Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer

谱系可塑性已成为前列腺癌治疗抵抗的重要机制 导致多种不同的肿瘤状态。最近的分类工作表明，除了雄激素 受体通路阳性的腺癌(CRPC-AD)和终末期神经内分泌肿瘤(NEPC) 肿瘤也富含以间充质和干细胞特征表达为特征的“杂交状态”。 这种表型被称为间叶性和干状前列腺癌(MSPC)。这件事的首要目标是 应用是确定MSPC表型潜在的新的分子机制，可以作为靶点 从治疗上讲。我们的假设是，PKCλ/ι的丢失 (由PrKCI基因编码)，通过上调 CD44/透明质酸(HA)轴诱导以上皮细胞活化为特征的间充质表型 EMT与促结缔组织增生性肿瘤间质的产生，两者都是肿瘤进展和治疗的关键事件 抵抗。我们假设PKCλ/ι控制的机制的详细特征 CD44/HA轴将提供有关MSPC进展和分子通路的关键新信息 将为选择对设计的新疗法有反应的患者提供理由 间充质/基质靶点。我们的初步数据表明：(1)人类MSPC的PRKCI水平较低 和高度促结缔组织间质；(2)在体前列腺上皮中PKCλ/ι缺失诱导EMT并促进 重建肿瘤微环境的促结缔组织增生性反应；(3)低PRKCI水平与 人类前列腺癌中CD44/HA轴的上调，支持这些发现与人类的相关性。基于 这些前提，在本提案中，我们将解决以下具体目标：目标1A：确定如何进行干预 CD44或其配体(OPN/Sp1、HA)可阻断PKCλ/ι促进的MSPC和苯扎鲁胺耐药。 目的1B：确定CD44/HA轴在基质激活中的作用和 基质-上皮反馈串扰；目标1C：确定蛋白激酶Cλ/ι调节的分子机制 CD44；目标2A：确定前列腺上皮CD44在体内驱动MSPC中的作用；目标2B：确定 前列腺癌间质CD44在体内驱动MSPC中的作用目的3A：确定PEGPH20的治疗潜力 苯扎鲁胺联合治疗MSPC肿瘤的临床疗效及靶点3B：探讨其作用机制 在单细胞级别上的操作。这项提议的结果将有助于更全面地理解 驱动MSPC类型的PCA的机制，并将是设计新的更具选择性和 治疗这种侵袭性肿瘤的有效方法。

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer that results into multiple different tumor states. Recent classifications efforts have revealed that besides the androgen receptor pathway positive adenocarcinomas (CRPC-AD) and the terminal neuroendocrine tumors (NEPC), there are also tumors enriched in a “hybrid state” characterized by the expression of mesenchymal and stem cell traits. This phenotype is termed mesenchymal and stem-like prostate cancer (MSPC). The overarching goal of this application is to identify novel molecular mechanisms underlying the MSPC phenotype that can be targeted therapeutically. Our hypothesis is that the loss of PKCλ/ ι (encoded by PRKCI gene), by upregulating the CD44/Hyaluronan (HA) axis, induces the mesenchymal phenotype characterized by the activation of epithelial EMT and the generation of desmoplastic tumor stroma, both critical events for tumor progression and therapy resistance. We postulate that the detailed characterization of the mechanisms whereby PKCλ/ ι controls the CD44/HA axis will provide critical new information on the molecular pathways leading to MSPC progression and will offer a rationale for the selection of patients susceptible to respond to new therapies designed at mesenchymal/stromal targets. Our preliminary data demonstrate that (1) human MSPC has low PRKCI levels and a highly desmoplastic stroma; (2) PKCλ/ ι loss in the prostate epithelium in vivo induces EMT and promotes a desmoplastic response that remodels the tumor microenvironment; (3) Low PRKCI levels correlate with upregulation of the CD44/HA axis in human PCa, supporting the human relevance of these findings. Based on these premises, in this proposal we will address the following specific Aims: Aim 1A: Determine how interfering with CD44 or its ligands (OPN/SPP1, HA) block MSPC and enzalutamide resistance promoted by PKCλ/ ι- deficiency in the epithelium; Aim 1B: Determine the role of the CD44/HA axis in stromal activation and the stromal-epithelial feedback crosstalk; Aim 1C: Determine the molecular mechanism whereby PKCλ/ ι regulates CD44; Aim 2A: Determine the role of prostate epithelial CD44 in driving MSPC in vivo; Aim 2B: Determine the role of prostate stromal CD44 in driving MSPC in vivo; Aim 3A: Determine the therapeutic potential of PEGPH20 in combination with enzalutamide in the treatment of MSPC tumors and Aim 3B: Investigate its mechanism of action at a single-cell level. The results of this proposal will contribute to a more comprehensive understanding of the mechanisms driving the MSPC type of PCa and will be key for the design of new more selective and effective therapies for this type of aggressive neoplasia.