# Non-cell autonomous consequences of cytoplasmic DNA

> **NIH NIH F31** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $39,711

## Abstract

PROJECT SUMMARY/ABSTRACT
Genomic instability is a hallmark of cancer and can drive high rates of chromosome segregation errors during
mitotic cell division, which can generate abnormal structures called micronuclei that entrap mis-segregated
chromosomes. Micronuclei are susceptible to massive DNA damage, triggering the catastrophic pulverization of
the entrapped chromosome into small DNA fragments, a process termed chromothripsis. In addition to
generating genomic rearrangements that drive cancer development, DNA fragments from micronuclei can also
mis-accumulate and persist in the cytoplasm. These cytoplasmic DNAs are detected by the cytosolic DNA sensor
cGAS, resulting in the cell-autonomous activation of the STING pathway to trigger an innate immune response.
Although the cGAS-STING signaling mechanisms are well defined, the fate of cytoplasmic DNAs following
recognition by cGAS remains a critical knowledge gap. Here I propose to investigate non-cell autonomous roles
of cytoplasmic DNAs, which hold critical implications in how genomically unstable cancer cells can elicit inter-
cellular responses with the tumor microenvironment. I hypothesize that cytoplasmic DNAs derived from
fragmented chromosomes in micronuclei become exported for uptake by neighboring cells. To test this
hypothesis, I will leverage an experimental system enabling chromosome-specific induction of micronuclei and
cytoplasmic DNA followed by tracking of specific cytoplasmic DNA fragments that harbor a selectable marker.
In Aim 1, I will determine whether and how cytoplasmic DNAs are released into the extracellular environment to
facilitate non-cell autonomous activation of the cGAS-STING pathway in adjacent cells. I will further determine
whether extracellular DNA derived from the cytoplasm of host cells can be taken up by recipient cells, which will
be monitored by live-cell imaging using a dCas9-based cytoplasmic DNA reporter. In Aim 2, I will track the
incorporation of cytoplasmic DNAs into recipient cell nuclei and determine whether these fragments can integrate
into the host genome. This will be studied using a combination of cytogenetics and whole-genome sequencing
to investigate the possibility of lateral DNA transfer between human cells. Despite occurring frequently in
bacteria, inter-cellular DNA transfer has been a longstanding challenge to test in the context of human cancer.
These studies have potential for broad impact by advancing our understanding of cancer cell interactions,
including the transfer of oncogenes and/or mutations from chromosomally unstable cancer cells to non-cancer
cells in the tumor microenvironment.

## Key facts

- **NIH application ID:** 10906019
- **Project number:** 5F31CA284510-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Elizabeth Maurais
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $39,711
- **Award type:** 5
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906019

## Citation

> US National Institutes of Health, RePORTER application 10906019, Non-cell autonomous consequences of cytoplasmic DNA (5F31CA284510-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906019. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*