Novel UV-induced melanoma mouse model dependent on Endothelin3 signaling.
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ABSTRACT:
SUBMITTER: Benaduce AP
PROVIDER: S-EPMC4150852 | biostudies-literature | 2014 Sep
REPOSITORIES: biostudies-literature
Publications
Novel UV-induced melanoma mouse model dependent on Endothelin3 signaling.
Benaduce Ana Paula AP Batista Deannys D Grilo Gabriel G Jorge Karen K Cardero Diana D Milikowski Clara C Kos Lidia L
Pigment cell & melanoma research 20140703 5
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Project description:Human melanomas exhibit relatively high somatic mutation burden compared to other malignancies. These somatic mutations may produce neoantigens that are recognized by the immune system, leading to an antitumor response. By irradiating a parental mouse melanoma cell line carrying three driver mutations with UVB and expanding a single-cell clone, we generated a mutagenized model that exhibits high somatic mutation burden. When inoculated at low cell numbers in immunocompetent C57BL/6J mice, YUMMER1.7 (Yale University Mouse Melanoma Exposed to Radiation) regresses after a brief period of growth. This regression phenotype is dependent on T cells as YUMMER1.7 tumors grow significantly faster in immunodeficient Rag1-/- mice and C57BL/6J mice depleted of CD4 and CD8 T cells. Interestingly, regression can be overcome by injecting higher cell numbers of YUMMER1.7, which results in tumors that grow without effective rejection. Mice that have previously rejected YUMMER1.7 tumors develop immunity against higher doses of YUMMER1.7 tumor challenge. In addition, escaping YUMMER1.7 tumors are sensitive to anti-CTLA-4 and anti-PD-1 therapy, establishing a new model for the evaluation of immune checkpoint inhibition and antitumor immune responses.
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Project description:NME1 is a metastasis-suppressor gene (MSG), capable of suppressing metastatic activity in cell lines of melanoma, breast carcinoma and other cancer origins without affecting their growth in culture or as primary tumours. Herein, we selectively ablated the tandemly arranged Nme1 and Nme2 genes to assess their individual impacts on metastatic activity in a mouse model (HGF:p16-/-) of ultraviolet radiation (UVR)-induced melanoma. Metastatic activity was strongly enhanced in both genders of Nme1- and Nme2-null mice, with stronger activity in females across all genotypes. The study ascribes MSG activity to Nme2 for the first time in an in vivo model of spontaneous cancer, as well as a novel metastasis-suppressor function to Nme1 in the specific context of UVR-induced melanoma.
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Project description:In eukaryotic cells, DNA damage triggers activation of checkpoint signaling pathways that coordinate cell cycle arrest and repair of damaged DNA. These DNA damage responses serve to maintain genome stability and prevent accumulation of genetic mutations and development of cancer. The p38 MAPK was previously implicated in cellular responses to several types of DNA damage. However, the role of each of the four p38 isoforms and the mechanism for their involvement in DNA damage responses remained poorly understood. In this study, we demonstrate that p38γ, but not the other p38 isoforms, contributes to the survival of UV-treated cells. Deletion of p38γ sensitizes cells to UV exposure, accompanied by prolonged S phase cell cycle arrest and increased rate of apoptosis. Further investigation reveal that p38γ is essential for the optimal activation of the checkpoint signaling caused by UV, and for the efficient repair of UV-induced DNA damage. These findings have established a novel role of p38γ in UV-induced DNA damage responses, and suggested that p38γ contributes to the ability of cells to cope with UV exposure by regulating the checkpoint signaling pathways and the repair of damaged DNA.
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Project description:The use of bacteria as an alternative cancer therapy has been reinvestigated in recent years. SL7207: an auxotrophic Salmonella enterica serovar Typhimurium aroA mutant with immune-stimulatory potential has proven a promising strain for this purpose. Here, we show that systemic administration of SL7207 induces melanoma tumor growth arrest in vivo, with greater survival of the SL7207-treated group compared to control PBS-treated mice. Administration of SL7207 is accompanied by a change in the immune phenotype of the tumor-infiltrating cells toward pro-inflammatory, with expression of the TH 1 cytokines IFN-γ, TNF-α, and IL-12 significantly increased. Interestingly, Ly6C+ MHCII+ monocytes were recruited to the tumors following SL7207 treatment and were pro-inflammatory. Accordingly, the abrogation of these infiltrating monocytes using clodronate liposomes prevented SL7207-induced tumor growth inhibition. These data demonstrate a previously unappreciated role for infiltrating inflammatory monocytes underlying bacterial-mediated tumor growth inhibition. This information highlights a possible novel role for monocytes in controlling tumor growth, contributing to our understanding of the immune responses required for successful immunotherapy of cancer.
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Project description:PurposeTo investigate whether UV irradiation of the mouse eye can induce photoreceptor degeneration, producing a phenotype reminiscent of the rd10 mouse, left eyes of female C57Bl/6J mice were irradiated with a UV LED array (370 nm). A lens was placed between the cornea and LED, allowing illumination of about one-third of the retina. The short-term and long-term effects on the retina were evaluated.MethodsFirst, a dose escalation study, in which corneal dosages between 2.8 and 9.3 J/cm2 were tested, was performed. A dosage of 7.5 J/cm2 was chosen for the following characterization study. Before and after irradiation slit-lamp examinations, full-field electroretinography, spectral domain optical coherence tomography and macroscopy were performed. After different time spans (5 days to 12 weeks) the animals were sacrificed and the retinae used for immunohistochemistry or multielectrode array testing. Right eyes served as untreated controls.ResultsIn treated eyes, spectral domain optical coherence tomography revealed a decrease in retinal thickness to 53%. Full-field electroretinography responses decreased significantly from day 5 on in treated eyes. Multielectrode array recordings revealed oscillatory potentials with a mean frequency of 5.2 ± 0.6 Hz in the illuminated area. Structural changes in the retina were observed in immunohistochemical staining.ConclusionsUV irradiation proved to be efficient in inducing photoreceptor degeneration in the mouse retina, while leaving the other retinal layers largely intact. The irradiated area of treated eyes can be identified easily in spectral domain optical coherence tomography and in explanted retinae.Translational relevanceThis study provides information on anatomic and functional changes in UV-treated retina, enabling the use of this model for retinitis pigmentosa-like diseases in animals suited for experimental retinal surgery.
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