Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Dae-Seok Kim; Toshiharu Onodera; Jan-Bernd Funcke; Kyounghee Min; Qingzhang Zhu; Qian Lin; Shiuhwei Chen; Chanmin Joung; Min Kim; R. Max Wynn; Joselin Velasco; Charlotte Lee; Megan Virostek; Chao Li; Philipp E. Scherer

doi:10.1172/JCI187202

Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Dae-Seok Kim,¹ Toshiharu Onodera,¹ Jan-Bernd Funcke,¹ Kyounghee Min,¹ Qingzhang Zhu,¹ Qian Lin,¹ Shiuhwei Chen,¹ Chanmin Joung,¹ Min Kim,² R. Max Wynn,¹ Joselin Velasco,¹ Charlotte Lee,³ Megan Virostek,¹ Chao Li,¹ and Philipp E. Scherer¹

Published June 17, 2025 - More info

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Abstract

Pro-inflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the anti-inflammatory adenoviral RIDα/β protein complex in a cell type-specific manner. Suppression of adipocyte inflammation (“RID^ad mice”) in a mammary tumor model driven by MMTV-PyMT (“PyMT-RID^ad mice”) led to an elevated number of tumor-associated macrophages (TAMs) and upregulation of immunoregulatory molecules in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RID^ad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (“RID^MMTV mice”) decelerated mammary tumor growth without affecting tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation, specifically driven by the adipocyte, in breast cancer pathogenesis.

Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Dae-Seok Kim,¹ Toshiharu Onodera,¹ Jan-Bernd Funcke,¹ Kyounghee Min,¹ Qingzhang Zhu,¹ Qian Lin,¹ Shiuhwei Chen,¹ Chanmin Joung,¹ Min Kim,² R. Max Wynn,¹ Joselin Velasco,¹ Charlotte Lee,³ Megan Virostek,¹ Chao Li,¹ and Philipp E. Scherer¹

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Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Dae-Seok Kim,1 Toshiharu Onodera,1 Jan-Bernd Funcke,1 Kyounghee Min,1 Qingzhang Zhu,1 Qian Lin,1 Shiuhwei Chen,1 Chanmin Joung,1 Min Kim,2 R. Max Wynn,1 Joselin Velasco,1 Charlotte Lee,3 Megan Virostek,1 Chao Li,1 and Philipp E. Scherer1

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Dae-Seok Kim,¹ Toshiharu Onodera,¹ Jan-Bernd Funcke,¹ Kyounghee Min,¹ Qingzhang Zhu,¹ Qian Lin,¹ Shiuhwei Chen,¹ Chanmin Joung,¹ Min Kim,² R. Max Wynn,¹ Joselin Velasco,¹ Charlotte Lee,³ Megan Virostek,¹ Chao Li,¹ and Philipp E. Scherer¹