title: Loss of Trop2 promotes carcinogenesis and features of epithelial to mesenchymal transition in squamous cell carcinoma.
abstract: Trop2, an oncogenic cell surface protein under investigation as a therapeutic target, is commonly overexpressed in several epithelial tumor types yet its function in tumor biology remains relatively unexplored. To investigate the role of Trop2 in epithelial carcinogenesis, we generated Trop2(-/-) mice, which are viable and possess a normal lifespan. Contrary to expectations, Trop2 loss fails to suppress keratinocyte transformation. Instead, ras-transformed Trop2(-/-) keratinocytes preferentially pass through an epithelial to mesenchymal transition (EMT) and form tumors with spindle cell histology. Furthermore, Trop2 loss renders Arf-null mice susceptible to the formation of biphasic sarcomatoid carcinomas containing both squamous and spindle cell components upon carcinogen exposure in an otherwise skin cancer-resistant strain (C57BL/6). Immortalized keratinocytes derived from Trop2(-/-)Arf(-/-) mice exhibit enhanced proliferative and migratory capacity as well as increased activation of mitogen-activated protein kinase and Src prior to transformation. The clinical relevance of these findings was supported by studying the molecular epidemiology of Trop2 in primary head and neck squamous cell carcinomas. This analysis revealed that Trop2 mRNA levels are decreased in a subset of tumors with features of EMT, and total loss of Trop2 protein expression is observed in the spindle cell component of sarcomatoid carcinomas. Therefore, while previous studies have emphasized the potential importance of Trop2 gain of function, these results uncover a role for Trop2 loss in tumorigenesis and the mesenchymal transdifferentiation observed in a subset of squamous cell carcinomas.
authors.affiliation: Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri 63110, USA.
authors.forename: Jianbo
authors.initials: J
authors.lastname: Wang
authors.forename: Kaihua
authors.initials: K
authors.lastname: Zhang
authors.forename: Dorota
authors.initials: D
authors.lastname: Grabowska
authors.forename: Aimin
authors.initials: A
authors.lastname: Li
authors.forename: Yiyu
authors.initials: Y
authors.lastname: Dong
authors.forename: Ryan
authors.initials: R
authors.lastname: Day
authors.forename: Peter
authors.initials: P
authors.lastname: Humphrey
authors.forename: James
authors.initials: J
authors.lastname: Lewis
authors.forename: Raleigh D
authors.initials: RD
authors.lastname: Kladney
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Arbeit
authors.forename: Jason D
authors.initials: JD
authors.lastname: Weber
authors.forename: Christine H
authors.initials: CH
authors.lastname: Chung
authors.forename: Loren S
authors.initials: LS
authors.lastname: Michel
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000737:chemistry; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism*; D054337:Cell Dedifferentiation; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D012878:Skin Neoplasms / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000031:analogs & derivatives / Q000737:chemistry
chemical_list: C554292:12-O-tetradecanoylphorbol-1,3-acetate; D000951:Antigens, Neoplasm; D015815:Cell Adhesion Molecules; C544766:TROP2 protein, mouse; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate