932