Glioblastoma (GBM) is the most lethal primary brain cancer that is highly invasive and resistant to current treatments. Cancer invasion and tumor recurrence are universal in GBM patients despite maximal therapy. Some treatments such as anti-angiogenic regimens actually transform tumor growth towards a more invasive phenotype. Defining the mechanisms underlying the therapy-induced cancer invasion and tumor repopulation may help improve GBM treatment. GBMs contain abundant vessels consisting of endothelial cells (ECs) and pericytes. Pericytes play critical roles in maintaining vascular function and blood-brain (tumor) barriers. We found that the majority of vascular pericytes in GBMs are derived from glioma stem cells (GSCs), a highly plastic cellular subpopulation functionally defined by self-renewal, multipotency and tumor propagation. Selective targeting of GSC-derived pericytes disrupted tumor vessels and potently inhibited tumor growth, indicating that GSC-derived pericytes play crucial roles in supporting vascular structure and function to promote tumor growth. In addition, GSC-derived pericytes were detected on a subset of vessels in peritumoral brain, suggesting that these neoplastic pericytes have the capacity to migrate into brain tissues. Our recent study using cell lineage tracing demonstrated that GSC-derived pericytes have the potential to de-differentiate into GSCs that are able to grow tumors. Moreover, GSC-derived pericytes are highly resistant to current treatments, indicating that GSC-derived pericytes may function as a reservoir of tumor- initiating cells to promote cancer invasion and tumor recurrence by de-differentiating into GSCs after therapy. Thus, we hypothesize that GSC-derived pericytes are reserve cancer cells that contribute to the therapy-induced cancer invasion and tumor recurrence and targeting these neoplastic pericytes synergizes with current GBM treatments. We plan to test our hypothesis by pursuing three specific aims: 1. Determine roles of GSC-derived pericytes in the therapy-induced cancer invasion and tumor recurrence. 2. Define the molecular mechanisms driving de-differentiation of GSC-derived pericytes into GSCs. 3. Determine whether targeting GSC-derived pericytes synergizes with current GBM therapies. We will use in vivo cell lineage tracing, selective targeting and other new techniques to elucidate the roles of GSC-derived pericytes in the therapy-induced cancer progression and evaluate the synergistic impact of targeting GSC-derived pericytes with current therapies in a preclinical setting. The proposed studies will lay a solid foundation for the development of effective therapeutics or new treatment combinations to significantly improve survival of GBM patients.
Glioblastoma (GBM) is among the deadliest of all cancers. GBMs are highly invasive and resistant to current therapies. We previously demonstrated that glioma stem cells (GSCs) generate vascular pericytes of tumor vessels. In this proposal, we will define the role of GSC-derived pericytes in cancer invasion and tumor recurrence, and determine whether targeting these tumor pericytes synergizes with current treatments to improve therapeutic efficacy. We expect that the proposed studies will facilitate the development of novel therapeutics or new treatment combinations to effectively improve the survival of GBM patients.
|Man, Jianghong; Yu, Xingjiang; Huang, Haidong et al. (2018) Hypoxic Induction of Vasorin Regulates Notch1 Turnover to Maintain Glioma Stem-like Cells. Cell Stem Cell 22:104-118.e6|
|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|
|Shi, Yu; Ping, Yi-Fang; Zhou, Wenchao et al. (2017) Tumour-associated macrophages secrete pleiotrophin to promote PTPRZ1 signalling in glioblastoma stem cells for tumour growth. Nat Commun 8:15080|
|Zhou, Wenchao; Chen, Cong; Shi, Yu et al. (2017) Targeting Glioma Stem Cell-Derived Pericytes Disrupts the Blood-Tumor Barrier and Improves Chemotherapeutic Efficacy. Cell Stem Cell 21:591-603.e4|
|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|
|Fang, Xiaoguang; Zhou, Wenchao; Wu, Qiulian et al. (2017) Deubiquitinase USP13 maintains glioblastoma stem cells by antagonizing FBXL14-mediated Myc ubiquitination. J Exp Med 214:245-267|
|Shi, Yu; Zhou, Wenchao; Cheng, Lin et al. (2017) Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells. Cell Death Differ 24:167-180|
|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|