@article{c4ae53990c954e8da4bce670bf329bfe,
title = "SerpinB3 drives cancer stem cell survival in glioblastoma",
abstract = "Despite therapeutic interventions for glioblastoma (GBM), cancer stem cells (CSCs) drive recurrence. The precise mechanisms underlying CSC resistance, namely inhibition of cell death, are unclear. We built on previous observations that the high cell surface expression of junctional adhesion molecule-A drives CSC maintenance and identified downstream signaling networks, including the cysteine protease inhibitor SerpinB3. Using genetic depletion approaches, we found that SerpinB3 is necessary for CSC maintenance, survival, and tumor growth, as well as CSC pathway activation. Knockdown of SerpinB3 also increased apoptosis and susceptibility to radiation therapy. SerpinB3 was essential to buffer cathepsin L-mediated cell death, which was enhanced with radiation. Finally, we found that SerpinB3 knockdown increased the efficacy of radiation in pre-clinical models. Taken together, our findings identify a GBM CSC-specific survival mechanism involving a cysteine protease inhibitor, SerpinB3, and provide a potential target to improve the efficacy of GBM therapies against therapeutically resistant CSCs.",
keywords = "CP: Cancer, SerpinB3, cancer stem cell, cathepsin L, glioblastoma, lysosomal-mediated cell death",
author = "Adam Lauko and Josephine Volovetz and Turaga, {Soumya M.} and Defne Bayik and Silver, {Daniel J.} and Kelly Mitchell and Mulkearns-Hubert, {Erin E.} and Watson, {Dionysios C.} and Kiran Desai and Manav Midha and Jing Hao and Kathleen McCortney and Alicia Steffens and Ulhas Naik and Ahluwalia, {Manmeet S.} and Shideng Bao and Craig Horbinski and Yu, {Jennifer S.} and Lathia, {Justin D.}",
note = "Funding Information: We thank Drs. William Schiemann, Mark Jackson, and Alex Huang (Case Western Reserve University) for critical feedback and Gary Silverman, Clifford Luke, and Stephanie Markovina (Washington University in St. Louis School of Medicine) for discussions and advice about lysosomal assessments. We thank Ms. Karen Kasler and Dr. Robert Fairchild for their assistance with the Nanostring analysis. We thank Belinda Willard for assistance with the MS and proteomics analysis. We thank Dr. Wei-Xing Zo (Rutgers University) for the SerpinB3 overexpression constructs. We also thank members of the Lathia laboratory, including Katie Troike, Samuel Sprowls, Salma Ben Salem, Kristen Kay, Juyeun Lee, and Sabrina Wang, for insightful discussions, and Sadie Johnson for assistance with mouse work. We thank Ms. Amanda Mendelsohn for illustration assistance. This work is supported by National Institutes of Health (NIH) grants F30CA250254 (to A.L.), T32GM007250 (to A.L.), K99CA248611 (to D.B.), 5T32AI007024 (to D.C.W.), R01 NS117104 (to J.D.L. and C.H.), and R35 NS127083 (to J.D.L.). Work in the Lathia laboratory is also supported by the American Brain Tumor Association, the Case Comprehensive Cancer Center, the Lerner Research Institute, and NIH grants P01 CA245705 and R01 NS109742. Conceptualization, A.L. S.M.T. J.V. and J.D.L.; data analysis, A.L. S.M.T. J.V. D.B. D.J.S. K.M. E.E.M.-H. K.D. M.M. J.H. K.M. A.S. and D.C.W.; project administration, A.L. and J.D.L.; supervision, U.N. S.B. C.H. J.S.Y. and J.D.L.; funding acquisition, A.L. C.H. and J.D.L.; writing – original draft, A.L. E.E.M.-H. and J.D.L.; writing – review & editing, all of the authors. M.S.A. is the recipient of grants/research support from AstraZeneca, Abbvie, Bristol Myers Squibb, Bayer, Incyte, Pharmacyclics, Novocure, and Merck; is a shareholder in Doctible and Mimivax; and has received honoraria or consultation fees from Wiley, Abvvie, Bayer, Elsevier, Forma Therapeutics, Karyopharm Therapeutics, Tocagen, and VBI Vaccines. The remaining authors declare no competing interests. We worked to ensure gender balance in the recruitment of human subjects. We worked to ensure sex balance in the selection of non-human subjects. We worked to ensure diversity in experimental samples through the selection of the cell lines. Funding Information: We thank Drs. William Schiemann, Mark Jackson, and Alex Huang (Case Western Reserve University) for critical feedback and Gary Silverman, Clifford Luke, and Stephanie Markovina (Washington University in St. Louis School of Medicine) for discussions and advice about lysosomal assessments. We thank Ms. Karen Kasler and Dr. Robert Fairchild for their assistance with the Nanostring analysis. We thank Belinda Willard for assistance with the MS and proteomics analysis. We thank Dr. Wei-Xing Zo (Rutgers University) for the SerpinB3 overexpression constructs. We also thank members of the Lathia laboratory, including Katie Troike, Samuel Sprowls, Salma Ben Salem, Kristen Kay, Juyeun Lee, and Sabrina Wang, for insightful discussions, and Sadie Johnson for assistance with mouse work. We thank Ms. Amanda Mendelsohn for illustration assistance. This work is supported by National Institutes of Health (NIH) grants F30CA250254 (to A.L.), T32GM007250 (to A.L.), K99CA248611 (to D.B.), 5T32AI007024 (to D.C.W.), R01 NS117104 (to J.D.L. and C.H.), and R35 NS127083 (to J.D.L.). Work in the Lathia laboratory is also supported by the American Brain Tumor Association , the Case Comprehensive Cancer Center , the Lerner Research Institute , and NIH grants P01 CA245705 and R01 NS109742 . Publisher Copyright: {\textcopyright} 2022 The Author(s)",
year = "2022",
month = sep,
day = "13",
doi = "10.1016/j.celrep.2022.111348",
language = "English (US)",
volume = "40",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "11",
}
