# Single-cell dissection of cellular programs driving diffuse glioma evolution

> **NIH NIH K99** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $106,216

## Abstract

PROJECT SUMMARY / ABSTRACT
Research Plan: Diffuse glioma is currently incurable. Despite maximal treatment, the disease invariably relapses
due, in part, to its ability to evolve. Thus, an important barrier to curative glioma treatment is the plasticity of
malignant cells. Recent studies have shown that intra-tumoral heterogeneity fuels glioma evolution. Glioma
progression relies on cancer stem cells (CSCs). These cells represent the tumor re-populating force and
reconstitute the diverse hierarchy of cells composing the bulk of the tumor. In addition, CSCs may be more
resistant to existing anti-cancer therapies. Nevertheless, glioma cellular phenotype and its fitness for selection
result from both genetic and epigenetic alterations. Therefore, a major challenge in the study of glioma evolution
is to integrate genetic and epigenetic heterogeneity. To overcome this challenge, we developed novel multi-
modality single-cell sequencing technologies that enable direct integration across genetic, epigenetic, and
transcriptional dimensions of cell-to-cell variation. By leveraging this innovative single-cell genomics toolkit, I will
tackle the integration of genetic, epigenetic, and phenotypic heterogeneity across glioma primary clinical samples
to systematically dissect drivers of cellular states that underlie glioma differentiation and evolution. First, relying
on the ability to jointly genotype and transcriptionally profile thousands of glioma cells, I will define how cellular
states (e.g., CSCs vs. more differentiated cells) impact the transcriptional output of subclonal mutations (Aim 1).
Second, to test the hypothesis that epigenetic diversification significantly contributes to phenotypic diversity of
gliomas, I will assess the role of dysregulation of epigenetic mechanisms in transcriptional programs of gliomas,
and identify regulators (e.g., transcription and chromatin-modifying factors) likely to drive CSCs towards defined
malignant cellular states by performing CRISPR knock-out experiments in glioma cells (Aim 2). Third, leveraging
single-cell phylogenetic inferences and mathematical modeling of glioma plasticity, I will link differentiation
hierarchies and cellular plasticity with lineage histories of glioma cells, defining plasticity in cell-state identity and
its relation to genotype and epigenotype. These data will address the central question of the directionality of
glioma differentiation (i.e., how likely are differentiated glioma cells to revert to CSCs), validated through
experimental differentiation assays (Aim 3). There are no therapeutic strategies currently available to curb the
evolutionary adaptation of glioma. Thus, these studies may pave the way for the future design of novel and
improved therapeutic strategies aimed at targeting a specific glioma cellular phenotype.
Career Development Plan: I have outlined a 5-year career development plan to meet my goal of becoming an
independent investigator in cancer biology. I have assemble...

## Key facts

- **NIH application ID:** 9953558
- **Project number:** 1K99CA248955-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Federico Gaiti
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $106,216
- **Award type:** 1
- **Project period:** 2020-05-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9953558

## Citation

> US National Institutes of Health, RePORTER application 9953558, Single-cell dissection of cellular programs driving diffuse glioma evolution (1K99CA248955-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9953558. Licensed CC0.

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