Glioblastomas (GBMs) comprises >50% of all primary brain tumors and are the most malignant type with a 5-year survival rate of only 3.3%, despite standard-of-care (radiation, and temozolomide). Recently it has been shown that the majority of GBM cells do not have the capacity to recapitulate a phenocopy of the original tumor and that it is only a small subpopulation of glioma stem-like cells (GSCs; or tumor initiating cells) in the tumor have that this ability upon xenotransplantation in nude mice. These GSCs are known to be resistant to therapy and are thought to be largely responsive for tumor recurrence and patient death, thus providing a clinically-relevant model to study GBM. GBMs are highly heterogeneous and there is a complex interaction among different subtypes of tumor cells and stromal cells associated with the tumor which can modify the tumor itself as well as its microenvironment to promote tumor growth, invasion, angiogenesis and immune suppression. The transcriptome profiles of GBMs has identified four major subtypes, two of which, proneural (PN) and mesenchymal (MES), predominate. Further, single cell RNA sequencing has revealed that multiple GBM subtypes can reside within the same tumor. GBM with enriched MES properties typically display a more aggressive phenotype both in vitro and in vivo with pronounced radio/chemo resistance.
One aspect our work is to to screen for drugs which can increase therapeutic efficacy for GBM stem cells by either: (1) eradicating these cells; (2) revert GSCs into a more differentiated state which can then response to conventional therapies; (3) sensitizing GSCs to temozolomide; and (4) inhibit PMT in GSCs. We do this using state-of-the-art multiplex secreted bioluminescent reporters which we have developed and optimized for high-throughput screening as well as in vivo imaging to monitor these processes non-invasively.
Another aspect of our work is unravel the role of extracellular vesicles in GBM progression. Tumor cells have an insidious, “Trojan horse”-like mechanism to manipulate other tumor cells or normal cells in their environment using tumor-derived extracellular vesicles (tEVs). These vesicles, which are produced in abundance by tumor cells, contain both a representation and an enriched subset of cellular proteins and RNAs which can subvert the phenotype of recipient cells, including the normal cells in the tumor environs, as well as other tumor cells. While EVs can serve a normal function in cell-to-cell communication and elimination of proteins and RNAs from cells, tEVs effectively “hijack” this process to promote oncogenicity. Our goal is to understand the role of tEV in PMT phenotypic switch and immune suppression using different tEV-specific fluorescent and bioluminescent reporters which we have developed.
Working with our long-time collaborator Dr. Thomas Würdinger, we showed for the first time that blood platelets carry tumor-derived biomarkers and specific gene signatures that can distinguish patients with localized and metastasized tumors from healthy individuals. We called this phenomena tumor-educated platelets or TEP. We are currently evaluating TEP for pan-cancer, multi-class detection as well as biomarker discovery and their potential for longitudinal disease monitoring and response to therapy.