Abstract 5115: Establishing tumoroid and mouse models for functional validation of progression markers in DCIS
Authors: Stefan J. Hutten, Catrin Lutz, Stefano Annunziato, Ellen Tanger, Jelle Wesseling, Jos Jonkers
Journal: Cancer Research (2018)

Abstract Ductal Carcinoma in Situ (DCIS) is a starting lesion in the milk duct of the breast, which accounts for 25% of all ‘breast cancers' detected since the introduction of breast screening. DCIS is usually treated by surgery combined with radiotherapy, which can have a large impact on the life of patients. However, there is little to no evidence that treatment of low and intermediate grade DCIS reduces mortality, while women diagnosed with DCIS do perceive their risk of dying the same as patients with invasive disease. To reduce the negative perception and the overtreatment of DCIS, but assure proper treatment for high risk DCIS, it is critical to identify which factors can predict whether DCIS stays indolent or becomes invasive. We have successfully shown that it is possible to propagate tumor cells and organoids in vivo using intraductal injections. Adult female NSG and nude mice were injected intraductally into the mammary gland with suspensions of breast cancer cell and organoid lines as well as DCIS cell lines. Moreover, we were able to instigate a protocol for deriving fresh patient DCIS material to create in vitro primary tumoroid cultures, which we transplanted as suspended cells into NSG and nude mice. Tumor formation was examined via palpation and bioluminescence imaging. The resulting tumors will be compared to the original patient material to show that we are able to create a suitable in vivo model, retaining the morphologic and genomic features of the patient. In addition to these transplantation models we sought to take advantage of existing non-germline models for establishing a genetic DCIS model. To establish these, genes were selected from literature which are suspected to initiate DCIS formation. These genes were then incorporated in lentiviral vectors and injected in the mammary gland of immunocompetent mice. The mice will be sacrificed at set time points to follow DCIS initiation and progression to Invasive Ductal Carcinoma (IDC). For characterization, all these models will be subjected to in-depth histopathologic, transcriptomic, mutational, proteomic, immunologic and methylomic characterization, such as copy number sequencing, RNA sequencing and reverse-phase protein assays. Together these models will aid in finding factors initiating DCIS and finding the key characteristics driving DCIS to IDC switch, and ultimately making it possible to distinguish between high risk and low risk DCIS. On top of this, the in vitro and in vivo human DCIS models will place a unique opportunity for high-throughput drug screening to obtain sensitivity profiles. These will be combined with -omics data to identify (epi)genetic determinants of drug sensitivity. Citation Format: Stefan J. Hutten, Catrin Lutz, Stefano Annunziato, Ellen Tanger, Jelle Wesseling, Jos Jonkers. Establishing tumoroid and mouse models for functional validation of progression markers in DCIS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5115.