# N-cadherin in Extraskeletal Osteolineage Cells Modulates Tumor Growth

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $394,533

## Abstract

Abstract
The host microenvironment is necessary for tumor growth and metastasis, and a major determinant of
resistance to treatment and relapse. Expression of N-cadherin (Ncad), a calcium-dependent cell-cell adhesion
molecule, in cancer associated fibroblasts (CAF) has been reported to favor tumor growth. Ncad is the main
cadherin expressed in bone cells, where it functions in cell-cell adhesion, but also regulates signaling and
differentiation. In preliminary studies we found that, contrary to expectations, ablation of the Ncad gene (Cdh2)
in osteolineage cells – expressing the osteogenic marker, Osterix (Osx+) – does not affect bone engraftment
of breast cancer cells; however, subcutaneous tumors grow faster and lung metastases develop earlier than in
wild type littermates. We also find, unexpectedly, that Ncad is present in previously unrecognized Osx+ cells
in extra-skeletal tumors. These cells have a transcriptomic profile more similar to osteogenic cells than to CAF,
and favor tumor growth. Furthermore, Ncad in Osx+ cells down-regulates p38 responsive genes, a pro-
tumorigenic pathway. In human breast cancer, Osx+ are an index of poor prognosis. These preliminary results
demonstrate that Ncad in Osx+ cells is a negative regulator of cancer progression, an effect opposite to Ncad
reported action in CAF. We contend that Ncad exerts multiple and even opposite actions on tumorigenesis
depending on the cell context where it is expressed, via modulation of specific signaling pathways.
Based on these preliminary data, our central hypothesis is that Ncad in pro-tumorigenic Osx+ cells
restrains tumor growth by regulating signals that reprogram the tumor microenvironment. To test this
hypothesis, we propose the following Specific Aims: Specific Aim 1 – Modulation of extra-skeletal tumor
growth by Ncad in Osx+ cells; testing the hypothesis that Ncad in Osx+ cells restrains tumor growth; loss of
Ncad in TAOC increases tumor growth and metastases in mice. Osx+ Ncad+ cells correlate with tumor
grading in human breast cancer. Specific Aim 2 – Mechanisms of Ncad modulation of pro-tumorigenic signals
in tumor-associate Osx+ cells; testing the hypothesis that Ncad in Osx+ cells is an upstream regulator of p38
and Pten signaling; loss of Ncad in Osx+ cells results in accentuated expression of p38-dependent pro-
tumorigenic factors and decreased Pten dependent signals, leading to tumor microenvironment modification
and enhanced tumorigenesis. We will use in vivo approaches, including diphtheria toxin-induced selective cell
ablation, parabiosis, lineage tracking, as well as non-biased transcriptomic approaches (single cell RNAseq) to
unlock the cellular and molecular mechanisms by which Ncad in extraskeletal Osx+ cells affects tumor growth
and metastasis. We will also determine the clinical pathology correlates of Ncad expression in Osx+ cells in
human tumors. Results of the proposed studies will lay the foundations for the development of new markers of
tumor p...

## Key facts

- **NIH application ID:** 10071762
- **Project number:** 1R01CA243383-01A1
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** Roberto Civitelli
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $394,533
- **Award type:** 1
- **Project period:** 2020-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10071762

## Citation

> US National Institutes of Health, RePORTER application 10071762, N-cadherin in Extraskeletal Osteolineage Cells Modulates Tumor Growth (1R01CA243383-01A1). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10071762. Licensed CC0.

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