Kim Dae-Seok, Onodera Toshiharu, Funcke Jan-Bernd, Min Kyounghee, Zhu Qingzhang, Lin Qian, Chen Shiuhwei, Joung Chanmin, Kim Min, Wynn R Max, Velasco Joselin, Lee Charlotte, Virostek Megan, Li Chao, Scherer Philipp E
Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, United States of America.
Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, Ulsan, Korea, Republic of.
J Clin Invest. 2025 Jun 17;135(16). doi: 10.1172/JCI187202.
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 ("RIDad mice") in a mammary tumor model driven by MMTV-PyMT ("PyMT-RIDad 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-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression ("RIDMMTV 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.
脂肪细胞中的促炎信号对于健康的脂肪组织扩张、重塑和组织完整性至关重要。我们通过以细胞类型特异性方式局部表达抗炎腺病毒RIDα/β蛋白复合物，研究了在乳腺肿瘤发生过程中，靶向脂肪细胞或乳腺上皮细胞中的炎症的影响。在由MMTV-PyMT驱动的乳腺肿瘤模型（“PyMT-RIDad小鼠”）中抑制脂肪细胞炎症（“RIDad小鼠”）导致肿瘤相关巨噬细胞（TAM）数量增加以及乳腺脂肪垫（MFP）中免疫调节分子上调。这伴随着代谢功能障碍和乳腺发育异常。重要的是，这种表型与乳腺肿瘤发病加速、生长增强和肺转移相关。PyMT-RIDad小鼠的肿瘤表现出CD36表达上调，表明脂肪酸摄取增强。相反，通过表达RIDα/β抑制乳腺上皮细胞中的炎症（“RIDMMTV小鼠”）减缓了乳腺肿瘤生长，而不影响肿瘤发生或巨噬细胞积累。这些发现突出了在微环境中不同细胞类型中抑制炎症信号对肿瘤发展产生的不同影响。我们的结果强调了抑制脂肪细胞炎症导致肿瘤友好微环境、促进乳腺癌进展的作用。这项研究揭示了在乳腺癌发病机制中，特别是由脂肪细胞驱动的炎症之间的复杂相互作用。
