# Killing dormant tumor cells:  the role of autopagy

> **NIH NIH R03** · OHIO STATE UNIVERSITY · 2022 · $78,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Cancer patients are treated for a primary tumor typically by surgery followed by therapies to attempt to eradicate
all cancer cells. Unfortunately, in some cases, cancer cells leave the primary tumor, starting even before it has
been detected, and mobilize to other parts of the body including the bone marrow. These disseminated tumor
cells (DTCs) cause no evidence of disease and evade therapies targeting active cancer. DTCs can remain
dormant for months, years, or even decades, but if reactivated, they proliferate and cause metastatic tumors,
which are the major cause of cancer mortality. Autophagy is thought to be a survival mechanism used by DTCs
to manage stress in the foreign site. The goal of this project is to define autophagy pathways in dormant
tumor cells—knowledge that is essential if autophagy is to be pursued as a vulnerability to specifically
target DTCs and eradicate residual disease. Here a new Drosophila tumor model of dormancy will be
analyzed. In the tumor model, proliferation is regulated by inducible expression of oncogenic-Ras so that when
Ras expression is turned off, the cells rapidly arrest growth and become dormant. Importantly, the dormant fly
cells conserve cardinal features with mammalian DTCs that include stress signaling and autophagy. Preliminary
data show that when conventional autophagy is blocked, cells survive dormancy and remain autophagic
revealing the existence of an additional autophagy pathway. In Aim 1, the hypothesis that tumor cells
deficient in conventional (Atg5-mediated) autophagy survive dormancy by alternative (Rab9-mediated)
autophagy will be tested. CRISPR will be used to induce mutations (Atg5, Rab9, Atg5/Rab9) and the survival,
tumorigenicity, and autophagy phenotypes of the mutant cells will be analyzed. This will establish whether Rab9
mediates an additional pathway and reveal any cell biological differences between the conventional and
alternative pathways. In Aim 2, autophagy regulation and molecular signatures will be analyzed. Modulation
of expression of two master regulators of autophagy genes, FOXO and Mitf/TFEB, will be used to define
transcriptional control of Atg5 and Rab9 expression to test for independent or co-regulation of the pathways.
RNAseq analysis of Atg5 and Rab9 dormant mutant cells will be used to define the gene expression signature
correlated with each autophagy pathway and determine if perturbation of one pathway affects the other. The
proposed work is significant because it is expected to provide the first evidence of an alternative
autophagy pathway in dormant cancer. The study can be achieved in a two-year timeframe with RO3 support
because the team has prior experience, strong preliminary data are presented, and the analyses will be
expedited by use of the tractable Drosophila system. Many precedents for conservation of canonical processes
in cancer biology between Drosophila and mammalian systems support the idea that information gained her...

## Key facts

- **NIH application ID:** 10438115
- **Project number:** 1R03CA256269-01A1
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** AMANDA SIMCOX
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $78,750
- **Award type:** 1
- **Project period:** 2022-03-01 → 2024-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10438115

## Citation

> US National Institutes of Health, RePORTER application 10438115, Killing dormant tumor cells:  the role of autopagy (1R03CA256269-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10438115. Licensed CC0.

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