Laboratory of Cancer Lymphangiogenesis, Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Nat Commun. 2021 Nov 25;12(1):6889. doi: 10.1038/s41467-021-27108-8.
Inflammatory Breast Cancer (IBC) is a highly aggressive malignancy with distinct clinical and histopathological features whose molecular basis is unresolved. Here we describe a human IBC cell line, A3250, that recapitulates key IBC features in a mouse xenograft model, including skin erythema, diffuse tumor growth, dermal lymphatic invasion, and extensive metastases. A3250 cells express very high levels of the CCL2 chemokine and induce tumors enriched in macrophages. CCL2 knockdown leads to a striking reduction in macrophage densities, tumor proliferation, skin erythema, and metastasis. These results establish IBC-derived CCL2 as a key factor driving macrophage expansion, and indirectly tumor growth, with transcriptomic analysis demonstrating the activation of multiple inflammatory pathways. Finally, primary human IBCs exhibit macrophage infiltration and an enriched macrophage RNA signature. Thus, this human IBC model provides insight into the distinctive biology of IBC, and highlights potential therapeutic approaches to this deadly disease.
炎性乳腺癌（IBC）是一种具有独特临床和组织病理学特征的高度侵袭性恶性肿瘤，其分子基础尚未阐明。在这里，我们描述了一种人 IBC 细胞系 A3250，它在小鼠异种移植模型中再现了关键的 IBC 特征，包括皮肤红斑、弥漫性肿瘤生长、真皮淋巴管浸润和广泛转移。A3250 细胞表达非常高水平的趋化因子 CCL2，并诱导富含巨噬细胞的肿瘤。CCL2 敲低导致巨噬细胞密度、肿瘤增殖、皮肤红斑和转移的显著减少。这些结果确立了 IBC 衍生的 CCL2 作为驱动巨噬细胞扩张的关键因素，并且间接驱动肿瘤生长，转录组分析表明多个炎症途径的激活。最后，原发性人 IBC 表现出巨噬细胞浸润和丰富的巨噬细胞 RNA 特征。因此，这种人 IBC 模型提供了对 IBC 独特生物学的深入了解，并强调了针对这种致命疾病的潜在治疗方法。
