Glioblastomas are the most common primary brain tumor and the most lethal. Current glioblastoma therapy provides only palliation and these cancers are universally fatal. Although the concept of a tumor cell hierarchy remains controversial, increasing evidence supports the notion that subgroups of stem-like cancer cells contribute to tumor growth. These cancer stem cells stimulate the malignancy of tumor growth through preferential resistance to conventional therapies, stimulation of angiogenesis, and invasion into normal tissues. A central unexplained observation in the cancer stem cell hypothesis is the reestablishment of a cellular hierarchy despite growth advantages of the stem-like cells. Cancer stem cells express pro-differentiation factors, including bone morphogenetic proteins, which may promote the maintenance of differentiated tumor cells that provide signals in support of the cancer stem cells (e.g. Notch ligands, interleukin-6, and laminins). To determine potential microenvironmental interactions that maintain the cellular hierarchy, we interrogated secreted regulators of cellular differentiation that are associated with the cellular hierarchy. We find that glioblastoma stem cells express secreted antagonists of differentiation signals to maintain their growth. Further, forced expression of these molecules in non-stem tumor cells promotes stem-like features. The simultaneous expression of differentiating signals and their inhibitors may create tissue patterning with stem-like and differentiated populations, phenocopying development. As there is an association between expression of anti-differentiation signals and poor glioblastoma patient outcome, we hypothesize that targeting secreted inhibitors of microenvironmental differentiation cues may offer potential therapeutic benefit. The tumor microenvironment provides instructive cues to maintain the cellular hierarchy in both normal and neoplastic tissues;we are therefore developing a set of techniques to interrogate the cellular hierarchy in relevant microenvironments while representing appropriate molecular tumor phenotypes. Overall, this study will examine in vivo response of tumor cells to environmental influences such as bone morphogenic protein antagonists on the self-renewal and maintenance of stem cell-like tumor cells within their niche. Successful execution of this collaborative scientific endeavor promises to bring important new scientific insights into cancer biology, and may have profound implications for glioblastoma treatment paradigms.

Public Health Relevance

Glioblastoma is one of the most lethal of all human cancers with a need to develop novel therapies that disrupt mechanisms that maintain tumor growth. These tumors contain cells similar to normal stem cells that display resistance to current treatments. In the proposed studies, we will investigate the interaction between signals that stimulate differentiation and those that protect cells from differentiation that may contribute to these stem-like cancer cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA171652-01A1
Application #
8786649
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Snyderwine, Elizabeth G
Project Start
2014-08-15
Project End
2019-07-31
Budget Start
2014-08-15
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$420,976
Indirect Cost
$155,376
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Mack, Stephen C; Pajtler, Kristian W; Chavez, Lukas et al. (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101-105
Wang, Xiuxing; Prager, Briana C; Wu, Qiulian et al. (2018) Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression. Cell Stem Cell 22:514-528.e5
Wang, Xiuxing; Yang, Kailin; Xie, Qi et al. (2017) Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nat Neurosci 20:661-673
Wang, Xiuxing; Huang, Zhi; Wu, Qiulian et al. (2017) MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. Cancer Res 77:4947-4960
Miller, Tyler E; Liau, Brian B; Wallace, Lisa C et al. (2017) Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 547:355-359
Jin, Xun; Kim, Leo J Y; Wu, Qiulian et al. (2017) Targeting glioma stem cells through combined BMI1 and EZH2 inhibition. Nat Med 23:1352-1361
Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D et al. (2017) Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 214:2843-2857
Xie, Qi; Wu, Qiulian; Kim, Leo et al. (2016) RBPJ maintains brain tumor-initiating cells through CDK9-mediated transcriptional elongation. J Clin Invest 126:2757-72
Alvarado, Alvaro G; Turaga, Soumya M; Sathyan, Pratheesh et al. (2016) Coordination of self-renewal in glioblastoma by integration of adhesion and microRNA signaling. Neuro Oncol 18:656-66
Dermawan, Josephine Kam Tai; Hitomi, Masahiro; Silver, Daniel J et al. (2016) Pharmacological Targeting of the Histone Chaperone Complex FACT Preferentially Eliminates Glioblastoma Stem Cells and Prolongs Survival in Preclinical Models. Cancer Res 76:2432-42

Showing the most recent 10 out of 23 publications