Abstract LB150: Endothelial protein kinase D1 signaling induces development of aggressive cancer stem-like cells for breast cancer progression and lung metastasis

Abstract Breast cancers demonstrate robust angiogenesis known as vascular niches despite an abundance of endogenous antiangiogenic factors in the tumor microenvironment. Aberrant angiogenesis may contribute to therapeutic resistance in antiangiogenic treatment via interactions between vascular endothelial cells (ECs) and cancer stem-like cells (CSCs, a subset of malignant cells critical for tumor initiation, metastasis and therapeutic resistance). Emerging evidence suggests that ECs in the tumor vasculature may confer CSC features to cancer cells by developing abnormal vascular niches. Protein kinase D1 (PKD1), a serine threonine kinase upstream of PI3Kinase/Akt and MAPK/Erk1/2, regulates angiogenesis and tumor progression. By analyzing RNA-sequencing data in the Cancer Genome Atlas (TCGA), we also found a poorer overall survival of the patients in the PKD1 high cohort compared with the patients with PKD1 low in BC tissues. Interestingly, our recent studies suggest that enhanced EC PKD1 signaling facilitates arteriolar niche formation for CSC self-renewal in breast cancers. However, the role and mechanisms of EC PKD-1 signaling in arteriolar niche establishment for CSC expansion in tumor progression is a critical yet underexplored and underappreciated field. We propose that EC PKD1 signaling in the vascular niches is essential for the expansion of CSCs to promote malignant progression of BCs. To test this hypothesis, we established a BC model in EC-specific PKD1 knockout mice and the control mice and developed a co-culture model of ECs and BC cells. By combining with molecular and cellular approaches and immunofluorescence microscopy, we observed that EC PKD1 signaling was critical for BC growth and survival of tumor-bearing mice, and particularly important in metastasis of BCs to the lungs. Analysis of the BC models indicated that there was an obvious enrichment of CSCs in the tumor vasculature of EC PKD1-positive mice. Moreover, there was a significant increase in expression of CD44 and ALDH1, the key CSC-related genes in BCs, in the primary tumors of mice with lung metastases. Co-culture of human microvascular ECs with human BC cells further confirmed that ECs promoted the expression of these two genes in tumor cells, along with the expression of other genes related to CSC self-renewal and epithelial mesenchymal transition. Co-culture with ECs also led to an increase in cell migration and colony formation in BCs. Importantly, the PKD1 signaling dictated the changes in CSC-related gene expression and aggressive behaviors in BC cells. In conclusion, EC PKD1 signaling in the vascular niches is critical for phenotype switching of BC cells to aggressive CSC features, thereby promoting BC progression and lung metastasis. Targeting PKD1-signaling-induced arteriolar niche establishment and this niche interaction with CSCs could provide potential novel and effective therapeutic strategies against tumor angiogenesis and CSC expansion. Citation Format: Abdellah Akil, Atul Kumar, Emily Spangler, Runhua Liu, Adam W. Beck, Lizhong Wang, Bassel El-Rayes, Bin Ren. Endothelial protein kinase D1 signaling induces development of aggressive cancer stem-like cells for breast cancer progression and lung metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB150.