title: Maspin Expression in Prostate Tumor Cells Averts Stemness and Stratifies Drug Sensitivity.
abstract: Future curative cancer chemotherapies have to overcome tumor cell heterogeneity and plasticity. To test the hypothesis that the tumor suppressor maspin may reduce microenvironment-dependent prostate tumor cell plasticity and thereby modulate drug sensitivity, we established a new schematic combination of two-dimensional (2D), three-dimensional (3D), and suspension cultures to enrich prostate cancer cell subpopulations with distinct differentiation potentials. We report here that depending on the level of maspin expression, tumor cells in suspension and 3D collagen I manifest the phenotypes of stem-like and dormant tumor cell populations, respectively. In suspension, the surviving maspin-expressing tumor cells lost the self-renewal capacity, underwent senescence, lost the ability to dedifferentiate in vitro, and failed to generate tumors in vivo. Maspin-nonexpressing tumor cells that survived the suspension culture in compact tumorspheres displayed a higher level of stem cell marker expression, maintained the self-renewal capacity, formed tumorspheres in 3D matrices in vitro, and were tumorigenic in vivo. The drug sensitivities of the distinct cell subpopulations depend on the drug target and the differentiation state of the cells. In 2D, docetaxel, MS275, and salinomycin were all cytotoxic. In suspension, while MS275 and salinomycin were toxic, docetaxel showed no effect. Interestingly, cells adapted to 3D collagen I were only responsive to salinomycin. Maspin expression correlated with higher sensitivity to MS275 in both 2D and suspension and to salinomycin in 2D and 3D collagen I. Our data suggest that maspin reduces prostate tumor cell plasticity and enhances tumor sensitivity to salinomycin, which may hold promise in overcoming tumor cell heterogeneity and plasticity.
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: M Margarida
authors.initials: MM
authors.lastname: Bernardo
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kaplun
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Sijana H
authors.initials: SH
authors.lastname: Dzinic
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Li
authors.affiliation: Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Irish
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Adelina
authors.initials: A
authors.lastname: Mujagic
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Jakupovic
authors.affiliation: Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan. Department of Microscopy, Imaging and Cytometry Resources Core, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Jessica B
authors.initials: JB
authors.lastname: Back
authors.affiliation: Department of Microscopy, Imaging and Cytometry Resources Core, Wayne State University School of Medicine, Detroit, Michigan.
authors.forename: Eric
authors.initials: E
authors.lastname: Van Buren
authors.affiliation: Peking University Health Science Center, Beijing, China.
authors.forename: Xiang
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Ivory
authors.initials: I
authors.lastname: Dean
authors.affiliation: Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors.forename: Yong Q
authors.initials: YQ
authors.lastname: Chen
authors.affiliation: Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan. Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Heath
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Wael
authors.initials: W
authors.lastname: Sakr
authors.affiliation: Department of Pathology, Wayne State University School of Medicine, Detroit, Michigan. Tumor Biology and Microenvironment Program, Barbara Ann Karmanos Cancer Institute, Detroit, Michigan. Department of Oncology, Wayne State University School of Medicine, Detroit, Michigan. ssheng@med.wayne.edu.
authors.forename: Shijie
authors.initials: S
authors.lastname: Sheng
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000494:pharmacology; D002448:Cell Adhesion / Q000502:physiology; D018929:Cell Culture Techniques; D054337:Cell Dedifferentiation / Q000502:physiology; D045744:Cell Line, Tumor; D000066670:Cell Plasticity / Q000187:drug effects / Q000502:physiology; D000066673:Cell Self Renewal / Q000502:physiology; D016922:Cellular Senescence; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011714:Pyrans / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015843:Serpins / Q000502:physiology*; D013535:Suspensions; D043823:Taxoids / Q000494:pharmacology; D059016:Tumor Microenvironment; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D000077143:Docetaxel; D009363:Neoplasm Proteins; D011714:Pyrans; D011725:Pyridines; D015843:Serpins; D013535:Suspensions; D043823:Taxoids; C085344:SERPIN-B5; C118739:entinostat; C010327:salinomycin; D000095662:Polyether Polyketides