title: Suicide Gene-Engineered Stromal Cells Reveal a Dynamic Regulation of Cancer Metastasis.
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 cancer metastasis that has counter-intuitive ramifications for CAF-targeted therapy.
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Keyue
authors.initials: K
authors.lastname: Shen
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Samantha
authors.initials: S
authors.lastname: Luk
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Elman
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Murray
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.
authors.forename: Shilpaa
authors.initials: S
authors.lastname: Mukundan
authors.affiliation: Department of Surgery, Center for Engineering in Medicine and Surgical Services, Massachusetts General Hospital, Harvard Medical School and the Shriners Hospitals for Children, Boston, Massachusetts 02114, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: Biju
authors.initials: B
authors.lastname: Parekkadan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001859:Bone Neoplasms / Q000556:secondary; D045744:Cell Line, Tumor; D002633:Chemotaxis / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic; D041722:Genes, Transgenic, Suicide; D005818:Genetic Engineering; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000556:secondary; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D010641:Phenotype; D017154:Stromal Cells / Q000378:metabolism* / Q000473:pathology*; D014161:Transduction, Genetic
chemical_list: D016207:Cytokines