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
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
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Research Article Inflammation Metabolism Oncology

Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Abstract

Proinflammatory 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 antiinflammatory 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 and upregulation of immunoregulatory molecules in the mammary fat pad. 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.

Authors

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

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Figure 5

Metabolic dysfunction and increased lipid uptake in tumors of PyMT-RIDad mice.

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Metabolic dysfunction and increased lipid uptake in tumors of PyMT-RIDad...
(A) Representative immunostaining of CD36 in the tumors. n = 3/group. Scale bars: 500 μm. The image of a different area of the same tissue section is shown in Supplemental Figure 7. (B) Representative immunostaining of FABP4 in the tumors. n = 3/group. Scale bars: 300 μm. (C) Schematic representation of the experimental design for the metabolic phenotyping, tumor development, and triolein uptake. n = 5–6/group. (D) Oral glucose tolerance test. (E) Intraperitoneal insulin tolerance test (ITT). (F–I) Triolein uptake into the tumor (F), mammary fat pad (MFP; G), gonadal white adipose tissue (gWAT; H), and liver (I). n = 5–6/group. Data are displayed as mean ± SEM and were analyzed by unpaired 2-tailed t tests (D–I).