Inflammatory breast cancer (IBC) is a highly aggressive subtype of breast cancer characterized by rapidly arising diffuse erythema and edema. Genomic studies have not identified consistent alterations and mechanisms that differentiate IBC from non-IBC tumors, suggesting that the microenvironment could be a potential driver of IBC phenotypes. Here, using single-cell RNA sequencing, multiplex staining, and serum analysis in IBC patients, we identified enrichment of a subgroup of luminal progenitor (LP) cells containing high expression of the neurotropic cytokine pleiotrophin (PTN) in IBC tumors. PTN secreted by the LP cells promoted angiogenesis by directly interacting with the NRP1 receptor on endothelial tip cells located in both IBC tumors and the affected skin. NRP1 activation in tip cells led to recruitment of immature perivascular cells in the affected skin of IBC, which are correlated with increased angiogenesis and IBC metastasis. Together, these findings reveal a role for crosstalk between LPs, endothelial tip cells, and immature perivascular cells via PTN-NRP1 axis in the pathogenesis of IBC, which could lead to improved strategies for treating IBC.

中文翻译：

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管腔祖细胞亚群分泌多效蛋白以促进炎性乳腺癌的血管生成和转移

炎性乳腺癌（IBC）是一种高度侵袭性的乳腺癌亚型，其特征是迅速出现弥漫性红斑和水肿。基因组研究尚未确定区分 IBC 与非 IBC 肿瘤的一致改变和机制，这表明微环境可能是 IBC 表型的潜在驱动因素。在这里，我们利用 IBC 患者的单细胞 RNA 测序、多重染色和血清分析，确定了 IBC 肿瘤中含有高表达亲神经细胞因子多效素 (PTN) 的管腔祖细胞 (LP) 细胞亚群的富集。 LP 细胞分泌的 PTN 通过直接与位于 IBC 肿瘤和受影响皮肤的内皮尖端细胞上的 NRP1 受体相互作用，促进血管生成。尖端细胞中的 NRP1 激活导致 IBC 受影响皮肤中未成熟的血管周围细胞的募集，这与血管生成和 IBC 转移的增加相关。总之，这些发现揭示了 LP、内皮尖端细胞和未成熟血管周围细胞之间通过 PTN-NRP1 轴串扰在 IBC 发病机制中的作用，这可能会导致 IBC 治疗策略的改进。