Role of the CD44/Hyaluronan axis in mesenchymal prostate cancer

CD44/透明质酸轴在间充质前列腺癌中的作用

• 批准号: 10745413
• 负责人: Maria Teresa Diaz Meco Conde
• 金额: $ 54.98万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745413
• 关键词: Adenocarcinoma; Androgen Receptor; Appearance; Applications Grants; Automobile Driving; Back; CD44 gene; Carcinoma; Cell Reprogramming; Cells; Classification; Clinical; Cues; Data; Desmoplastic; Development; Developmental Process; Epithelial Cells; Epithelium; Event; Extracellular Matrix; Feedback; Generations; Genes; Goals; Human; Hyaluronan; Hyaluronidase; Hybrids; In Vitro; Laboratories; Ligands; Malignant neoplasm of prostate; Mesenchymal; Metabolism; Modeling; Molecular; Neoplasm Metastasis; Neoplasms; Neuroendocrine Tumors; Neurosecretory Systems; Pathway interactions; Patient Selection; Phenotype; Population; Predisposition; Property; Prostate; Prostatic Neoplasms; Publishing; Regulation; Resistance; Role; Signal Transduction; Testing; Therapeutic; Tumor Cell Invasion; Tumor Promotion; Up-Regulation; Work; atypical protein kinase C; cancer cell; cancer type; castration resistant prostate cancer; design; effective therapy; enzalutamide; in vivo; neoplastic cell; non-oncogenic; novel; novel therapeutics; pressure; programs; prostate cancer cell; prostate cancer progression; response; stem; stem cells; stem-like cell; stemness; targeted treatment; therapeutic target; therapy design; therapy resistant; trait; tumor; tumor microenvironment; tumor progression

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.

谱系可塑性已成为前列腺癌治疗抵抗的重要机制， 最近的分类工作表明，除了雄激素之外，还有多种不同的肿瘤状态。 受体途径阳性腺癌（CRPC-AD）和终末神经内分泌肿瘤（NEPC） 也是富含“混合状态”的肿瘤，其特征是间充质和干细胞特征的表达。 这种表型被称为间充质和干细胞样前列腺癌（MSPC）。 应用是确定 MSPC 表型背后可靶向的新分子机制 我们的假设是 PKCλ/ι 的治疗损失 （由 PRKCI 基因编码），通过上调 CD44/透明质酸 (HA) 轴，诱导以上皮细胞激活为特征的间充质表型 EMT 和促纤维增生性肿瘤基质的产生，都是肿瘤进展和治疗的关键事件 我们假设 PKCλ/ι 控制机制的详细特征。 CD44/HA 轴将提供有关导致 MSPC 进展和的分子途径的重要新信息 将为选择对设计的新疗法敏感的患者提供基本原理 我们的初步数据表明 (1) 人类 MSPC 具有较低的 PRKCI 水平。 (2)体内前列腺上皮中的PKCλ/ι损失诱导EMT并促进 重塑肿瘤微环境的促纤维增生反应；(3) 低 PRKCI 水平与相关 人类 PCa 中 CD44/HA 轴的上调，支持这些发现的人类相关性。 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 CD44 或其配体 (OPN/SPP1、HA) 一起阻断 PKCλ/ι- 促进的 MSPC 和恩杂鲁胺耐药性 上皮细胞缺陷；目标 1B：确定 CD44/HA 轴在基质激活和 基质-上皮反馈串扰；目标 1C：确定 PKCλ/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 的作用；目标 2B：确定 前列腺基质 CD44 在体内驱动 MSPC 中的作用；目标 3A：确定 PEGPH20 的治疗潜力； 与恩杂鲁胺联合治疗 MSPC 肿瘤和目标 3B：研究其机制 该提案的结果将有助于更全面的理解。 驱动 MSPC 类型 PCa 的机制的研究将是设计新的更具选择性和 针对此类侵袭性肿瘤的有效疗法。