SummaryGlioblastoma (GBM) is the most lethal primary brain cancer that is highly invasive and resistantto current treatments. Cancer invasion and tumor recurrence are universal in GBM patientsdespite maximal therapy. Some treatments such as anti-angiogenic regimens actually transformtumor growth towards a more invasive phenotype. Defining the mechanisms underlying thetherapy-induced cancer invasion and tumor repopulation may help improve GBM treatment.GBMs contain abundant vessels consisting of endothelial cells (ECs) and pericytes. Pericytesplay critical roles in maintaining vascular function and blood-brain (tumor) barriers. We foundthat the majority of vascular pericytes in GBMs are derived from glioma stem cells (GSCs), ahighly plastic cellular subpopulation functionally defined by self-renewal, multipotency and tumorpropagation. Selective targeting of GSC-derived pericytes disrupted tumor vessels and potentlyinhibited tumor growth, indicating that GSC-derived pericytes play crucial roles in supportingvascular structure and function to promote tumor growth. In addition, GSC-derived pericyteswere detected on a subset of vessels in peritumoral brain, suggesting that these neoplasticpericytes have the capacity to migrate into brain tissues. Our recent study using cell lineagetracing demonstrated that GSC-derived pericytes have the potential to de-differentiate intoGSCs that are able to grow tumors. Moreover, GSC-derived pericytes are highly resistant tocurrent 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 GSCsafter therapy. Thus, we hypothesize that GSC-derived pericytes are reserve cancer cells thatcontribute to the therapy-induced cancer invasion and tumor recurrence and targetingthese neoplastic pericytes synergizes with current GBM treatments. We plan to test ourhypothesis by pursuing three specific aims: 1. Determine roles of GSC-derived pericytes in thetherapy-induced cancer invasion and tumor recurrence. 2. Define the molecular mechanismsdriving de-differentiation of GSC-derived pericytes into GSCs. 3. Determine whether targetingGSC-derived pericytes synergizes with current GBM therapies. We will use in vivo cell lineagetracing, selective targeting and other new techniques to elucidate the roles of GSC-derivedpericytes in the therapy-induced cancer progression and evaluate the synergistic impact oftargeting GSC-derived pericytes with current therapies in a preclinical setting. The proposedstudies will lay a solid foundation for the development of effective therapeutics or new treatmentcombinations to significantly improve survival of GBM patients.
|Effective start/end date||7/15/16 → 4/30/21|
- National Institutes of Health: $346,719.00
Neoplastic Stem Cells