American Association for Cancer Research
15417786mcr140164-sup-129080_1_supp_2560156_n99z4b.png (1.85 MB)

Supplementary Figure 4 from Loss of Keratinocytic RXRα Combined with Activated CDK4 or Oncogenic NRAS Generates UVB-Induced Melanomas via Loss of p53 and PTEN in the Tumor Microenvironment

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posted on 2023-04-03, 16:28 authored by Daniel J. Coleman, Sharmeen Chagani, Stephen Hyter, Anna M. Sherman, Christiane V. Löhr, Xiaobo Liang, Gitali Ganguli-Indra, Arup K. Indra

Supplementary Figure S4: An increase in infiltrating macrophages is observed in melanocytic lesions from Cdk4R24cmice with epidermal-specific knockout of Rxra, but not in Rxraep-/- Tyr-NRASQBtK mice. No change in infiltrating CD4+ T-cells observed in melanocytic lesions from either Cdk4R24c or Tyr-NRASQ61K mice with epidermal-specific knockout of Rxra. (A, B) No change in infiltrating macrophages, as determined by fluorescent immunohistochemistry (I HC) of of 5 J.lm paraffin sections (MAC1 antigen), was observed in Rxraep-/- 1 Tyr-NRAS061K mice as compared to RxraL2/L2 controls. (C, D) An increase in infiltrating macrophages was observed in Rxraep-/- 1 Cdk4R24c mice as compared to RxraL2/L2 controls. (E-H) No change in infiltrating CD4+ T-cells as determined by fluorescent IHC was observed in Rxraep-/- Tyr-NRAS061K or Rxraep-/- Cdk4R24c mice as compared to RxraL 21L2 controls. Scale bars= 50 J.lm. ** = p :5 0.01



Understanding the molecular mechanisms behind formation of melanoma, the deadliest form of skin cancer, is crucial for improved diagnosis and treatment. One key is to better understand the cross-talk between epidermal keratinocytes and pigment-producing melanocytes. Here, using a bigenic mouse model system combining mutant oncogenic NRASQ61K (constitutively active RAS) or mutant activated CDK4R24C/R24C (prevents binding of CDK4 by kinase inhibitor p16INK4A) with an epidermis-specific knockout of the nuclear retinoid X receptor alpha (RXRαep−/−) results in increased melanoma formation after chronic ultraviolet-B (UVB) irradiation compared with control mice with functional RXRα. Melanomas from both groups of bigenic RXRαep−/− mice are larger in size with higher proliferative capacity, and exhibit enhanced angiogenic properties and increased expression of malignant melanoma markers. Analysis of tumor adjacent normal skin from these mice revealed altered expression of several biomarkers indicative of enhanced melanoma susceptibility, including reduced expression of tumor suppressor p53 and loss of PTEN, with concomitant increase in activated AKT. Loss of epidermal RXRα in combination with UVB significantly enhances invasion of melanocytic cells to draining lymph nodes in bigenic mice expressing oncogenic NRASQ61K compared with controls with functional RXRα. These results suggest a crucial role of keratinocytic RXRα to suppress formation of UVB-induced melanomas and their progression to malignant cancers in the context of driver mutations such as activated CDK4R24C/R24C or oncogenic NRASQ61K.Implications: These findings suggest that RXRα may serve as a clinical diagnostic marker and therapeutic target in melanoma progression and metastasis. Mol Cancer Res; 13(1); 186–96. ©2014 AACR.