Abstract 1007: Spatial, temporal and heterogeneous changes in transport phenotype in liver metastasis of breast cancer
Authors: Sadigova Aygul , Kai Megumi , Liu Yan Ting , Nguyen Thao , Hashimoto Chihiro , Yokoi Kenji 
Published: June 2022

Abstract
Various heterogeneities in response of metastatic tumors to systemic anti-cancer therapy are major source of therapeutic resistance. Cancer cells from bulk tumors and cancer cell lines are not clonal. A highly heterogeneous tumor microenvironment is known to develop by subclones. Furthermore, metastasis can evolve during the disease progression as well as in response to systemic therapies. These spatial and temporal variations of heterogeneity in tumors can affect blood perfusion and vascular permeability which can determine the level of mass/anti-cancer drugs transport to tumors (we refer to as “transport phenotype”). Insufficient drug transport to tumor in vivo can generate transport-based therapeutic resistance even for agents with proven efficacy against the target cancer cell lines in vitro. Our goal is to understand spatial and temporal heterogeneity in transport of mass/anti-cancer drugs to metastatic tumors to overcome the therapeutic resistance. The study of bulk tumors will provide a mixture of different functions from heterogeneous sets of various clones. We sought to establish single cell-derived clones from a 4T1 parental murine breast cancer cell line in order to dissect and simplify the heterogeneity in polyclonal cell populations in tumors. First, we found heterogeneous accumulation of systemically injected PEGylated liposomal doxorubicin (PLD) among multiple, experimental liver metastases of 4T1 parental (polyclonal) breast cancer in mouse. Intravital Microscopy imaging of liver metastases through a window chamber over time revealed different transport phenotypes, in terms of circulation and diffusion of systemically injected fluorescent tracers around/inside parental (polyclonal) tumors. Furthermore, transport phenotype can be modulated from one to another after PLD therapy, creating possible mechanisms of transport based on drug resistance. When single cell clone-derived metastases were established, a clone dependent difference in transport phenotype was found. Interestingly transport phenotype even in clonal tumors was temporally evolved and increased its heterogeneity. These data suggest that transport phenotype cannot be determined solely by genotype of tumor and can be evolved and more heterogeneous as a function of tumor growth and systemic chemotherapy. Clinical implication of our findings is that transport of therapeutics to tumor and its efficacy may not be predicted by DNA-based assay for clinical decision-making and transport-based therapeutics resistance will eventually occur in every tumor types.
Citation Format: Aygul Sadigova, Megumi Kai, Yan Ting Liu, Thao Nguyen, Chihiro Hashimoto, Kenji Yokoi. Spatial, temporal and heterogeneous changes in transport phenotype in liver metastasis of breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1007.