# Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $500,945

## Abstract

Metastasis to distant organs is the major cause of breast cancer-related death. Bone is the most frequent
destination of metastasis. Over 45% first-site metastases occur to bone, as compared to 19% to lung, 5% to liver
and 2% to brain. Patients with skeleton as the first site of metastasis usually have better prognosis than those
with visceral organs as first site. However, in more than two third of cases, bone metastases will not be confined
to the skeleton, but rather subsequently occur to other organs and eventually kill patients. This raises the
possibility of secondary metastatic dissemination from the initial bone lesions to other sites. In fact, some
metastases first found in non-bone organs may be seeded from subclinical bone micrometastases as well, as
suggested by the finding that cancer cells arrived in the bone can acquire more aggressive phenotypes even
before establishing overt metastases. Recent genomic analyses indeed concluded that the majority of
metastases result from seeding from other metastases, rather than primary tumors. Thus, it is of imperative
importance to investigate further metastatic seeding from bone lesions, as it might lead to prevention of the
terminal stage, multi-organ metastases that ultimately cause the vast majority of deaths. Despite the potential
relevance, we know very little about metastasis-to-metastasis seeding. Current pre-clinical models focus on
seeding from primary tumors, but cannot distinguish further dissemination. Taking advantage of a recently
developed approach that selectively deliver cancer cells to hind limb bones, we have uncovered frequent
metastatic seeding from established bone lesions to multiple other organs. This seeding is hypothetically enabled
by the bone microenvironment-induced effects that confer more stem-like properties through a combination of
clonal selection and epigenomic adaptation. In this application, we will elucidate the underlying mechanisms and
temporal course of this process in order to provide the first ever insights into time window and strategies of
potential therapeutic interventions. We hypothesize that clonal selection and epigenetic adaptation driven by the
bone microenvironment engender the ability of disseminated breast cancer cells to further metastasize and
blockade of the microenvironment-induced alterations may confine bone metastases and prevent further
dissemination to other fetal organs. Our specific aims are 1) to characterize the kinetics of metastatic seeding
from bone lesions and determine potential therapeutic windows accordingly, and 2) to identify key druggable
targets and design therapeutic strategies against secondary metastatic seeding from bone lesions. This project
is innovative and impactful because it is the first in the field that focuses on secondary metastasis and the
profound reprogramming effects of bone microenvironment on metastatic seeding. The outcome will likely
generate significant impact on our understanding of metastati...

## Key facts

- **NIH application ID:** 10028080
- **Project number:** 1R01CA251950-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Xiang Zhang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $500,945
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10028080

## Citation

> US National Institutes of Health, RePORTER application 10028080, Mechanistic and therapeutic investigation of secondary metastatic seeding from breast cancer bone lesion (1R01CA251950-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10028080. Licensed CC0.

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