CCR7-Mediated Lymphovascular Invasion Promotes Metastatic Spread in Inflammatory Breast Cancer

Caren Iliana Sanchez, BS, BA (Advisor: Wendy Woodward, MD, PhD)

Inflammatory breast cancer (IBC) is a rare but highly aggressive form of breast cancer that accounts for a disproportional amount of breast cancer deaths. A hallmark characteristic of IBC is extensive lymphovascular space invasion (LVSI) by tumor emboli and is associated with higher proliferation rates, increased tumor angiogenesis and lymphangiogenesis, and early metastasis, contributing to its aggressive clinical course. Despite advances in trimodal therapy, the prognosis for IBC remains significantly worse than for non-inflammatory breast cancer.

CCR7, a chemokine receptor normally involved in immune cell trafficking, has been implicated in promoting tumor migration towards lymphatic vessels through its ligands CCL19 and CCL21. Despite the strong preliminary evidence of high CCR7 expression in IBC, its functional role in driving lymphatic invasion and the precise underlying mechanisms, as well as the impact of targeting CCR7 in IBC, remain largely uncharacterized. We hypothesize that the CCR7-CCL19/CCL21 chemokine axis serves as a mediator of IBC metastasis by coordinating multiple cellular processes including migration, invasion, and lymphovascular trafficking through the activation of signaling pathways that drive the metastatic cascade in IBC.

CCR7 expression was characterized in IBC patient samples and pre-clinical models. IBC patient tumors were analyzed for mutations and expression of CCR7 and its ligands, CCL19 and CCL21. We screened IBC cell lines and novel PDX models for protein expression and protein localization. The functional role of CCR7 in IBC migration, proliferation, and downstream signaling was investigated using pharmacological inhibition of CCR7 and a CRISP-mediated partial knockdown of CCR7. Downstream signaling was analyzed via Western blot.

Results show that CCR7 is broadly expressed across IBC patient samples, PDX models, and established IBC cell lines. However, expression of CCL19 and CCL21 is notably absent. Functional modulation of CCR7 altered migratory behavior and influenced downstream signaling pathways associated with cell survival.

These findings support a model in which CCR7 contributes to the aggressive phenotype of inflammatory breast cancer by promoting migration and survival through activation of downstream signaling networks. Our results further suggest that CCR7-mediated effects are highly dependent upon the tumor microenvironment context and likely involve interactions with lymphatic-derived chemokine gradients. This work established CCR7 as a biologically relevant mediator of IBC progression and provides a foundation for future studies investigating CCR7-targeted therapeutic strategies to disrupt lymphovascular spread in IBC. 

Advisory Committee:

• Wendy Woodward, MD, PhD, Chair
• Melissa Aldrich, PhD
• Chandra Bartholomeusz, PhD
• Francesca Cole, PhD
• Jeffrey Frost, PhD