Sayali Onkar, Daisong Liu, Darcie Seachrist, Jian Zou, Christopher Merkel, Insa Thale, Alexander Chih-Chieh Chang, Linda Klei, Jian Chen, Kristen Weber Bonk, Kai Ding, Laura Savariau, Megan Yates, Jagmohan Hooda, Laura Stabile, Laura Rigatti, Peter C Lucas, George Tseng, Keri Ruth, Creg J Workman, Adrian V Lee, Dario A A Vignali, Steffi Oesterreich
Invasive lobular breast carcinoma (ILC) is the most common special histological subtype of breast cancer, which accounts for 10-15% of all cases. To study the phenotype characteristics, metastatic growth kinetic and immune microenvironment of ILC, we developed an orthotopically transplantable cell line model from the spontaneous mammary fat pad tumor of CDH1-PTEN dual knockout C57BL/6 mouse with Cre-loxP system, designated CPT6. CPT6 recapitulates single-file growth pattern of human ILC, with pleomorphic features and a high mitotic index. RNA sequencing together with whole exome sequencing reveals a luminal A subtype with targetable driver mutations such as Kras G12C. As a novel orthotopically transplantable ILC model in immune competent mice, CPT6 shows robust in vivo growth and metastatic rate, and has moderate immunogenicity which appears to be T-cell independent. We also profiled the immune microenvironment of CPT6, revealing a myeloid-rich environment with dominant M2-macrophage population, which is concordant with human ILC. In summary, this model recapitulates human ILC phenotype and represents a valuable preclinical platform for evaluating immunotherapy and other therapeutic strategies for invasive lobular breast carcinoma.