Antibody-activation of connexin hemichannels in bone osteocytes with ATP release suppresses breast cancer and osteosarcoma malignancy
Manuel A. Riquelme,
Xuewei Wang,
Francisca M. Acosta,
Jingruo Zhang,
Jeffery Chavez,
Sumin Gu,
Peng Zhao,
Wei Xiong,
Ningyan Zhang,
Guo Li,
Saranya Srinivasan,
Chaoyu Ma,
Manjeet K. Rao,
Lu-Zhe Sun,
Nu Zhang,
Zhiqiang An,
Jean X. Jiang
Affiliations
Manuel A. Riquelme
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Xuewei Wang
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Francisca M. Acosta
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Jingruo Zhang
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Jeffery Chavez
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Sumin Gu
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Peng Zhao
The Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA
Wei Xiong
The Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA
Ningyan Zhang
The Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA
Guo Li
Immunology & Molecular Genetics, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Saranya Srinivasan
Immunology & Molecular Genetics, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Chaoyu Ma
Immunology & Molecular Genetics, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Manjeet K. Rao
Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Lu-Zhe Sun
Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA
Nu Zhang
Immunology & Molecular Genetics, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; South Texas Veterans Health Care System, San Antonio, TX 78229, USA
Zhiqiang An
The Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX 77030, USA; Corresponding author
Jean X. Jiang
Departments of Biochemistry and Structural Biology, Microbiology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA; Corresponding author
Summary: Bone tissue represents the most frequent site of cancer metastasis. We developed a hemichannel-activating antibody, Cx43-M2. Cx43-M2, directly targeting osteocytes in situ, activates osteocytic hemichannels and elevates extracellular ATP, thereby inhibiting the growth and migration of cultured breast and osteosarcoma cancer cells. Cx43-M2 significantly decreases breast cancer metastasis, osteosarcoma growth, and osteolytic activity, while improving survival rates in mice. The antibody’s inhibition of breast cancer and osteosarcoma is dose dependent in both mouse and human cancer metastatic models. Furthermore, Cx43-M2 enhances anti-tumor immunity by increasing the population and activation of tumor-infiltrating immune-promoting effector T lymphocytes, while reducing immune-suppressive regulatory T cells. Our results suggest that the Cx43-M2 antibody, by activating Cx43 hemichannels and facilitating ATP release and purinergic signaling, transforms the cancer microenvironment from a supportive to a suppressive state. Collectively, our study underscores the potential of Cx43-M2 as a therapeutic for treating breast cancer bone metastasis and osteosarcoma.
