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FIGURE 3 from NRF2 Activation in Trp53;p16-deficient Mice Drives Oral Squamous Cell Carcinoma

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posted on 2024-02-21, 14:40 authored by Samera H. Hamad, Rani S. Sellers, Nathan Wamsley, Paul Zolkind, Travis P. Schrank, Michael B. Major, Bernard E. Weissman

Characterization of oral squamous cell carcinomas from CPN mice. Invasive OSCC from a CPN mouse stained for H&E (A). B, NRF2. PANCK (C) and vimentin (D). Scale bar = 200 µm. Images were taken using a BX61-Neville microscope.

Funding

HHS | NIH | National Cancer Institute (NCI)

HHS | NIH | National Institute of Environmental Health Sciences (NIEHS)

HHS | NIH | National Institute of Dental and Craniofacial Research (NIDCR)

Golberg Foundation

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ARTICLE ABSTRACT

Aberrant activation of the NRF2/NFE2L2 transcription factor commonly occurs in head and neck squamous cell carcinomas (HNSCC). Mouse model studies have shown that NRF2 activation alone does not result in cancer. When combined with classic oncogenes and at the right dose, NRF2 activation promotes tumor initiation and progression. Here we deleted the tumor suppressor genes p16INK4A and p53 (referred to as CP mice), which are commonly lost in human HNSCC, in the presence of a constitutively active NRF2E79Q mutant (CPN mice). NRF2E79Q expression in CPN mice resulted in squamous cell hyperplasia or dysplasia with hyperkeratosis in the esophagus, oropharynx, and forestomach. In addition, CPN mice displayed oral cavity squamous cell carcinoma (OSCC); CP mice bearing wild-type NRF2 expression did not develop oral cavity hyperplasia, dysplasia or OSCC. In both CP and CPN mice, we also observed predominantly abdominal sarcomas and carcinomas. Our data show that in the context of p53 and p16 tumor suppressor loss, NRF2 activation serves oncogenic functions to drive OSCC. CPN mice represent a new model for OSCC that closely reflects the genetics of human HNSCC. Human squamous cancers frequently show constitutive NRF2 activation, associated with poorer outcomes and resistance to multiple therapies. Here, we report the first activated NRF2-driven and human-relevant mouse model of squamous cell carcinoma that develops in the background of p16 and p53 loss. The availability of this model will lead to a clearer understanding of how NRF2 contributes to the initiation, progression, and therapeutic response of OSCC.

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