Abstract 1030: Circulating tumor cells from patients' blood induce tumors in a personalized xenograft mouse model: A functional approach to assess the patients' premetastatic disease state
Authors: Shraga Netta R. , Lieberman Amihai , Moskovits Neta , Livoff Alejandro , Solomonov Evgeny , Shachar Inbar Ben , Popovtzer Aron , Stemmer* Salomon M. , Haviv* Izhak 
Published: August 2018

Background: Circulating tumor cells (CTCs) originate from both primary and metastatic solid tumors and infiltrate the blood system. Although the metastatic potential of the single CTC cell is unknown, CTCs in circulation have been reported to have prognostic value as early predictors of relapse in cancers including ovarian, breast, colorectal, prostate, lung, bladder, head and neck and melanoma. As metastatic spread remains the major problem in cancer treatment, it is of great importance to characterize the subpopulations of CTCs with the highest metastatic potential.

Methods: Peripheral blood mononuclear cells (MNCs) or bone marrow MNCs, were collected from each of over 60 cancer patients and grafted separately to immunodeficient NOD.Cg-Prkdc.scid.Il2rgtm1Wjl/SzJ (NSG) mice. Additionally, CTCs were enriched by either CD8 T-cell depletion or by a size-based filtration system. Tumors that developed in the mice were confirmed to be human tumors by demonstrating that they have human HLA expression and by comparing their tumor type by an independent pathologist to that of the donor patient's. The CTC-derived tumors were passaged to naive NSG mice to establish the scale up potential for treatment-groups. To facilitate future research of CTC-derived tumors, we have established a Biobank for CTC-derived tumors with matched samples of the patient's MNCs, plasma, tumor biopsy(s) and patient-biopsy derived xenograft (PDX) tumors. Additional characterization of the CTC-derived tumors was performed, such as comparison to the driver-mutations of the original tumor-biopsies and expression of epithelial or mesenchymal markers. The clinical relevance of the CTC-derived tumors was assessed by long term follow-up of each patient's disease progression.

Results: CTC-derived tumors were detected in xenografts in 15 cases, within an average of eight months post grafting, representing a 25% success rate. The CTC-derived tumors were from a variety of cancers including: breast (6), colon (1), lung (2), pancreatic (1), ovarian (1), malignant-mesothelioma (1) head and neck (1) hepatocellular carcinoma (1) and sarcoma (1). The patients, whose blood or marrow contained tumorigenic CTCs, developed metastasis. Interestingly, there was a correlation between sites of CTC-derived tumors in the mice and sites of metastatic spread in the patients. CTC-derived tumors were successfully transferred to subsequent PDX mice, enabling the establishment of large treatment groups to study drug reactivity of these tumors.

Summary: This study describes a functional assay to characterize the CTCs subtypes with a high metastatic potential, which utilizes the capacity of CTCs to form tumors in a permissive immune-free environment. CTC-derived tumors may offer a new tool to predict the significance of these malignant cells and prevent metastatic spread.

Citation Format: Netta R. Shraga, Amihai Lieberman, Neta Moskovits, Alejandro Livoff, Evgeny Solomonov, Inbar Ben Shachar, Aron Popovtzer, Salomon M. Stemmer*, Izhak Haviv*. Circulating tumor cells from patients' blood induce tumors in a personalized xenograft mouse model: A functional approach to assess the patients' premetastatic disease state [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 1030.