Imaging the Unfolded Protein Response in Primary Tumors Reveals Microenvironments with Metabolic Variations that Predict Tumor Growth

Abstract

Cancer cells exist in harsh microenvironments that are governed by various factors, including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect cancer cell survival. While others have previously measured microenvironmental stressors in tumors, it remains difficult to detect the real-time activation of these downstream signaling pathways in primary tumors. In this study, we developed transgenic mice expressing an X-box binding protein 1 (XBP1)-luciferase construct that served as a reporter for endoplasmic reticulum (ER) stress and as a downstream response for the tumor microenvironment. Primary mammary tumors arising in these mice exhibited luciferase activity in vivo. Multiple tumors arising in the same mouse had distinct XBP1-luciferase signatures, reflecting either higher or lower levels of ER stress. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Visualizing distinct signaling pathways in primary tumors reveals unique tumor microenvironments with distinct metabolic signatures that can predict for tumor growth. Cancer Res; 70(1); 78-88.

Heteroclitic XBP1 peptides evoke tumor-specific memory cytotoxic T lymphocytes against breast cancer, colon cancer, and pancreatic cancer cells

“…T-bet and Eomes transcription factors are master regulators of Th1 development and are critical for optimal development of type 1 immune responses (18)(19)(20). In these studies, we evaluated T-bet, Eomes and granzyme B expression within the XBP1-CTL.…”

“…16,17 It has been demonstrated that XBP1 is activated in primary mammary tumors, and that its expression correlates with enhanced tumor growth. 18 In support of a direct role for XBP1 in tumorigenesis, the loss of XBP1 was shown to severely inhibit tumor growth. In addition, transformed cells with XBP1 deficiency were sensitized to hypoxia and underwent apoptosis, implicating XBP1 as a survival factor.…”

Tumor Stress Inside Out: Cell-Extrinsic Effects of the Unfolded Protein Response in Tumor Cells Modulate the Immunological Landscape of the Tumor Microenvironment

“…The GRP protein family, including GRP78, was originally discovered because of its upregulation in response to glucose deprivation (23). In their in vivo model of microenvironment-driven tumor cell ER stress, Spiotto et al (24) demonstrated that XBP-1-luciferase activity in spontaneous mammary tumors significantly increases when tumor-bearing mice are treated with 2-deoxyglucose (a nonmetabolizable glucose analog) and that glucose deprivation of tumor cells ex vivo causes a dramatic increase in XBP1-luciferase expression. Taken together, these findings demonstrate that hypoxia and low glucose are physiologically relevant inducers of ER stress in tumors in vivo.…”

Molecular Mechanisms and Physiological Significance of Organelle Interactions and Cooperation

“…Hypoxia induced in a HIF-1α-independent manner XBP1 expression and activated splicing of its mRNA, resulting in increased levels of XBP1s (RomeroRamirez et al, 2004). XBP1s colocalizes with hypoxia markers in tumors, and loss of XBP1 increases the sensitivity of transformed cells to hypoxia-induced apoptosis and inhibits tumor growth (Wouters and Koritzinsky, 2008;Spiotto et al, 2010).…”