TY - JOUR
T1 - N-cadherin in osteolineage cells modulates stromal support of tumor growth
AU - Fontana, Francesca
AU - Xiang, Jingyu
AU - Su, Xinming
AU - Tycksen, Eric
AU - Nassau, Rachel
AU - Fox, Gregory
AU - Leanza, Giulia
AU - Weilbaecher, Katherine
AU - Civitelli, Roberto
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/6
Y1 - 2021/6
N2 - Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.
AB - Tumor growth and metastases are dependent on interactions between cancer cells and the local environment. Expression of the cell–cell adhesion molecule N-cadherin (Ncad) is associated with highly aggressive cancers, and its expression by osteogenic cells has been proposed to provide a molecular “dock” for disseminated tumor cells to establish in pre-metastatic niches within the bone. To test this biologic model, we conditionally deleted the Ncad gene (Cdh2) in osteolineage cells using Osx-cre (cKO). Contrary to expectations, the metastatic breast cancer cell line PyMT-BO1 was able to form tumors in bone and to induce osteolysis in cKO as well as in control mice. Despite absence of Ncad, bone marrow stromal cells isolated from cKO mice were able to engage in direct cell–cell interactions with tumor cells expressing either N- or E-cadherin. However, subcutaneous PyMT-BO1 and B16F10 tumors grew larger in cKO relative to control littermates. Cell tracking experiments using the Ai9 reporter revealed the presence of Osx+ and Ncad+ cells in the stroma of extra-skeletal tumors and in a small population of lung cells. Gene expression analysis by RNAseq of Osx+ cells isolated from extra-skeletal tumors revealed alterations of pro-tumorigenic signaling pathways in cKO cells relative to control Osx+ cells. Thus, Ncad in Osx+ cells is not necessary for the establishment of bone metastases, but in extra-skeletal tumors it regulates pro-tumorigenic support by the microenvironment.
KW - Bone-tumor cell interactions
KW - N-cadherin
KW - Transcriptomics
KW - Tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85104065833&partnerID=8YFLogxK
U2 - 10.1016/j.jbo.2021.100356
DO - 10.1016/j.jbo.2021.100356
M3 - Article
C2 - 33912383
AN - SCOPUS:85104065833
SN - 2212-1374
VL - 28
JO - Journal of Bone Oncology
JF - Journal of Bone Oncology
M1 - 100356
ER -