Characterization of Ras-driven Melanoma: Understanding the Relationship Between Acute Loss of p16Ink4a and Somatic Activation of Ras in Melanomagenesis Public Deposited

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  • March 20, 2019
  • Monahan, Kimberly Beth
    • Affiliation: School of Medicine, Curriculum in Genetics and Molecular Biology
  • Melanoma is a complex and heterogeneous disease. It is the only cancer with an increase in incidence over the last three decades, which is still continuing to rise, most likely due to an increase in sun exposure. Melanoma is known for its aggressive behavior, proclivity to metastasize and its remarkable resistance to conventional therapies. Melanoma is curable through surgery if caught early; however, progressive forms of this disease have less treatment options available. Only one FDA-drug is approved for treatment of metastatic disease (dacarbazine), which has a low success rate, with one in ten patients responding. The alarming rate of incidence and the continue failures of treatments, has left an urgency to better understand both the genetic and environmental factors involved in the pathogenesis of melanoma in order to develop more effective therapeutic agents. To date genetically engineered mouse models of melanoma exploit the use of both transgenes and germline knockout alleles which inherently do not reflect the somatic mutations commonly found in human melanoma. The p16INK4a-CDK4-RB and ARF-p53 tumor suppressor pathways are compromised in nearly all human melanomas. While heterozygous germline mutations of p16INK4a are associated with familial melanoma, most melanomas harbor somatic p16INK4a loss, with a significant minority also harboring somatic p53 inactivation. Here, we employ a novel p16INK4a conditional allele along with conditional p53 and K-Ras alleles to better model human melanoma. We found that there is potent synergy between melanocyte-specific loss of p16INK4a and/or p53 with activation of K-Ras in melanomagenesis. Melanoma is recognized as one the most immunogenic cancers. Immunotherapies have been developed to target metastatic melanoma by using treatments to boost the suppressed immune response; however they have shown a low response rate. Here we show that CD200, a negative regulator of the immune system, is overexpressed in melanoma and helps melanoma evade an immune response. Therefore, we believe that melanoma is a rational target of CD200-CD200R anti-cancer therapies.
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  • Sharpless, Norman
  • Open access

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