|Chow, Kin-hoe - The Jackson Laboratory|
|Park, Hee Jung - The Jackson Laboratory|
|George, Joshy - The Jackson Laboratory|
|Yamamoto, Keiko - The Jackson Laboratory|
|Gallup, Andrew - The Jackson Laboratory|
|Graber, Joel - The Jackson Laboratory|
|Chen, Yuanxin - Mayo Clinic|
|Jiang, Wen - University Of Texas|
|Steindler, Dennis - Jean Mayer Human Nutrition Research Center On Aging At Tufts University|
|Neilson, Eric - Northwestern University|
|Kim, Betty - Mayo Clinic|
|Yun, Kyuson - Weill Medical College - Cornell|
Submitted to: Cancer Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/14/2017
Publication Date: 8/4/2017
Citation: Chow, K., Park, H., George, J., Yamamoto, K., Gallup, A.D., Graber, J., Chen, Y., Jiang, W., Steindler, D., Neilson, E.G., Kim, B.G., Yun, K. 2017. S100A4 is a biomarker and regulator of glioma stem cells that is critical for mesenchymal transition in glioblastoma. Cancer Research. https://doi.org/10.1158/0008-5472.CAN-17-1294.
Interpretive Summary: Primary brain cancer, and in particular, a type of glioma referred to as glioblastoma ("GBM"), remains a difficult to treat disease because of cellular and patient disease heterogeneity. Even though we are beginning to amass a significant amount of data on the genetic, molecular and cellular biology of GBM, there is still a great deal we do not know about the tumor-initiating cells in this disease. With such information at hand, it is anticipated that existing and emerging (e.g. biological and immunotherapies) standard of care therapies will benefit from concurrent integrated medicine approaches including personalized and precision diet and nutrient therapies. This study was conducted in order to relate a well-known marker of astrocyte glial cells in the brain, S100A4, to glioma stem-like cells that are implicated in GBM tumorigenesis. Looking at animal models of glioma, we found that this marker is associated with brain cancer stem cell proliferation and fate choice whereby it plays a role in both cancer cell fate choice and migration: two events involved in dissemination and progression of disease that together contribute to resistance to current therapies.
Technical Abstract: Glioma stem cells (GSCs) and epithelial-mesenchymal transition (EMT) are strongly associated with therapy resistance and tumor recurrence, but the underlying mechanisms are incompletely understood. Here we show that S100A4 is a novel biomarker of GSCs. S100A4+ cells in gliomas are enriched with cancer cells that have tumor-initiating and sphere-forming abilities, with the majority located in perivascular niches where GSCs are found. Selective ablation of S100A4-expressing cells was sufficient to block tumor growth in vitro and in vivo. We also identified S100A4 as a critical regulator of GSC self-renewal in mouse and patient-derived glioma tumorspheres. In contrast to previous reports of S100A4 as a reporter of EMT, we discovered that S100A4 is an upstream regulator of the master EMT regulators SNAIL2 and ZEB along with other mesenchymal transition regulators in glioblastoma. Overall, our results establish S100A4 as a central node in a molecular network that controls stemness and EMT in glioblastoma, suggesting S100A4 as a candidate therapeutic target.