N-cadherin in osteolineage cells modulates stromal support of tumor growth
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 “doc...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2021-06-01
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| Series: | Journal of Bone Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212137421000105 |
| _version_ | 1818927482390183936 |
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| author | Francesca Fontana Jingyu Xiang Xinming Su Eric Tycksen Rachel Nassau Gregory Fox Giulia Leanza Katherine Weilbaecher Roberto Civitelli |
| author_facet | Francesca Fontana Jingyu Xiang Xinming Su Eric Tycksen Rachel Nassau Gregory Fox Giulia Leanza Katherine Weilbaecher Roberto Civitelli |
| author_sort | Francesca Fontana |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-20T03:13:43Z |
| format | Article |
| id | doaj.art-8c504094029a430e87c87faaa1326bf6 |
| institution | Directory Open Access Journal |
| issn | 2212-1374 |
| language | English |
| last_indexed | 2024-12-20T03:13:43Z |
| publishDate | 2021-06-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Bone Oncology |
| spelling | doaj.art-8c504094029a430e87c87faaa1326bf62022-12-21T19:55:24ZengElsevierJournal of Bone Oncology2212-13742021-06-0128100356N-cadherin in osteolineage cells modulates stromal support of tumor growthFrancesca Fontana0Jingyu Xiang1Xinming Su2Eric Tycksen3Rachel Nassau4Gregory Fox5Giulia Leanza6Katherine Weilbaecher7Roberto Civitelli8Division of Bone and Mineral Diseases, Musculoskeletal Research Center, United States; Division of Molecular Oncology, Department of Medicine, United StatesDivision of Molecular Oncology, Department of Medicine, United StatesDivision of Molecular Oncology, Department of Medicine, United StatesGenome Technology Access Center, Washington University School of Medicine, St. Louis, MO, United StatesDivision of Bone and Mineral Diseases, Musculoskeletal Research Center, United StatesDivision of Molecular Oncology, Department of Medicine, United StatesDivision of Bone and Mineral Diseases, Musculoskeletal Research Center, United StatesDivision of Molecular Oncology, Department of Medicine, United StatesDivision of Bone and Mineral Diseases, Musculoskeletal Research Center, United States; Corresponding author at: Division of Bone and Mineral Diseases, Washington University in St. Louis, 660 South Euclid – Campus Box 8301, St. Louis, MO 63110, United States.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.http://www.sciencedirect.com/science/article/pii/S2212137421000105N-cadherinBone-tumor cell interactionsTumor microenvironmentTranscriptomics |
| spellingShingle | Francesca Fontana Jingyu Xiang Xinming Su Eric Tycksen Rachel Nassau Gregory Fox Giulia Leanza Katherine Weilbaecher Roberto Civitelli N-cadherin in osteolineage cells modulates stromal support of tumor growth Journal of Bone Oncology N-cadherin Bone-tumor cell interactions Tumor microenvironment Transcriptomics |
| title | N-cadherin in osteolineage cells modulates stromal support of tumor growth |
| title_full | N-cadherin in osteolineage cells modulates stromal support of tumor growth |
| title_fullStr | N-cadherin in osteolineage cells modulates stromal support of tumor growth |
| title_full_unstemmed | N-cadherin in osteolineage cells modulates stromal support of tumor growth |
| title_short | N-cadherin in osteolineage cells modulates stromal support of tumor growth |
| title_sort | n cadherin in osteolineage cells modulates stromal support of tumor growth |
| topic | N-cadherin Bone-tumor cell interactions Tumor microenvironment Transcriptomics |
| url | http://www.sciencedirect.com/science/article/pii/S2212137421000105 |
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