# Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $414,033

## Abstract

PROJECT SUMMARY/ABSTRACT
Glioblastoma (GBM) is a devastating brain tumor lacking effective treatments. This is largely due to invasion of
GBM cells, which enables escape from resection and drives inevitable recurrence, typically 2 cm from the
location at diagnosis. Progress in developing therapies to combat this process has been slow due to problems
with the cells being studied and the methods of analysis. First, existing studies have failed to recognize that
infiltrating GBM cells extending beyond the tumor edge have evolved a unique adaptive cellular machinery due
to local stressors in their microenvironment. Unfortunately, these cells at the invasive tumor front are often not
the ones sampled in studies analyzing banked tumor tissue, which is typically procured from the readily
accessible central portions of the tumor. Another problem is that most studies of invasiveness have used two-
dimensional (2D) culture systems coated with a thin layer of ECM proteins, which fail to capture the
dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team has
developed intriguing data using site-directed biopsies from GBM and has tissue engineered platforms to study
invasion in vitro. Using site-directed biopsies, we have shown increased GBM cell invasiveness and increased
expression of invasion-promoting integrins and extracellular matrix (ECM) splice variants outside versus inside
enhancing MRI regions. We have also developed patient-derived xenografts (PDXs) from these site-directed
biopsies that exhibit more invasiveness when arising from the tumor edge. Our team also became among the
first to bioengineer 3D hydrogel systems as a discovery platform In GBM. We found that, as CD44-mediated
peritumoral invasion falls, perivascular integrin-based motility increases. Here, we will build upon this intriguing
data by investigating our central hypothesis that as GBM cells exit the tumor core, reciprocal interactions with
the microenvironment drive a targetable transition from peritumoral to perivascular invasion. These goals will
be accomplished through three aims: Aim 1 – Define changes in the tumor microenvironment promoting
invasive change as tumor cells egress away from the central core to the outer edge of GBM; Aim 2 - Refine
bioengineered culture models to replicate the microenvironment of the outer edge of GBM and identify the role
of TAMs in driving invasion in this region; and Aim 3 - Define the role of integrins in the invasiveness of GBM
cells from the outer tumor edge and identify druggable mediators of invasion in this region. To accomplish
these goals, we will use novel PDXs and tissue engineered platforms, along with CRISPRi, single-cell
technology, and site-directed biopsies. Our studies will discover novel mechanisms by which tumor cells and
their microenvironment are altered to drive increased invasiveness as cells migrate away from the tumor core.
This work will challenge conventional thinking by sho...

## Key facts

- **NIH application ID:** 10237253
- **Project number:** 5R01CA227136-04
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Manish Aghi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $414,033
- **Award type:** 5
- **Project period:** 2018-09-17 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10237253

## Citation

> US National Institutes of Health, RePORTER application 10237253, Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems (5R01CA227136-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10237253. Licensed CC0.

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