# Investigating Microenvironmental Interactions in Leptomeningeal Metastasis

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $410,835

## Abstract

PROJECT SUMMARY
Spread of cancer cells into the spinal fluid, or leptomeningeal metastasis (LM), is an increasingly common
complication of cancer that results in rapid neurologic disability and death. The spinal fluid represents a poor
medium for cell growth: it is hypoxic, with sparse metabolic intermediates, minimal protein, and few growth
factors. Despite this, select cancer cells survive and grow within this space. The mechanisms that underlie cancer
cell growth with the spinal fluid remain poorly understood. The primary objective of the proposed research is to
determine the mechanisms by which breast cancer cells grow within the spinal fluid. Preliminary data from patient
samples and mouse modeling suggest that cancer cells exploit innate immunity to improve their growth in the
spinal fluid. We hypothesize that cancer cell- macrophage interactions alter the cancer cell transcriptome to
enable cancer cells to access limiting substrates for growth such as iron. To address this hypothesis, we propose
to subject iteratively collected spinal fluid samples to multiple orthogonal analyses, including single cell RNA
sequencing, flow cytometry, bulk RNA sequencing and mass spectrometry. Cellular and molecular components
correlating with development of LM will generate a genes of interest list. This list will be curated through gain-of-
function and loss-of-function studies in syngeneic mouse models of LM. These mouse models together with in
vitro growth assays will enable granular dissection of the molecular mechanisms governing cancer cell growth
within the spinal fluid. This approach will enable us to: 1. Address cellular transcriptional adaptations to the low-
iron environment of the spinal fluid; 2. Determine mechanistic consequences of adaptation to this low iron
microenvironment; and 3. Establish cancer cell-macrophage interactions in leptomeningeal metastasis. This
translational approach will improve understanding of the essential steps that govern cancer cell growth within
the spinal fluid in human disease, identifying key mechanistic steps for rational targeting strategies in the future.

## Key facts

- **NIH application ID:** 10248536
- **Project number:** 5R01CA245499-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** ADRIENNE A. BOIRE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $410,835
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10248536

## Citation

> US National Institutes of Health, RePORTER application 10248536, Investigating Microenvironmental Interactions in Leptomeningeal Metastasis (5R01CA245499-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10248536. Licensed CC0.

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