Role of KIT in Early Melanoma Development

描述(由申请人提供)：这项建议的目标是确定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，在与原发黑色素瘤相邻的非皮损皮肤中，存在一种由遗传异常的黑素细胞组成的场效应。有证据表明，这些野细胞可能是局部复发的来源。场效应似乎仅限于黑色素瘤，具有扁桃状生长模式，即表皮内黑素细胞在基底表皮内以单一单位排列的模式，如肢端黑色素瘤和恶性扁桃体黑色素瘤。这些黑色素瘤类型经常在KIT信号通路中有激活的基因改变。由于KIT在黑素细胞向真皮基底层的迁移和归巢中起着至关重要的作用，因此假设KIT通路的激活代表了启动事件，随后是形成临床和组织学可检测病变所需的额外基因改变的获得。为了验证这一假设，这位候选人开发了一个早期人类黑色素瘤进展的异种移植模型。具体地说，她将研究基因工程黑素细胞和表达相关KIT突变的黑色素瘤细胞在移植到免疫缺陷小鼠身上的人类皮肤重建中的表皮内迁移。同时，候选人将评估试剂盒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表面上完全切除后复发的趋势提供解释，并将提供使用试剂盒抑制剂治疗早期黑色素瘤的可能性。

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.