Imaging the unfolded protein response in primary tumors reveals microenvironments with metabolic variations that predict tumor growth.
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.
Spiotto
Michael T
MT
Department of Radiation Oncology, Stanford University, Stanford, California 94305-5152, USA.
Banh
Alice
A
Papandreou
Ioanna
I
Cao
Hongbin
H
Galvez
Michael G
MG
Gurtner
Geoffrey C
GC
Denko
Nicholas C
NC
Le
Quynh Thu
QT
Koong
Albert C
AC
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D000071701:Regulatory Factor X Transcription Factors; D015398:Signal Transduction / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D056811:Unfolded Protein Response / Q000502:physiology*; D000071717:X-Box Binding Protein 1
D004268:DNA-Binding Proteins; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse