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，除了雄激素外， 受体途径阳性腺癌（CRPC-AD）和终末神经内分泌肿瘤（NEPC）， 也是以表达间充质细胞和干细胞特征为特征的“杂交状态”富集的肿瘤。 这种表型被称为间充质和干细胞样前列腺癌（MSPC）。这个项目的首要目标是 应用是确定MSPC表型的新的分子机制， 治疗上我们的假设是PKCλ/ ι的缺失 （由PRKCI基因编码），通过上调 CD 44/透明质酸（HA）轴，诱导间充质表型，其特征在于上皮细胞的活化， EMT和促结缔组织增生性肿瘤间质的产生，都是肿瘤进展和治疗的关键事件 阻力我们假设，PKCλ/ ι控制细胞凋亡的机制的详细特征， CD 44/HA轴将为导致MSPC进展的分子途径提供重要的新信息， 将为选择对设计的新疗法敏感的患者提供依据， 间充质/基质靶点。我们的初步数据表明：（1）人MSPC具有低PRKCI水平， （2）体内前列腺上皮中PKCλ/1的丢失诱导EMT并促进EMT的发生。 重塑肿瘤微环境的促结缔组织增生反应;（3）低PRKCI水平与 在人PCa中的CD 44/HA轴的上调，支持这些发现的人相关性。基于 在这些前提下，在本提案中，我们将解决以下具体目标：目标1A：确定如何干扰 与CD 44或其配体（OPN/SPP 1，HA）一起阻断由PKCλ/1促进的MSPC和Enzalutamide抗性。 目的1B：确定CD 44/HA轴在间质活化中的作用， 基质-上皮反馈串扰;目的1C：确定PKCλ/i调节的分子机制 目的2A：确定前列腺上皮CD 44在体内驱动MSPC中的作用;目的2B：确定前列腺上皮CD 44在体内驱动MSPC中的作用。 前列腺基质CD 44在体内驱动MSPC中的作用;目的3A：确定PEGPH 20的治疗潜力 与Enzalutamide联合治疗MSPC肿瘤，目的3B：研究其作用机制 在单细胞水平上起作用。这一提议的结果将有助于更全面地了解 驱动MSPC型PCa的机制，将是设计新的更具选择性和 有效的治疗方法。

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.