# Spatiotemporal modeling of cancer-niche interactions in breast cancer bone metastasis

> **NIH NIH U01** · METHODIST HOSPITAL RESEARCH INSTITUTE · 2020 · $549,065

## Abstract

ABSTRACT
About 20-40% of breast cancer patients develop metastasis to the bone, years to even decades after surgical
removal of primary tumors. Little is known about the biology of the latent, microscopic bone metastases before
they outgrow to overt osteolytic macrometastases. This represents a significant gap in our understanding of
bone metastasis. Targeting cancer cells that have not fully adapted to the bone microenvironment might
provide therapeutic benefit and prevent the occurrence of overt metastases. Bone and bone marrow comprise
of several highly distinctive microenvironment niches. Dormant, single disseminated tumor cells (DTCs) reside
in the perivascular niche, whereas proliferative, multi-cell bone micrometastases (BMMs) are found in the
osteogenic niche that exhibits features of active osteogenesis. Mechanisms through which the transition of
different niches occurs to switch fates of metastatic seeds remain elusive. The overall objectives of this project
are to investigate the spatiotemporal dynamics, the molecular crosstalk, and the therapeutic targets underlying
the interaction between breast cancer cells and different microenvironment niches in bone. We will pursue
three specific aims. First, we will dissect the spatiotemporal dynamics of the perivascular and osteogenic
niches and the cancer-niche interactions in bone micrometastasis models. We will use high-resolution, whole-
bone, multi-photon microscopy and laser-captured microdissection (LCM) followed by transcriptome profiling
(LCM-seq) to obtain relative localization and mutual impacts between cancer cells and niche cells in situ.
Second, we will integrate transcriptomic and imaging data and develop computational models for discovery of
new mechanisms and therapies toward blockade of cancer-niche interactions. Established and new algorithms
will be used to uncover the microenvironment molecules, and autocrine and paracrine signaling pathways
mediating niche-tumor interactions. Drug-repurposing analyses will be carried out to identify potential therapies
that have already been used for other diseases. We will achieve a systematic understanding of early-stage
bone colonization and generate testable mechanistic and therapeutic hypotheses. Third, we will validate the
discovered mechanisms and predicted drug efficacies in animal models. The Zhang laboratory has adopted
and established a series of genetically engineered mouse models and bone metastasis assays, which will be
utilized to validate computational predictions generated by computational modeling by the Wong group. Both
metastatic burden and frequency/distribution of DTCs and BMMs will be examined as endpoints. This study will
unbiasedly profile the molecular process of early stage metastasis progression in the bone from DTCs to
BMMs at single-to-few cell resolutions. This knowledge is unprecedented and critical for the ultimate
understanding of metastasis latency, a long-standing clinical challenge. The modeling tool de...

## Key facts

- **NIH application ID:** 10056730
- **Project number:** 1U01CA253553-01
- **Recipient organization:** METHODIST HOSPITAL RESEARCH INSTITUTE
- **Principal Investigator:** STEPHEN TC WONG
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $549,065
- **Award type:** 1
- **Project period:** 2020-09-15 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10056730

## Citation

> US National Institutes of Health, RePORTER application 10056730, Spatiotemporal modeling of cancer-niche interactions in breast cancer bone metastasis (1U01CA253553-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10056730. Licensed CC0.

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