The invasive lobular cancer cell line encyclopedia (ICLE) for studying potential biomarkers and exploring therapeutic opportunities.

Invasive lobular carcinoma (ILC), the most common histological "special type" of breast cancer, accounts for ∼10-15% of all breast cancer diagnoses and is characterized by unique clinical features and metastatic spread. Despite the unique pathobiology of ILC, studies of how its molecular alterations can be linked to new treatments have been hindered by the scarcity of well-characterized cell line models. To address this, we generated the ILC Cell Line Encyclopedia (ICLE), a comprehensive multi-omic characterization of cell lines derived from ILC or cell lines referred to as ILC-like derived from unannotated tumors with features of ILC such as loss of E-cadherin. Using consensus multi-omic subtyping, we confirmed the luminal status of previously established ILC cell lines and uncovered additional ILC/ILC-like cell lines with luminal features and RNA/DNA copy number similarity to ILC tumors. ICLE cell lines retained molecular alterations in key ILC genes at a similar frequency to both primary and metastatic ILC tumors. Importantly, ICLE cell lines recapitulated the CDH1 alteration landscape of ILC tumors including enrichment of truncating mutations and biallelic inactivation of CDH1 . Optical genome mapping uncovered novel genomic rearrangements including structural variations in CDH1 and other functional gene fusions and revealed breast cancer specific patterns of chromothripsis in chromosomes 8, 11 and 17. Aberrant DNAm events and integrative analysis with RNA expression revealed epigenetic activation of TFAP2B , an emerging biomarker preferentially expressed in lobular disease. Finally, towards the goal of identifying novel druggable vulnerabilities in ILC, publicly available RNAi loss of function breast cancer cell line datasets revealed numerous putative vulnerabilities cytoskeletal components, focal adhesion and PI3K/AKT pathway in ICLE vs NST cell lines. We addressed the lack of suitable models to study E-cadherin deficient breast cancers by comprehensively characterizing multi-omic features of both established and putative ILC models and showed their similarity to tumors and highlighting novel druggable vulnerabilities.