Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth

Cancer cells exist in harsh microenvironments which are governed by various factors including hypoxia and nutrient deprivation. These microenvironmental stressors activate signaling pathways that affect a cancer cell’s 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. Here, 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. We find that primary mammary tumors arising in these mice possessed 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. Primary tumors with undetectable XBP1-luciferase activity gained bioluminescent signal after transplantation indicating that the level of XBP1-luciferase activity reflected unique microenvironments of individual primary tumors. Furthermore, variations in ER stress reflected metabolic and hypoxic differences between tumors. Finally, XBP1-luciferase activity correlated with tumor growth rates. Thus, we can visualize distinct signaling pathways in primary tumors that reflect unique tumor microenvironments, distinct metabolic signatures and may predict for tumor growth.