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Novel Therapeutic Target Identified Through Phage Display in Glioma Stem Cells

Review of "Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation" from STEM CELLS by Stuart P. Atkinson

The presence of glioma stem cells (GSCs) in glioblastoma, a prevalent malignant intrinsic brain tumor with poor prognosis [1] and few effective treatments [2], has been linked to resistance to chemotherapy/radiation therapy and an increase in invasiveness, angiogenesis, and immunosuppression [3]. The application of phage display as a screening strategy [4] aims to uncover novel molecular targets/pathways in GSCs that may aid a deeper understanding of disease progression and perhaps provide a target for novel treatment options.

Researchers led by James K. C. Liu (H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL) and Jeremy N. Rich (UC San Diego, University of California, San Diego, La Jolla, CA, USA) previously described VAV3 as a novel molecular target in GSCs using an in vivo phage display biopanning strategy [5]. In their most recent research, the results of which have been recently reported in STEM CELLS [6], the authors again took advantage of phage display to highlight the EYA1 (Eyes Absent 1)‐MYC axis as a potential therapeutic target for glioblastoma treatment.

In this exciting new study, Kim et al. began by employing orthogonal in vitro (GSCs) and in vivo (intracranially xenografted glioma tumors) phage display biopanning strategies using a combination of negative and positive selection steps to isolate a GSC-specific targeting peptide (AWEFYFP). Subsequent in silico analysis of this peptide via protein BLAST matching led to the identification of the tyrosine phosphatase and transcriptional coactivator EYA1 as a GSC‐specific factor. Notably, the AWEFYFP peptide matched with the N‐terminal domain of EYA1, which harbors a transcriptional coactivator component [7]. Excitingly, the authors demonstrated the preferential expression of EYA1 in GSCs, but not differentiated tumor progeny, thereby confirming the results from the phage display.

Finally, the team discovered a discovered evidence that EYA1 may maintain GSCs through MYC, a central mediator of GSC maintenance; indeed, EYA1 knockdown led to a decrease in Myc expression and GSC proliferation, migration, and self‐renewal in vitro and the inhibition of tumor growth in vivo, thereby underscoring the potential importance of this interaction in the treatment of glioblastoma patients. The authors also note that EYA1 locates to the perivascular niche, suggesting that it may promote tumor angiogenesis.

Overall, this exciting new study underscores the application of phage display in identifying novel cell-specific factors and highlights the EYA1‐MYC axis in GSCs as a new target for the development of anti-glioblastoma therapeutics.

For more on phage display, glioma stem cells, and novel glioblastoma treatments, stay tuned to the Stem Cells Portal!

References

  1. Omuro A and DeAngelis LM, Glioblastoma and Other Malignant Gliomas: A Clinical Review. JAMA 2013;310:1842-1850.
  2. Stupp R, Lukas RV, and Hegi ME, Improving survival in molecularly selected glioblastoma. The Lancet 2019;393:615-617.
  3. Pointer KB, Clark PA, Zorniak M, et al., Glioblastoma cancer stem cells: Biomarker and therapeutic advances. Neurochemistry International 2014;71:1-7.
  4. Smith GP, Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 1985;228:1315.
  5. Liu JK, Lubelski D, Schonberg DL, et al., Phage display discovery of novel molecular targets in glioblastoma-initiating cells. Cell Death & Differentiation 2014;21:1325-1339.
  6. Kim J, She C, Potez M, et al., Phage display targeting identifies EYA1 as a regulator of glioblastoma stem cell maintenance and proliferation. STEM CELLS 2021;39:853-865.
  7. Rayapureddi JP, Kattamuri C, Steinmetz BD, et al., Eyes absent represents a class of protein tyrosine phosphatases. Nature 2003;426:295-298.