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The Justy mutant mouse strain produces a spontaneous murine model of salivary gland cancer with myoepithelial and basal cell differentiation.

ABSTRACT: We previously identified a novel mutant mouse strain on the C3HeB/FeJ background named Justy. This strain bears a recessive mutation in the Gon4l gene that greatly reduces expression of the encoded protein, a nuclear factor implicated in transcriptional regulation. Here, we report that Justy mutant mice aged 6 months or older spontaneously developed carcinomas with myoepithelial and basaloid differentiation in salivary glands with an incidence of ?25%. Tumors developed proximate to submandibular glands and to a lesser extent in the sublingual and parotid glands. Histologically, tumors often had central cavitary lesions filled with necrotic debris that were lined by tumor cells, and had spindle and epithelioid cell differentiation with lesser basaloid to clear cell features. Tumor tissue often had variable evidence of a high mitotic rate, pleomorphism, and invasion into adjacent salivary glands. Neoplastic cells had diffuse immunoreactivity for pancytokeratin (AE1/AE3) and p63. Although CK5/6 immunostaining was seen in the much of the tumor cells, it was often lacking in pleomorphic areas. Tumor cells lacked immunoreactivity for alpha-smooth muscle actin, S100, c-Kit, and glial fibrillary acid protein. In addition, tumors had immunoreactivity for phosphorylated and total epidermal growth factor receptor, suggesting that EGFR signaling may participate in growth regulation of these tumors. These findings indicate that the salivary gland carcinomas occur spontaneously in Justy mice, and that these tumors may offer a valuable model for study of EGFR regulation. In combination, our data suggest that Justy mice warrant further investigation for use as a mouse model for human salivary gland neoplasia.

SUBMITTER: Simons AL

PROVIDER: S-EPMC3669254 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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The Justy mutant mouse strain produces a spontaneous murine model of salivary gland cancer with myoepithelial and basal cell differentiation.

Simons Andrean L AL Lu Ping P Gibson-Corley Katherine N KN Robinson Robert A RA Meyerholz David K DK Colgan John D JD

Laboratory investigation; a journal of technical methods and pathology 20130422 6

We previously identified a novel mutant mouse strain on the C3HeB/FeJ background named Justy. This strain bears a recessive mutation in the Gon4l gene that greatly reduces expression of the encoded protein, a nuclear factor implicated in transcriptional regulation. Here, we report that Justy mutant mice aged 6 months or older spontaneously developed carcinomas with myoepithelial and basaloid differentiation in salivary glands with an incidence of ∼25%. Tumors developed proximate to submandibular ...[more]

PMID: 23608756

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Project description:The salivary epithelium initiates as a solid mass of epithelial cells that are organized into a primary bud that undergoes morphogenesis and differentiation to yield bilayered acini consisting of interior secretory acinar cells that are surrounded by contractile myoepithelial cells in mature salivary glands. How the primary bud transitions into acini has not been previously documented. We document here that the outer epithelial cells subsequently undergo a vertical compression as they express smooth muscle ?-actin and differentiate into myoepithelial cells. The outermost layer of polarized epithelial cells assemble and organize the basal deposition of basement membrane, which requires basal positioning of the polarity protein, Par-1b. Whether Par-1b is required for the vertical compression and differentiation of the myoepithelial cells is unknown. Following manipulation of Par-1b in salivary gland organ explants, Par-1b-inhibited explants showed both a reduced vertical compression of differentiating myoepithelial cells and reduced levels of smooth muscle ?-actin. Rac1 knockdown and inhibition of Rac GTPase function also inhibited branching morphogenesis. Since Rac regulates cellular morphology, we investigated a contribution for Rac in myoepithelial cell differentiation. Inhibition of Rac GTPase activity showed a similar reduction in vertical compression and smooth muscle ?-actin levels while decreasing the levels of Par-1b protein and altering its basal localization in the outer cells. Inhibition of ROCK, which is required for basal positioning of Par-1b, resulted in mislocalization of Par-1b and loss of vertical cellular compression, but did not significantly alter levels of smooth muscle ?-actin in these cells. Overexpression of Par-1b in the presence of Rac inhibition restored basement membrane protein levels and localization. Our results indicate that the basal localization of Par-1b in the outer epithelial cells is required for myoepithelial cell compression, and Par-1b is required for myoepithelial differentiation, regardless of its localization.

