# Jagged1-dependent tumor-stromal interactions in bone metastasis

> **NIH NIH R01** · PRINCETON UNIVERSITY · 2020 · $370,575

## Abstract

Summary
Osteoblasts are emerging as a key component of tumor microenvironment in breast cancer bone metastasis. It
has been demonstrated recently that disseminated breast cancer cells interact with the osteoblastic niche to
survive and colonize the bone. However, the detailed mechanism for the interaction between tumor cells and
osteoblastic niche in bone colonization remains mostly uncharacterized. Furthermore, almost no studies have
been done to elucidate the functions of osteoblasts in the resistance of bone metastasis to traditional therapies
(i.e., chemotherapy and radiation therapy). In our preliminary studies, we discovered that chemotherapy
significantly increases Jagged1 expression level in osteoblasts and in mesenchymal stem/stromal cells
(MSCs), the precursors of osteoblasts. Transgenic expression of Jagged1 in osteoblasts in our newly created
Col1a1-Jagged1 transgenic mouse model significantly increases the formation of bone metastasis.
Importantly, we have developed a humanized monoclonal antibody against Jagged1 (15D11), which
demonstrated promising therapeutic effects against bone metastasis in preliminary studies. We hypothesize
that the increased expression of Jagged1 in MSCs and osteoblasts promote bone colonization of
breast cancer and contribute to chemoresistance and radioresistance by providing survival signaling
to metastatic tumor cells. Neutralizing antibodies against Jagged1 may block bone metastasis formation and
outgrowth, and sensitize them to traditional therapy. Col1a1-Jagged1 and a series of well establish mouse
models will be used for bone metastasis allograft and xenograft studies to evaluate the functional importance
of osteoblast Jagged1 in bone metastasis formation and treatment resistance. We will use Jagged1
neutralizing antibody 15D11 in vivo to test its synergistic effect with chemotherapy, radiation therapy and
osteoclast-targeting therapy. Furthermore, we will perform experiments to understand the exact molecular
pathways leading to elevated expression of Jagged1 in osteoblast in response to chemotherapy, as well as
Jagged1-dependent osteoblast-tumor interaction in promoting metastatic colonization and treatment resistance
in bone. Our proposed studies will confirm the importance of osteoblast Jagged1 in bone metastasis
colonization and treatment resistance. We will also reveal molecular signaling/pathways responsible for the
Jagged1-dependent function of the osteoblast niche in bone colonization and treatment resistance. Successful
pre-clinical testing of Jagged1 neutralizing antibody will also pave the way toward their application in human
patients in the near future. Therefore, we believe our study will likely have a significant impact on improving the
treatment of metastatic breast cancer.

## Key facts

- **NIH application ID:** 9842280
- **Project number:** 5R01CA212410-04
- **Recipient organization:** PRINCETON UNIVERSITY
- **Principal Investigator:** Yibin Kang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $370,575
- **Award type:** 5
- **Project period:** 2017-01-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842280

## Citation

> US National Institutes of Health, RePORTER application 9842280, Jagged1-dependent tumor-stromal interactions in bone metastasis (5R01CA212410-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9842280. Licensed CC0.

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