title: Notch1 Activation or Loss Promotes HPV-Induced Oral Tumorigenesis.
abstract: Viral oncogene expression is insufficient for neoplastic transformation of human cells, so human papillomavirus (HPV)-associated cancers will also rely upon mutations in cellular oncogenes and tumor suppressors. However, it has been difficult so far to distinguish incidental mutations without phenotypic impact from causal mutations that drive the development of HPV-associated cancers. In this study, we addressed this issue by conducting a functional screen for genes that facilitate the formation of HPV E6/E7-induced squamous cell cancers in mice using a transposon-mediated insertional mutagenesis protocol. Overall, we identified 39 candidate driver genes, including Notch1, which unexpectedly was scored by gain- or loss-of-function mutations that were capable of promoting squamous cell carcinogenesis. Autochthonous HPV-positive oral tumors possessing an activated Notch1 allele exhibited high rates of cell proliferation and tumor growth. Conversely, Notch1 loss could accelerate the growth of invasive tumors in a manner associated with increased expression of matrix metalloproteinases and other proinvasive genes. HPV oncogenes clearly cooperated with loss of Notch1, insofar as its haploinsufficiency accelerated tumor growth only in HPV-positive tumors. In clinical specimens of various human cancers, there was a consistent pattern of NOTCH1 expression that correlated with invasive character, in support of our observations in mice. Although Notch1 acts as a tumor suppressor in mouse skin, we found that oncogenes enabling any perturbation in Notch1 expression promoted tumor growth, albeit via distinct pathways. Our findings suggest caution in interpreting the meaning of putative driver gene mutations in cancer, and therefore therapeutic efforts to target them, given the significant contextual differences in which such mutations may arise, including in virus-associated tumors.
authors: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: Rong
authors: R
authors: Zhong
authors: Center for Research Informatics, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: Riyue
authors: R
authors: Bao
authors: Functional Genomics Facility, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: Pieter W
authors: PW
authors: Faber
authors: Integrated Microscopy Core; The University of Chicago; Chicago, IL USA.
authors: Vytautas P
authors: VP
authors: Bindokas
authors: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: John
authors: J
authors: Bechill
authors: Department of Pathology, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: Mark W
authors: MW
authors: Lingen
authors: Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, Illinois, 60637, United States.
authors: Michael T
authors: MT
authors: Spiotto
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D001943:Breast Neoplasms / Q000473:pathology / Q000821:virology; D002273:Carcinogens; D018289:Carcinoma, Verrucous / Q000473:pathology / Q000821:virology; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D003043:Cocarcinogenesis; D004251:DNA Transposable Elements; D018450:Disease Progression; D005260:Female; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009062:Mouth Neoplasms / Q000235:genetics* / Q000821:virology; D016254:Mutagenesis, Insertional; D009361:Neoplasm Invasiveness; D009857:Oncogenes; D010212:Papilloma / Q000139:chemically induced / Q000473:pathology / Q000821:virology; D027383:Papillomaviridae / Q000472:pathogenicity*; D051881:Receptor, Notch1 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012878:Skin Neoplasms / Q000139:chemically induced / Q000473:pathology; D013047:Specific Pathogen-Free Organisms; D013629:Tamoxifen / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014412:Tumor Virus Infections / Q000503:physiopathology*; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000821:virology
chemical_list: D002273:Carcinogens; D004251:DNA Transposable Elements; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D013629:Tamoxifen; D015112:4-Nitroquinoline-1-oxide; D015127:9,10-Dimethyl-1,2-benzanthracene; D013755:Tetradecanoylphorbol Acetate