Role of KIT in Early Melanoma Development

KIT 在早期黑色素瘤发展中的作用

• 批准号: 8708777
• 负责人: Susana Ortiz Urda
• 金额: $ 12.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-04 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708777
• 关键词: Area; Artificial skin; Biological Markers; Cell Line; Cells; Clinical; Critiques; Dermis; Detection; Development; Early treatment; Epidermis; Event; Excision; Face; Factor Analysis; GAB2 gene; Genetic Engineering; Goals; Growth; Histologic; Homing; Human; Hutchinson' s Melanotic Freckle; Imatinib; Immunodeficient Mouse; Individual; KIT gene; Label; Lateral; Lesion; Malignant Neoplasms; Melanoma Cell; Modeling; Mucous Membrane; Mus; Mutation; N-Cadherin; PTPN11 gene; Pathway interactions; Pattern; Phenotype; Recurrence; Residual state; Role; Signal Pathway; Site; Skin; Somatic Mutation; Source; Stem Cell Factor; Surgical margins; Techniques; Testing; Therapeutic; Time; Variant; Writing; Xenograft Model; cell motility; in vivo; inhibitor/antagonist; meetings; melanoblast; melanocyte; melanoma; migration; mutant; novel therapeutic intervention

DESCRIPTION (provided by applicant): The goal of this proposal is to identify the earliest melanoma precursors and to study the mechanisms of intraepidermal melanoma progression. Recent studies have identified a field effect comprised of genetically abnormal melanocytes in the non-lesional skin adjacent to primary melanomas. Evidence suggests that these field cells may be a source of local recurrences. The field effect appears to be confined to melanomas with a lentiginous growth pattern i.e. an intraepidermal growth pattern in which melanocytes are arranged as single units within the basilar epidermis such as acral and lentigo maligna melanomas. These melanoma types frequently have activating genetic alterations in the KIT signaling pathway. Since KIT has an essential role in melanocyte migration and homing of melanoblasts to the basal dermis, the hypothesis is that KIT pathway activation represents the initiating event that is subsequently followed by the acquisition of additional genetic alterations required to form clinically and histologically detectable lesions. To test this hypothesis, the candidate has developed a xenograft model of early human melanoma progression. Specifically, she will study the intraepidermal migration of genetically engineered melanocytes and melanoma cells expressing relevant KIT mutations seeded into human skin reconstructs grafted onto immunodeficient mice. In parallel, the candidate will evaluate the impact of KIT inhibitors on intraepidermal melanoma progression. These studies will provide an explanation for the tendency of certain melanoma types to recur after apparently complete excision and will offer the possibility to use KIT inhibitors to treat early melanoma.

描述（由申请人提供）：该提案的目标是识别最早的黑色素瘤前体并研究表皮内黑色素瘤进展的机制。最近的研究发现，原发性黑色素瘤附近的非病变皮肤中存在由遗传异常黑色素细胞组成的场效应。有证据表明这些野外细胞可能是局部复发的根源。场效应似乎仅限于具有雀斑样生长模式的黑色素瘤，即表皮内生长模式，其中黑素细胞在基底表皮内排列为单个单元，例如肢端黑色素瘤和恶性雀斑样黑色素瘤。这些黑色素瘤类型经常在 KIT 信号通路中发生激活性基因改变。由于 KIT 在黑素细胞迁移和黑素细胞归巢至真皮基底层中起着重要作用，因此假设 KIT 途径激活代表起始事件，随后获得形成临床和组织学可检测病变所需的额外遗传改变。为了检验这一假设，候选人开发了早期人类黑色素瘤进展的异种移植模型。具体来说，她将研究表达相关 KIT 突变的基因工程黑色素细胞和黑色素瘤细胞的表皮内迁移，这些细胞被植入移植到免疫缺陷小鼠的人类皮肤重建中。与此同时，候选人将评估 KIT 抑制剂对表皮内黑色素瘤进展的影响。这些研究将为某些黑色素瘤类型在明显完全切除后复发的趋势提供解释，并将提供使用 KIT 抑制剂治疗早期黑色素瘤的可能性。