Molecular mechanisms of prostate cancer metastasis

虽然局部浸润性前列腺癌几乎总是可以治愈的，但转移性前列腺癌通常是致命的。 我们的研究集中在阐明促进转移进展的机制和基础 转移瘤的表型异质性。为此，我们开发了一系列基因工程 描述转移性前列腺癌表型异质性的小鼠模型(GEMM)。这个 这个GEMM集合的核心是NPKEYFP小鼠模型，它可以产生高度穿透性的骨骼 转移。这一模型得到了额外的GEMM的补充，即NPMEYFP和NPp53EYFP小鼠，即 表现出独特的转移表型。我们已经对大块组织进行了转录分析 这些GEMM的单细胞水平的前列腺癌和转移，以确定候选驱动因素(硕士 转移进展和表型异质性的调节因子(MRS)。此外，我们已经分离出 从这些转移的GEMM中提取循环肿瘤细胞(CTCs)，以在细胞水平上研究它们的异质性。在……里面 具体地说，我们已经建立了一条分离和分子表征有机化合物的管道 并在单细胞水平上对CTCs进行研究。我们的调查揭示了几个影响 我们的研究方向。特别是，我们的发现支持特定突变事件(如 P53功能的丧失和MYC和RAS信号的激活)以及细胞的可塑性是 转移进展和表型异质性。 因此，我们将调查我们的假设，即转移的异质性代表着 分子、细胞和组织差异如下：在目标1中，我们将研究转移的机制 研究进展：(A)通过分析一种新的GEMM来研究组蛋白甲基转移酶NSD2的作用 NSD2在前列腺癌中功能的获得；以及(B)研究转移的细胞内在机制 原发肿瘤、肺和骨转移的单细胞水平进展。在目标2中，我们将调查 通过对我们的GEMM的分析，发现转移的表型异质性的分子机制 转移表型的范围。在目标3中，我们将检查循环肿瘤细胞(Ctc)的细胞异质性。 在单细胞水平上，使用器官模型和单细胞测序方法。总而言之，我们的 研究在复杂的可诱导小鼠模型、单细胞分析、 研究癌症中心问题的有机培养方法和计算系统方法 生物学。我们对前列腺癌转移的精确建模研究最终可能有助于指导个性化 病人护理。

Although locally invasive prostate cancer is nearly always curable, metastatic prostate cancer is usually fatal. Our research is focused on elucidating mechanisms that promote metastatic progression and underlie phenotypic heterogeneity of metastases. Toward this end, we have developed a series of genetically engineered mouse models (GEMMs) that recapitulate the phenotypic heterogeneity of metastatic prostate cancer. The centerpiece of this collection of GEMMs is the NPKEYFP mouse model, which develops highly penetrant bone metastasis. This model is complemented by additional GEMMs, namely the NPMEYFP and NPp53EYFP mice, that display distinctive metastatic phenotypes. We have performed transcriptomic analyses at the bulk tissue and single-cell level of prostate tumors and metastases from these GEMMs to identify candidate drivers (master regulators (MRs)) of metastatic progression and phenotypic heterogeneity. Furthermore, we have isolated circulating tumor cells (CTCs) from these metastatic GEMMs to study their heterogeneity at the cellular level. In particular, we have established a pipeline to isolate and molecularly characterize individual CTCs as organoids and to study the CTCs at the single-cell level. Our investigations have uncovered several themes that shape the direction of our research. In particular, our findings support the concept that specific mutational events (such as loss of function of p53 and activation of MYC and RAS signaling) as well as cellular plasticity are key drivers of metastatic progression and phenotypic heterogeneity. Thus, we will investigate our hypothesis that heterogeneity of metastasis represents the culmination of molecular, cellular, and organismal differences, as follows: In Aim 1, we will study mechanisms of metastatic progression by: (a) investigating the role of the histone methyltransferase NSD2 by analyses of a new GEMM with gain of function of NSD2 in prostate tumors; and (b) studying cell-intrinsic mechanisms of metastatic progression at the single-cell level in primary tumors and lung and bone metastases. In Aim 2, we will investigate molecular mechanisms of phenotypic heterogeneity of metastasis by analyses of our GEMMs that display a range of metastatic phenotypes. In Aim 3, we will examine cellular heterogeneity of circulating tumor cells (CTCs) at the single-cell level using organoid models and single-cell sequencing approaches. Taken together, our studies are highly innovative in their combination of sophisticated inducible mouse models, single-cell analyses, organoid culture methods, and computational systems approaches to investigate a central problem in cancer biology. Our studies of precision modeling of prostate cancer metastasis may ultimately help guide individualized patient care.