It is well established that a subset of cells within primary breast cancers can undergo an epithelial-to-mesenchymal transition (EMT), although the role of EMT in metastasis remains controversial. We previously demonstrated that breast cancer cells that had undergone an oncogenic EMT could increase metastasis of neighboring cancer cells via non-canonical paracrine-mediated activation of GLI activity that is dependent on SIX1 expression in the EMT cancer cells. However, the mechanism by which these SIX1-expressing EMT cells activate GLI signaling remained unclear. In this study, we demonstrate a novel mechanism for activation of GLI-mediated signaling in epithelial breast tumor cells via EMT cell-induced production and secretion of VEGF-C. We show that VEGF-C, secreted by breast cancer cells that have undergone an EMT, promotes paracrine-mediated increases in proliferation, migration, and invasion of epithelial breast cancer cells, via non-canonical activation of GLI-signaling. We further show that the aggressive phenotypes, including metastasis, imparted by EMT cells on adjacent epithelial cancer cells can be disrupted by either inhibiting VEGF-C in EMT cells or by knocking down NRP2, a receptor which interacts with VEGF-C, in neighboring epithelial cancer cells. Interrogation of TCGA and GEO public datasets supports the relevance of this pathway in human breast cancer, demonstrating that VEGF-C strongly correlates with activation of Hedgehog signaling and EMT in the human disease. Our study suggests that the VEGF-C/NRP2/GLI axis is a novel and conserved paracrine means by which EMT cells enhance metastasis, and provides potential targets for therapeutic intervention in this heterogeneous disease.
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This work was supported by R01CA224867 to HLF and MTL, and F99CA234940 to HZ. We would like to thank the Functional Genomics Shared Resource (SR), the Cell Technologies SR, and the Animal Imaging SR of the University of Colorado Cancer Center (P30CA046934) for help with these studies. We would also like to acknowledge support from The Dan L. Duncan Comprehensive Cancer Center (BCM, P30CA125123) and the Cancer Prevention and Research Initiative of Texas (CPRIT) (BCM, RP170691).
Conflict of interest
MTL is a Founder and Limited Partner in StemMed Ltd, and a Founder and Manager in StemMed Holdings, its General Partner. He is also a Founder and equity stake holder in Tvardi Therapeutics Inc. The remaining authors do not have any conflicts of interest.
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Kong, D., Zhou, H., Neelakantan, D. et al. VEGF-C mediates tumor growth and metastasis through promoting EMT-epithelial breast cancer cell crosstalk. Oncogene 40, 964–979 (2021). https://doi.org/10.1038/s41388-020-01539-x