Abstract P1-03-05: Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer

Abstract

Abstract Triple-negative breast cancer (TNBC) is a particularly aggressive form of breast cancer with high risk of recurrence and approximately 22% rate of five-year survival when the disease becomes metastatic. Thus, understanding of mechanisms supporting metastatic colonization of distant organs is of critical importance for the development of new therapies and possibly improved outcomes. Syngeneic mouse models suggest the role of innate immune cells, particularly neutrophils, in support of metastatic dissemination of TNBC. However, it is not possible to study human cancer in immunocompetent mice. Furthermore, organoids or other 3D tissue models do not allow investigations of distant organs colonization with metastatic TNBC tumors. Here, we used humanized mice and patient-derived xenograft (PDX) from treatment naïve primary TNBC tumors to investigate the mechanisms that promote metastasis. NSG mice with transgenic expression of human hematopoietic cytokines SCF/GM-CSF/IL-3 were engrafted with human CD34+ hematopoietic progenitor cells (HPCs) to generate humanized (h)NSG-SGM3 mice. All eleven (11) analyzed to date PDX tumors grew after orthotopic implantation at week 8-12. The presence of distant metastasis was determined by macroscopic evaluation of distant organs and further confirmed by E-cadherin and cytokeratin 19 expression using polychromatic immunofluorescence on frozen tissue section. Among 11 PDX tumors tested, five did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastasis (lung and liver). Transcriptional profiling with RNAseq revealed significant differences in the immune landscape of primary and metastatic tumors. In particular, liver metastases were enriched in myeloid and plasma cell transcripts. Further analysis is ongoing to uncover specific pathways involved. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis. Citation Format: Chun I Yu, Te-Chia Wu, Kyung In Kim, Francesca Menghi, Vanessa Oliveira, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Patient-derived xenografts in humanized mice classify metastatic potential of primary triple negative breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-03-05.