Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis

Scientific Reports
Keyue ShenBiju Parekkadan

Abstract

Cancer-associated fibroblasts (CAFs) are a major cancer-promoting component in the tumor microenvironment (TME). The dynamic role of human CAFs in cancer progression has been ill-defined because human CAFs lack a unique marker needed for a cell-specific, promoter-driven knockout model. Here, we developed an engineered human CAF cell line with an inducible suicide gene to enable selective in vivo elimination of human CAFs at different stages of xenograft tumor development, effectively circumventing the challenge of targeting a cell-specific marker. Suicide-engineered CAFs were highly sensitive to apoptosis induction in vitro and in vivo by the addition of a simple small molecule inducer. Selection of timepoints for targeted CAF apoptosis in vivo during the progression of a human breast cancer xenograft model was guided by a bi-phasic host cytokine response that peaked at early timepoints after tumor implantation. Remarkably, we observed that the selective apoptosis of CAFs at these early timepoints did not affect primary tumor growth, but instead increased the presence of tumor-associated macrophages and the metastatic spread of breast cancer cells to the lung and bone. The study revealed a dynamic relationship between CAFs and ...Continue Reading

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Citations

Nov 5, 2016·Nature Reviews. Drug Discovery·Yufang ShiYing Wang
May 16, 2019·Stem Cells Translational Medicine·Ayesha AijazBiju Parekkadan
Mar 3, 2021·Journal of Experimental & Clinical Cancer Research : CR·Weiqiang HuangJian Guan
Mar 30, 2021·Advanced Functional Materials·Amanda X ChenSangeeta N Bhatia
Jun 29, 2021·European Journal of Nuclear Medicine and Molecular Imaging·Fan DingDewei Tang

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Methods Mentioned

BETA
transgenic
xenograft
fluorescence-activated cell sorting
flow cytometry
Assay

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