Defining and Characterizing Drivers of Lethal Metastatic Prostate Cancer

前列腺癌(PC)是美国癌症相关死亡的第二大原因。我们的目标是 拟议的研究是确定从惰性到致命性转变所必需的遗传因素。 转移性前列腺癌。我们已经从RapidCaP的肿瘤和转移中建立了原代细胞系 致死性PC小鼠模型(PTEN和TP53缺失)。我们的初步数据突显了一个根本性的转变 与转移相关的细胞表型和生长信号。最重要的是， 激酶受体的缺失是这一肿瘤转移相关细胞重编程事件的关键。这些 离散的蜂窝状态与不同的信令行为相关联，这启用或限制 癌细胞的转移潜能。因此，我们现在的重点是描绘激酶在PC中的作用 肿瘤转移及控制原发灶向远处转移转移的信号级联反应 活着。在这项建议中，我们将从机械上验证受体在PC细胞谱系中的作用 重新编程和维持转移性EMT样表型(目标1和3)。接下来，我们将评估 PI3K/mTOR信号轴在缺乏型PC中的作用(目标2)。为落实建议的目标，我们会 与受体信号和前列腺癌疾病生物学方面的专家密切合作。我们的背景 在小鼠遗传学中，细胞生物学和翻译肿瘤学与所需的专业知识很好地结合在一起 并揭开致命转移性PC细胞的遗传依赖性。

Prostate cancer (PC) is the second leading cause of cancer-related deaths in the USA. The goal of our proposed research is to identify genetic factors that are essential for the switch from indolent to lethal metastatic prostate cancer. We have generated primary cell lines from tumor and metastasis of the RapidCaP mouse model for lethal PC (PTEN and TP53 deficient). Our preliminary data highlights a fundamental shift in cellular phenotype and growth signaling associated with the transition to metastasis. Most importantly, the loss of TAM kinase receptor is key for this metastasis associated cellular reprogramming event. These discrete cellular states are associated with divergent signaling behavior, which enables or restricts the metastatic potential of cancer cells. Therefore, our focus is now on delineating the role of TAM kinases in PC metastasis and the signaling cascade controlling the switch from primary to distant metastatic disease in vivo. In this proposal we will mechanistically validate the role of TAM receptors in PC cellular lineage reprogramming and maintenance of pro-metastatic EMT-like phenotype (Aims 1 and 3). Next, we will assess the role of PI3K/mTOR signaling axis in TAM-deficient PC (Aim 2). To execute the proposed aims, we will closely collaborate with experts in receptor signaling and prostate cancer disease biology. Our background in mouse genetics, cell biology and translational oncology is well aligned with the expertise required to carry out the proposed work and unravel the genetic dependencies of lethal metastatic PC cells.