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。 我们的研究重点是阐明促进转移进展的机制， 转移的表型异质性。为此，我们开发了一系列基因工程 小鼠模型（GEMM），概括了转移性前列腺癌的表型异质性。的 这一系列GEMM的核心是NPKEYFP小鼠模型，它发育出高度渗透性的骨 转移该模型由另外的GEMM补充，即NPMEYFP和NPp 53 EYFP小鼠， 显示出独特的转移表型。我们已经在大量组织中进行了转录组学分析， 前列腺肿瘤的单细胞水平和这些GEMM的转移，以识别候选驱动因素（主 调节因子（MR））的转移进展和表型异质性。此外，我们还分离出 循环肿瘤细胞（CTC）从这些转移GEMM研究其异质性在细胞水平。在 特别是，我们已经建立了一个管道来分离和分子表征单个CTC作为类器官 并在单细胞水平上研究CTC。我们的调查揭示了几个主题，塑造了 我们的研究方向。特别是，我们的发现支持了特定突变事件（如 p53功能的丧失以及MYC和RAS信号传导的激活）以及细胞可塑性是 转移进展和表型异质性。 因此，我们将研究我们的假设，即异质性的转移代表的顶点， 分子、细胞和生物学差异，如下：在目标1中，我们将研究转移性肿瘤的机制， 进展：（a）通过分析新的GEMM研究组蛋白甲基转移酶NSD 2的作用 在前列腺肿瘤中获得NSD 2的功能;和（B）研究转移性前列腺癌的细胞内在机制。 在原发性肿瘤和肺及骨转移中的单细胞水平进展。在目标2中，我们将研究 通过分析我们的GEMM，显示了转移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类器官模型和单细胞测序方法。总的来说，我们的 这些研究是高度创新的，它们结合了复杂的诱导型小鼠模型，单细胞分析， 类器官培养方法和计算机系统方法来研究癌症的核心问题 生物学我们对前列腺癌转移精确建模的研究可能最终有助于指导个体化治疗。 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.