Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages
Abstract Background High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tu...
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BMC
2025-04-01
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| Series: | Journal of Translational Medicine |
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| Online Access: | https://doi.org/10.1186/s12967-025-06444-z |
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| author | Yuying Tan Yong-Guang Yang Xiaoying Zhang Lei Zhao Xiaocong Wang Wentao Liu |
| author_facet | Yuying Tan Yong-Guang Yang Xiaoying Zhang Lei Zhao Xiaocong Wang Wentao Liu |
| author_sort | Yuying Tan |
| collection | DOAJ |
| description | Abstract Background High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tumor-associated macrophages (TAMs) and high fibrosis. However, the mechanism of high fibrosis in such tumors is still under debate. Methods We first investigated the correlation between tumor-derived osteopontin (OPN) and tumor fibrosis as well as TAM enrichment using a tumor model characterized by OPN genetic inactivation or overexpression. We further compared the effects of macrophage depletion on tumor fibrosis in mice bearing TNBC tumors (4T1 WT or 4T1 Spp1 − KO ). To elucidate the mechanism by which TAMs promote tumor fibrosis, we evaluated their potential to recruit cancer-associated fibroblasts (CAFs) through in vitro migration assays and compared the production of transforming growth factor-beta 1 (TGFβ1) among different TAM subpopulations. Results Our study revealed that OPN secretion by tumor cells correlates positively with both tumor fibrosis and TAM enrichment. Specifically, within the enriched TAM population, Ly6C+CD206− TAMs recruit CAFs via CCL5 secretion, while Ly6C−CD206high TAMs secrete TGFβ1 to activate CAFs. Blocking the tumor cell-derived OPN can effectively prevent tumor fibrosis. Conclusions This study shows that tumor-derived OPN primarily drives TAM enrichment in mouse cancer model, indirectly promoting tumor fibrosis through Ly6C+CD206−/low and Ly6C−CD206high TAMs. Our findings have potential application in preventing tumors from excessive fibrosis and enhancing the efficacy of immunotherapy and chemotherapy. |
| format | Article |
| id | doaj-art-1b14ee1252f34b18b672e4bf4a613443 |
| institution | OA Journals |
| issn | 1479-5876 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Translational Medicine |
| spelling | doaj-art-1b14ee1252f34b18b672e4bf4a6134432025-08-20T02:16:07ZengBMCJournal of Translational Medicine1479-58762025-04-0123111310.1186/s12967-025-06444-zTumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophagesYuying Tan0Yong-Guang Yang1Xiaoying Zhang2Lei Zhao3Xiaocong Wang4Wentao Liu5Key Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin UniversityEchocardiography Department, The First Hospital of Jilin UniversityKey Laboratory of Organ Regeneration & Transplantation of the Ministry of Education, The First Hospital of Jilin UniversityAbstract Background High fibrosis of the tumor microenvironment (TME) not only impedes the effective infiltration of T cells but also serves as a physical barrier to inhibit the penetration of chemotherapy drugs. Triple-negative breast cancer (TNBC) is characterized by significant infiltration of tumor-associated macrophages (TAMs) and high fibrosis. However, the mechanism of high fibrosis in such tumors is still under debate. Methods We first investigated the correlation between tumor-derived osteopontin (OPN) and tumor fibrosis as well as TAM enrichment using a tumor model characterized by OPN genetic inactivation or overexpression. We further compared the effects of macrophage depletion on tumor fibrosis in mice bearing TNBC tumors (4T1 WT or 4T1 Spp1 − KO ). To elucidate the mechanism by which TAMs promote tumor fibrosis, we evaluated their potential to recruit cancer-associated fibroblasts (CAFs) through in vitro migration assays and compared the production of transforming growth factor-beta 1 (TGFβ1) among different TAM subpopulations. Results Our study revealed that OPN secretion by tumor cells correlates positively with both tumor fibrosis and TAM enrichment. Specifically, within the enriched TAM population, Ly6C+CD206− TAMs recruit CAFs via CCL5 secretion, while Ly6C−CD206high TAMs secrete TGFβ1 to activate CAFs. Blocking the tumor cell-derived OPN can effectively prevent tumor fibrosis. Conclusions This study shows that tumor-derived OPN primarily drives TAM enrichment in mouse cancer model, indirectly promoting tumor fibrosis through Ly6C+CD206−/low and Ly6C−CD206high TAMs. Our findings have potential application in preventing tumors from excessive fibrosis and enhancing the efficacy of immunotherapy and chemotherapy.https://doi.org/10.1186/s12967-025-06444-zOsteopontinFibrosisTumor microenvironmentTumor-associated macrophageCancer-associated fibroblast |
| spellingShingle | Yuying Tan Yong-Guang Yang Xiaoying Zhang Lei Zhao Xiaocong Wang Wentao Liu Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages Journal of Translational Medicine Osteopontin Fibrosis Tumor microenvironment Tumor-associated macrophage Cancer-associated fibroblast |
| title | Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages |
| title_full | Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages |
| title_fullStr | Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages |
| title_full_unstemmed | Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages |
| title_short | Tumor cell-derived osteopontin promotes tumor fibrosis indirectly via tumor-associated macrophages |
| title_sort | tumor cell derived osteopontin promotes tumor fibrosis indirectly via tumor associated macrophages |
| topic | Osteopontin Fibrosis Tumor microenvironment Tumor-associated macrophage Cancer-associated fibroblast |
| url | https://doi.org/10.1186/s12967-025-06444-z |
| work_keys_str_mv | AT yuyingtan tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages AT yongguangyang tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages AT xiaoyingzhang tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages AT leizhao tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages AT xiaocongwang tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages AT wentaoliu tumorcellderivedosteopontinpromotestumorfibrosisindirectlyviatumorassociatedmacrophages |