Project description:IntroductionBreast cancer is thought to arise in mammary epithelial stem cells. There is, therefore, a large amount of interest in identifying these cells. The breast is a complex tissue consisting of two epithelial layers (an outer myoepithelial/basal layer and an inner luminal epithelial layer) as well as a large non-epithelial component (fibroblasts, endothelial cells, lymphocytes, adipocytes, neurons and myocytes). The definitive identification of a mammary epithelial stem cell population is critically dependent on its purity. To date, this has been hampered by the lack of suitable markers to separate out the two epithelial layers, and to remove contaminating non-epithelial cells.MethodsMouse mammary glands were dissociated and stained with CD24. Cells were sorted into separate populations based on CD24 expression and assessed for luminal epithelial and myoepithelial/basal markers by direct fluorescent microscopy and real time PCR. The stem/progenitor potential of these cell populations was assessed in vivo by cleared mammary fat pad transplantation.ResultsThree populations of CD24 expressing cells were identified: CD24Negative, CD24Low and CD24High. Staining of these cells with cytokeratin markers revealed that these populations correspond to non-epithelial, myoepithelial/basal and luminal epithelial cells, respectively. Cell identities were confirmed by quantitative PCR. Cleared mammary fat pad transplantation of these cell populations revealed that extensive mammary fat pad repopulation capacity segregates with the CD24Low cells, whilst CD24High cells have limited repopulation capacity.ConclusionDifferential staining of mammary epithelial cells for CD24 can be used to simultaneously isolate pure populations of non-epithelial, myoepithelial/basal and luminal epithelial cells. Furthermore, mammary fat pad repopulation capacity is enriched in the CD24Low population. As separation is achieved using a single marker, it will be possible to incorporate additional markers to further subdivide these populations. This will considerably facilitate the further analysis of mammary epithelial subpopulations, whilst ensuring high purity, which is key for understanding mammary epithelial stem cells in normal tissue biology and carcinogenesis.

Project description:BackgroundTo the authors' knowledge, there are no approved therapies for recurrent, metastatic (R/M) salivary gland carcinoma (SGC), but molecularly targeted therapies warrant ongoing investigation. In the current study, the authors have reported on the efficacy of tipifarnib in patients with aggressive HRAS-mutant, R/M SGC.MethodsThe current prospective, nonrandomized, multicenter, international cohort study involved 8 centers and was conducted from May 2015 to June 2019. The median follow-up was 22 months (range, 6-55 months). Subjects with HRAS-mutant R/M SGC (any histology) and disease progression within the last 6 months were enrolled. Tipifarnib was dosed orally twice daily. The authors determined the objective response rate using Response Evaluation Criteria in Solid Tumors (version 1.1), duration of response, and molecular predictors of response.ResultsA total of 13 patients with R/M SGC were enrolled; all had received prior systemic therapy (1-3 regimens). One objective response was observed; an additional 7 of 12 evaluable patients (58%) had stable disease as their best response with a median duration of 9 months (range, 3-14 months). Five of 7 patients had >10% tumor regression and 6 of 7 had stable disease lasting >6 months. Q61R was the most frequent activating HRAS mutation noted (7 of 13 patients; 54%), but gene variant and allele frequency did not correlate with outcomes. The median progression-free survival was 7 months (95% confidence interval, 5.9-10.1 months), and the median overall survival was 18 months (95% confidence interval, 9.6-22.4 months) with approximately 58.6% of patients alive at 1 year. Survival was similar regardless of HRAS mutant variant or co-occurring PIK3CA alterations. No participant discontinued treatment because of toxicity.ConclusionsTipifarnib resulted in modest clinical activity with a promising disease control rate among patients with HRAS-mutant, R/M SGC who developed disease progression within the last 6 months.

Dataset Information

The Justy mutant mouse strain produces a spontaneous murine model of salivary gland cancer with myoepithelial and basal cell differentiation.

Publications

The Justy mutant mouse strain produces a spontaneous murine model of salivary gland cancer with myoepithelial and basal cell differentiation.

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