# Role of SerpinB3 in glioblastoma cancer stem cells

> **NIH NIH F30** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $35,135

## Abstract

Project Summary
 ROLE OF SERPINB3 IN GLIOBLASTOMA CANCER STEM CELLS
Glioblastoma (GBM) is the most aggressive primary malignant brain tumor, with a median survival of 18-20
months. Despite therapeutic interventions including surgery, radiation, and chemotherapy, multiple clones of
chemo- and radiotherapy-resistant cells repopulate the tumor, resulting in recurrence and a high rate of patient
mortality. These cells are referred to as cancer stem cells (CSCs) due to their ability to self-renew and generate
the cellular heterogeneity present in the tumor. Our lab identified junctional adhesion molecule-A (JAM-A) on
CSCs and, through functional studies, demonstrated that JAM-A is both necessary and sufficient for self-renewal
and tumor growth. We determined that JAM-A signals via Akt in GBM CSCs to sustain pluripotency transcription
factor activity; however, the intermediate signaling network is yet to be fully elucidated. To further delineate this
pathway, we immunoprecipitated JAM-A from GBM CSCs and performed mass spectrometry to determine the
proteins to which JAM-A directly binds. This analysis led to the identification of the serine/cysteine protease
inhibitor SerpinB3 as a binding partner. Interestingly, SerpinB3 does not contain the conserved PDZ domain that
is present on nearly every other known JAM-A binding partner. Although multiple pro-tumorigenic mechanisms,
including regulation of TGF-β1 and inhibition of apoptosis, have been proposed for SerpinB3 in the context of
other cancers, very little is known about the function of the protein in GBM CSCs, and its relationship to JAM-A
is yet to be elucidated. Using in vitro CSC functional assays, I have accumulated evidence that SerpinB3 is
necessary for the maintenance of CSCs and that reduction of SerpinB3 attenuates TGF-β1 expression. Based
on these observations, I hypothesize that SerpinB3 interaction with JAM-A is essential for the maintenance of
GBM CSCs through regulation of TGF-β1 and inhibition of apoptosis. Aim 1 will test the hypothesis that SerpinB3
maintains the CSC state through inhibition of apoptosis and upregulation of TGF-β1. I will disrupt the lysosomal
membrane with siramesine to elucidate the role of SerpinB3 in the inhibition of apoptosis. Additionally, I will
investigate the role of SerpinB3 in the regulation of TGF-β1 signaling in CSCs. Aim 2 will test the hypothesis that
targeting the JAM-A/SerpinB3 interaction will compromise self-renewal and GBM growth. I will utilize DSSO
crosslinking to determine the region of interaction between the two proteins. Finally, I will determine the
consequence of disrupting the JAM-A/SerpinB3 interaction on the CSC state with small interfering peptides.
Successful completion of this project will advance our understanding of how the CSCs state is maintained in
GBM via specific JAM-A intracellular binding domains, bridging cellular communication and cell signaling. The
studies outlined in this fellowship will provide me an opportunity to g...

## Key facts

- **NIH application ID:** 10877960
- **Project number:** 5F30CA250254-05
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Adam Lauko
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $35,135
- **Award type:** 5
- **Project period:** 2022-07-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10877960

## Citation

> US National Institutes of Health, RePORTER application 10877960, Role of SerpinB3 in glioblastoma cancer stem cells (5F30CA250254-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10877960. Licensed CC0.

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