Apoptosis in Melanoma Progression and Chemoresistance

描述（由申请人提供）：黑色素瘤进展和化疗耐药性的分子基础的鉴定受到了众所周知的肿瘤间和肿瘤内异质性的阻碍，并且受到以下事实的阻碍：在其转化为转移性细胞期间，人黑色素细胞在多个存活和细胞死亡信号级联中获得了大量的遗传和表观遗传改变。了解哪些改变是疾病的原因（以及哪些是副产品），它们在黑色素瘤发展的每个步骤（即从癌前病变到原位和转移性病变）的具体影响，以及具体而言，它们如何影响治疗反应，仍然是皮肤肿瘤学的主要挑战。 该提议将检验以下假设：线粒体细胞死亡途径的失活在人黑素细胞转化、侵袭和转移期间提供关键的存活优势，并且这种失活必须被补偿或绕过以克服黑色素瘤化学抗性。 为了解释肿瘤异质性，我们将利用密歇根大学产生的大型黑色素瘤肿瘤库，对黑色素瘤进展所有阶段的关键线粒体凋亡调节剂进行全面分析（目标1）。由于黑色素瘤发病机制中的起始事件在很大程度上是未知的，因此将特别强调恶性前和早期黑色素瘤。同时，我们将剖析线粒体途径对人类黑素细胞和黑色素瘤细胞的转化（目的2）和致瘤性（目的3）的功能贡献，以及它们对化疗药物的反应（目的4）。在这种情况下，我们的研究设计的一个重要考虑是，黑色素瘤的产生不仅仅是由于正常黑色素细胞突变的结果，但基质隔室也是重要的决定因素。因此，我们将工程黑素细胞病变与特定缺陷的凋亡途径，并确定其对肿瘤生长的设置，概括了人类黑色素瘤在体内的架构的影响。最后，我们将利用我们的初步研究与药理学策略，能够绕过线粒体细胞死亡缺陷，最终目标是确定新的治疗方法，能够克服黑色素瘤耐药性。 细胞凋亡的缺陷并不限于黑色素瘤的控制，因为细胞存活增加是肿瘤生物学中的一般概念。因此，我们研究的方法和结果可能与其他各种侵袭性肿瘤类型相关，并可能为合理设计改进的治疗方法提供基础。

DESCRIPTION (provided by applicant): The identification of the molecular basis of melanoma progression and chemoresistance has been hampered by a notorious inter- and intra-tumor heterogeneity, and by the fact that during their transformation into metastatic cells, human melanocytes acquire a large number of genetic and epigenetic alterations in multiple survival and cell death signaling cascades. Understanding which alterations are causative of the disease (and which a byproduct), what are their specific impact at each step of melanoma development (i.e. from pre-malignant to in situ and metastatic lesions), and specifically, how do they affect treatment response, remain major challenges in cutaneous oncology. This proposal will test the hypothesis that inactivation of the mitochondrial cell death pathway provides a critical survival advantage during human melanocyte transformation, invasion and metastasis, and that this inactivation has to be compensated or bypassed to overcome melanoma chemoresistance. To account for tumor heterogeneity, we will take advantage of a large melanoma tumor bank generated at the University of Michigan to perform a comprehensive analysis of critical mitochondrial apoptotic modulators at all stages of melanoma progression (Aim 1). Special emphasis will be dedicated to pre-malignant and early melanomas, since initiating events in melanoma pathogenesis are largely unknown. In parallel, we will dissect the functional contribution of the mitochondrial pathway to transformation (Aim 2) and tumorigenicity (Aim 3) of human melanocytes and melanoma cells, and to their response to chemotherapeutic agents (Aim 4). In this context, an important consideration of our research design is that melanomas do not arise simply as a consequence of mutations in normal melanocytes, but stromal compartments are important determinants as well. We will therefore engineer melanocytic lesions with specific defects in apoptotic pathways and determine their impact on tumor growth in settings that recapitulate the architecture of human melanoma in vivo. Finally, we will exploit our preliminary studies with pharmacological strategies able to bypass mitochondrial cell death defects, with the ultimate goal of identifying new treatments able to overcome melanoma chemoresistance. Defects in apoptosis are not limited to the control of melanoma as increased cell survival is a general concept in tumor biology. Therefore, the approaches and results of our studies may be relevant to a variety of other aggressive tumor types and may provide the basis for rational design of improved therapies.