A Subpopulation of Luminal Progenitors Secretes Pleiotrophin to Promote Angiogenesis and Metastasis in Inflammatory Breast Cancer

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 patients with IBC, 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 cross-talk 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. SIGNIFICANCE: Nonmalignant luminal progenitor cells expressing pleiotrophin promote angiogenesis by activating NRP1 and induce a prometastatic tumor microenvironment in inflammatory breast cancer, providing potential therapeutic targets for this aggressive breast cancer subtype.