Abstract P5-01-05: Transcriptional signature of metastatic triple negative breast cancer in humanized mice

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 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 ten PDX tumors tested, four did not develop metastasis, four developed only lung metastasis and two developed multi-organ metastases (lung and liver). We find that different TNBC PDX tumors have different metastatic potential. Their metastatic potential is linked with differences in cellular composition and transcriptional signatures at the level of the primary tumor. Interferon Response signature is enriched in primary TNBC PDXs with metastatic potential, while non-metastatic primary tumors display a TNF signature as well as allograft rejection signature. Furthermore, liver metastases were enriched in myeloid transcripts. Thus, our model enables mechanistic and pre-clinical studies of human TNBC metastasis. Citation Format: Chun I Yu, Te-Chia Wu, Francesca Menghi, Joshy George, Kyung In Kim, Florentina Marches, Edison T Liu, Jacques Banchereau, Karolina Palucka. Transcriptional signature of metastatic triple negative breast cancer in humanized mice [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-01-05.