# Dissecting spatiotemporal heterogeneity of glioblastoma evolution under therapy

> **NIH NIH K99** · UNIVERSITY OF MIAMI SCHOOL OF MEDICINE · 2024 · $163,402

## Abstract

PROJECT SUMMARY:
Glioblastoma (GBM) is an uncurable form of primary brain tumor with extremely poor prognosis. Despite multi-
modal therapy including surgery, irradiation and chemotherapy, all patients experience tumor progression. No
standard of care is established in recurrent or progressive GBM. The identification of a neuronal cellular state of
GBM as a more differentiated state enriched at recurrence and periphery of the tumor provides new insights into
how neuronal activity regulates tumor invasion. Deconvolution of normal cell types from single-cell RNAseq and
bulk tumors revealed that neuronal state of GBM is associated with high infiltration of non-malignant cells. The
intricate synaptic communications between neurons and brain tumor cells are crucial for glioma progression and
resistance to standard therapies, which is supported by ample data from the rapidly emerging field of “cancer
neuroscience”. However, the molecular mechanisms driving enhanced neuronal activity at recurrence remains
to be understood. Dissecting the spatiotemporal dynamics of glioma eco-system during evolution will be
necessary to identify therapeutic vulnerability of recurrent GBM. Here, proteogenomics and single-nuclei
RNAseq profiling of matched primary and recurrent GBM IDH wild-type suggest that the evolutionary transition
from a more proliferative-progenitor towards the neuronal state in GBM is regulated by both genetic and post-
genetic molecular events and potential functional interactions between malignant and non-malignant cells. In
Aim 1, the development of a multiomics-based network diffusion approach will enlighten subnetworks of
proteins/phospho-proteins significantly affected by upstream genetic events driving activation of neuronal
programs during progression. Generation of in silico knock-out networks screen and integrative analysis of
proteomics and pharmacological data of cancer cell lines will prioritize lethal and essential proteins in the
subnetworks to identify potential therapeutic vulnerabilities in neuronal-recurrent GBM. In Aim 2, single-nuclei
and spatial transcriptomics profiling of matched primary and recurrent GBM IDH wild-type will identify the
functional connections between neurodevelopmental tumor cellular states and cell types in tumor
microenvironment. The development of a spatial informed cell–cell communications algorithm and the
reconstruction of intercellular signaling networks will infer the key functional interactions between
neurodevelopmental tumor cellular states and cell types in tumor microenvironment along with the potential effect
of these interactions on downstream regulatory molecular pathways. These studies lay the foundation for my
future research program and will advance the understanding of the molecular mechanisms mediating glioma
connectomes and driving glioma invasion. These studies will advance the neuroscience field through discovery
of targetable pathways and proteins providing therapeutic opportunities f...

## Key facts

- **NIH application ID:** 10785231
- **Project number:** 1K99CA286730-01
- **Recipient organization:** UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
- **Principal Investigator:** Simona Migliozzi
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $163,402
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10785231

## Citation

> US National Institutes of Health, RePORTER application 10785231, Dissecting spatiotemporal heterogeneity of glioblastoma evolution under therapy (1K99CA286730-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10785231. Licensed CC0.

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