# Targeting cooperative mechanisms of metastatic colonization in osteosarcoma

> **NIH NIH R01** · RESEARCH INST NATIONWIDE CHILDREN'S HOSP · 2024 · $447,149

## Abstract

While studying mechanisms of metastasis in osteosarcoma, we discovered that individual tumor cells respond
differently when exposed to the foreign lung environment. Our early data suggest a hypothesis: that a small
group of tumor cells survives the initial encounter with the lungs by stopping cell division and liberally producing
inflammatory cytokines. The reaction of these rare “anchor” cells changes the surrounding lung tissue in ways
that prepare it for colonization by rapidly proliferating tumor cells (“growth” cells). The cytokines released by
anchor cells appear to alter the behavior of the surrounding lung cells, prompting a wound healing response.
Unlike the normal wound healing response, however, this wound never heals.
The environment created by this wound response is markedly different from that of the normal, healthy lung.
Most importantly, cells and cytokines that make up the wound create an environment where growth cells not only
survive, but proliferate rapidly, outcompeting the anchor cells to become the dominant subtype within the
metastatic tumor. Here, we outline a research plan to test this hypothesis, rigorously evaluating our proposed
mechanisms that establish the early metastatic niche and asking whether chemotherapy selectively kills growth
cells, inadvertently leaving anchor cells intact to re-establish metastases once therapy ceases.
The project is divided into three Aims. Aim 1 tests hypotheses relating to the mechanisms by which anchor cells
create a fertile metastatic niche by activating the wound-healing machinery of the lung and facilitates
identification of the lung-to-tumor signals that make this a fertile environment for growth cells.
In the second Aim, we will determine how anchor and growth cells come about—whether distinct clones come
pre-programmed for anchor or growth cell activity or whether dynamic developmental processes regulate
maintenance of subpopulations within each tumor. Understanding this will be important for designing treatment
regimens that maintain efficacy while minimizing toxicity.
Finally, we will evaluate the use of pharmacologic inhibitors that target anchor cells directly or indirectly to see if
these can augment the effects of conventional therapies and overcome resistance and relapse. By identifying
agents that selectively target anchor cells, we can develop combination regimens that target both groups of
tumor cells, rendering resistant disease treatable.
The cooperation between cancer cells with discrete behaviors has immediate implications for treatment and
suggests a need to develop strategies that target both growth cells and anchor cells. This work could drive a
paradigm shift that would revolutionize the care of patients with osteosarcoma.

## Key facts

- **NIH application ID:** 10916186
- **Project number:** 5R01CA260178-03
- **Recipient organization:** RESEARCH INST NATIONWIDE CHILDREN'S HOSP
- **Principal Investigator:** RYAN D. ROBERTS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $447,149
- **Award type:** 5
- **Project period:** 2022-07-06 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916186

## Citation

> US National Institutes of Health, RePORTER application 10916186, Targeting cooperative mechanisms of metastatic colonization in osteosarcoma (5R01CA260178-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10916186. Licensed CC0.

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