Multi-omic characterization of ILC and ILC-like cell lines as part of ILC cell line encyclopedia (ICLE) defines new models to study potential biomarkers and explore therapeutic opportunities.

Invasive lobular carcinoma (ILC), the most common histological "special type", accounts for ∼10-15% of all BC diagnoses, is characterized by unique features such as E-cadherin loss/deficiency, lower grade, hormone receptor positivity, larger diffuse tumors, and specific metastatic patterns. Despite ILC being acknowledged as a disease with distinct biology that necessitates specialized and precision medicine treatments, the further exploration of its molecular alterations with the goal of discovering new treatments has been hindered due to the scarcity of well-characterized cell line models for studying this disease. To address this, we generated the ILC Cell Line Encyclopedia (ICLE), providing a comprehensive multi-omic characterization of ILC and ILC-like cell lines. Using consensus multi-omic subtyping, we confirmed luminal status of previously established ILC cell lines and uncovered additional ILC/ILC-like cell lines with luminal features for modeling ILC disease. Furthermore, most of these luminal ILC/ILC-like cell lines also showed RNA and copy number similarity to ILC patient tumors. Similarly, ILC/ILC-like cell lines also retained molecular alterations in key ILC genes at similar frequency to both primary and metastatic ILC tumors. Importantly, ILC/ILC-like cell lines recapitulated the alteration landscape of ILC patient tumors including enrichment of truncating mutations in and biallelic inactivation of gene. Using whole-genome optical mapping, we uncovered novel genomic-rearrangements including novel structural variations in and functional gene fusions and characterized breast cancer specific patterns of chromothripsis in chromosomes 8, 11 and 17. In addition, we systematically analyzed aberrant DNAm events and integrative analysis with RNA expression revealed epigenetic activation of - an emerging biomarker of lobular disease that is preferentially expressed in lobular disease. Finally, towards the goal of identifying novel druggable vulnerabilities in ILC, we analyzed publicly available RNAi loss of function breast cancer cell line datasets and revealed numerous putative vulnerabilities cytoskeletal components, focal adhesion and PI3K/AKT pathway in ILC/ILC-like vs NST cell lines. In summary, we addressed the lack of suitable models to study E-cadherin deficient breast cancers by first collecting both established and putative ILC models, then characterizing them comprehensively to show their molecular similarity to patient tumors along with uncovering their novel multi-omic features as well as highlighting putative novel druggable vulnerabilities. Not only we expand the array of suitable E-cadherin deficient cell lines available for modelling human-ILC disease but also employ them for studying epigenetic activation of a putative lobular biomarker as well as identifying potential druggable vulnerabilities for this disease towards enabling precision medicine research for human-ILC.