Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents

Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents

Bibliographic Details
Main Author: Hennessey, Rebecca Coral
Language:English
Published: The Ohio State University / OhioLINK 2018
Subjects:
Biomedical Research
Genetics
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1531389152704598
id ndltd-OhioLink-oai-etd.ohiolink.edu-osu1531389152704598
record_format oai_dc
collection NDLTD
language English
sources NDLTD
topic Biomedical Research
Genetics
spellingShingle Biomedical Research
Genetics
Hennessey, Rebecca Coral
Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
author Hennessey, Rebecca Coral
author_facet Hennessey, Rebecca Coral
author_sort Hennessey, Rebecca Coral
title Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
title_short Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
title_full Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
title_fullStr Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
title_full_unstemmed Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents
title_sort optimized mouse models for the discovery of novel targets and testing of melanoma preventative agents
publisher The Ohio State University / OhioLINK
publishDate 2018
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1531389152704598
work_keys_str_mv AT hennesseyrebeccacoral optimizedmousemodelsforthediscoveryofnoveltargetsandtestingofmelanomapreventativeagents
_version_ 1719454229254373376
spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15313891527045982021-08-03T07:07:31Z Optimized Mouse Models for the Discovery of Novel Targets and Testing of Melanoma Preventative Agents Hennessey, Rebecca Coral Biomedical Research Genetics Cutaneous melanoma is the fifth most commonly diagnosed cancer in the United States and the deadliest of the skin cancers. Genetic predisposition and ultraviolet (UV) radiation are strong risk factors for cutaneous melanoma development. Estimates suggest that 90% of melanomas are attributed to sun exposure which contains UV, yet the mechanism by which UV promotes melanomagenesis is not completely understood. Melanoma can be divided into four genetic subtypes based upon the oncogenic driver: BRAF-mutant, NRAS-mutant, NF1-mutant, or triple wild-type. Of these four subtypes, BRAF- and NRAS-mutant melanomas are the most frequent, accounting for ~50% and ~30% of all melanomas, respectively. We assembled genetically engineered mouse models (GEMMs) to replicate these two genetic subtypes of melanoma. <i>TpB</i> mice express oncogenic Braf<sup>600E</sup> from the endogenous gene promoter and exhibit p16<sup>INK4a</sup> loss in melanocytes. By contrast, melanocytes in <i>TpN</i> mice express oncogenic Nras<sup>61R</sup> from the endogenous gene locus and show loss of p16<sup>INK4a</sup>. Both <i>TpN</i> and <i>TpB</i> mice develop spontaneous melanomas. To mimic UV exposure from the sun, <i>TpN</i> and <i>TpB</i> mice were irradiated with a single, physiologically relevant dose of UVB which resulted in accelerated melanoma onset. Through the creation of <i>TpN</i> derivatives, <i>Tp</i> and <i>TN</i> mice, it was determined that expression of Nras<sup>61R</sup> is a sufficient driver of melanoma development. While the loss of p16<sup>INK4a</sup> is unable to drive melanoma development, in combination with Nras<sup>61R</sup> expression, loss of p16<sup>INK4a</sup> contributes to melanoma incidence and growth rate. Therefore, both Braf<sup>600E</sup> and Nras<sup>61R</sup>, which are frequently found in benign melanoma precursors (nevi), cooperate with UVB to drive melanomagenesis. Frequently, GEMMs do not genetically replicate the human solid tumors they are modeling. As UVB exposure cooperated with oncogenic Nras and Braf to hasten melanoma development, we examined the ability of UVB to `humanize’ the genomic landscape of <i>TpN</i> and <i>TpB</i> tumors. Whole exome sequencing revealed a shift in the genetic profiles of UVB-irradiated <i>TpN</i> and <i>TpB</i> tumors. Exposure to UVB resulted in an increase in single nucleotide variants, which were enriched for the UV signature. Ingenuity Pathway Analysis found UVB targeted genes were associated with dermatological diseases, especially cutaneous melanoma. Further analysis defined conserved and genotype-dependent canonical pathways, in UVB-exposed <i>TpN</i> and <i>TpB</i> melanomas, that may represent key events required for melanomagenesis. Genomic characterization of <i>TpN</i> and <i>TpB</i> tumors reveals the importance of incorporating UVB exposure into these models to accurately replicate human melanomas. To mitigate melanoma risk, sunscreen use is widely advocated; yet, the ability of sunscreens to prevent melanoma remains controversial. Here, we used our UVB-sensitive <i>TpN</i> mice as a preclinical testing model to examine the ability of six compositionally diverse commercial aerosol sunscreens to prevent melanoma. While all sunscreens delayed spontaneous melanoma formation and blocked UVB-induced DNA damage, differences in aerosol output (i.e. amount applied/cm<sup>2</sup>) led to variability in the melanoma preventative efficacy of products with identical sunburn protection factor (SPF) ratings. It is well-established that consumers apply less than the recommended amount of sunscreen. Our data provide experimental evidence to support the idea that sunscreen application has a greater impact on the efficacy of SPF30 sunscreens than product formulation. Overall, the data presented here highlights the importance of incorporating UV into melanoma GEMMs to increase biological and genetic relevance, and provides an example of the versatility that these models can provide in melanomagenesis studies. 2018 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1531389152704598 http://rave.ohiolink.edu/etdc/view?acc_num=osu1531389152704598 restricted--full text unavailable until 2023-08-06 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.

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