# How the 3D Architecture of the Brain Shapes Cancer Cell Fate Decisions

> **NIH NIH DP2** · DANA-FARBER CANCER INST · 2024 · $1,068,000

## Abstract

Project Summary/Abstract
 In preliminary studies, my colleagues and I used a single cell RNA sequencing to profile gene expression
within individual cells of pediatric brain tumors. My single cell profiles provided the first direct evidence of a
concept long suspected but never directly tested – namely that pediatric brain cancers arise from relatively
uncommitted neural progenitors that become developmentally stalled in a replication-competent state. That
being said, my preliminary observations have a central limitation – namely that scRNAseq destroys information
about spatial relationships: who is next to whom within the tumor and within the brain?
 Why should we care about nearest neighbor relationships between tumor cells and the cellular
components of normal brain? The answer is embedded within an emerging body of data highlighting functional
interactions between tumor and tumor microenvironment. Within brain tumors, cell division, fate choice decisions,
development and survival are regulated by short range interactions between presenter and receiver cell types.
All of these informative cell:cell interactions are erased by conventional genomic profiling methods including
scRNAseq.
 I propose here that combinatorial transcriptional codes identified by scRNAseq can localize cancer stem
cells and cancer cell subtypes in 3D-space within the brain where conventional immunochemical markers fail.
To test this proposal, I will (i) generate combinatorial transcriptional codes unique to the various cancer cells and
tumor-associated normal cells from my existing single cell dataset; (ii) design specific primers for these
combinatorial identifiers and; (iii) visualize cell:cell contacts by performing in situ sequencing on patient-derived
tumor samples and on normal brain tissue samples.
 I will focus on pediatric gliomas, the most common tumor type of childhood. My study plan has two
question-oriented, hypothesis-driven aims and a third goal-oriented aim (with a useful deliverable). Aim one
asks why some cells within high grade gliomas exit the replication competent state to differentiate while others
remain replication competent. Is the developmental cue intrinsic (i.e. a developmental “clock”) or extrinsic (e.g.
a short range ligand:receptor interaction)? Aim two asks why some gliomas invade and others do not. I will use
methodology summarized above to test the hypothesis that malignant or benign phenotypes are an outcome of
differential “addictions” to local mitogenic signals from normal neural cell types. Aim three is to expand my data
sets on glioma into a tumor-wide single cell atlas of normal cell contacts with most major forms of pediatric brain
cancer.

## Key facts

- **NIH application ID:** 11009679
- **Project number:** 4DP2NS127705-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Mariella Gruber Filbin
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,068,000
- **Award type:** 4N
- **Project period:** 2021-09-30 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11009679

## Citation

> US National Institutes of Health, RePORTER application 11009679, How the 3D Architecture of the Brain Shapes Cancer Cell Fate Decisions (4DP2NS127705-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11009679. Licensed CC0.

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