Microenvironmental drivers of indolent to aggressive prostate cancer switch mediated by combined MYC Activation and PTEN loss

MYC 激活和 PTEN 缺失联合介导的惰性前列腺癌向侵袭性前列腺癌转变的微环境驱动因素

• 批准号: 10518917
• 负责人: Srinivasan Yegnasubramanian
• 金额: $ 33.53万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518917
• 关键词: 3-Dimensional; ATAC-seq; Animals; Automobile Driving; CXCL5 gene; Cell Nucleus; Cells; Characteristics; DNA; Data; Development; Disease; Disease Progression; Engineering; Epithelial; Fibroblasts; Genetic; Genetic Transcription; Genomics; Human; Immune Evasion; Immunosuppression; In Situ; Indolent; Infiltration; Inflammatory; Knock-out; Lesion; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of prostate; Maps; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Myeloid-derived suppressor cells; Outcome; PET/CT scan; PTEN gene; Pathogenesis; Patients; Pharmacology; Phenotype; Population; Positron-Emission Tomography; Prostate; Prostate Adenocarcinoma; Prostatectomy; Reporting; Role; Sampling; Signal Transduction; Testing; Tissues; Up-Regulation; base; cancer cell; cancer invasiveness; chemokine; comparative; genome-wide; imaging approach; macrophage; molecular imaging; molecular pathology; mouse model; neoplastic cell; novel; overexpression; prospective; receptor; recruit; synergism; tumor; tumor progression; tumor-immune system interactions

Project Summary/Abstract: There is a critical need to understand the pathogenesis of aggressive vs indolent prostate cancer. The combination of PTEN loss and MYC copy number gain predicts poor outcome in prostate cancer. Moreover, PTEN loss, even in low grade lesions, can indicate the presence of high grade aggressive prostate cancer. We found a synergistic interaction in driving aggressive prostatic adenocarcinoma by combining Pten loss with MYC overexpression in a mouse model (BMPC mice). However, the molecular mechanisms by which MYC and PTEN cooperate in driving aggressive disease are not known. We hypothesize that the combination stimulates a cell non-autonomous immune evasion mechanism through recruitment of immunosuppressive myeloid cells and cancer associated fibroblasts. We additionally hypothesize that these microenvironmental alterations accompanying progression to aggressive cancer with PTEN loss may have already been conditioned in PIA lesions within the proving ground from which these neoplastic cells initially emerged. These hypotheses are based on strong preliminary data and prior reports indicating that: i) the chemokine Cxcl5 is upregulated upon Pten deletion in prostate cancer precursors with high aggressive potential (BMPC PIN), and are associated with recruitment of polymorphonuclear myeloid derived suppressor cells (PMN-MDSCs) and with increased M2 macrophages in BMPC invasive cancers; ii) these increases in myeloid cells in BMPC cancers parallel observations of increased M2 macrophages in high grade human prostate cancer and in association with PTEN loss; iii) aggressive human prostate cancer lesions with PTEN loss and in BMPC animals often harbor a reactive stroma, which is correlated with FAP expression, and which has been implicated as a driver of immunosuppression and cancer cell invasion; and iv) expression of CXCL5, and of FAP in the stroma, is associated with a subset of PIA lesions, suggesting that these features may already be conditioned in the PIA proving ground and reawakened during progression to aggressive disease with PTEN loss. In Aim 1, we hypothesize that Pten loss in BMPC PIN precursors leads to induction of the chemokine Cxcl5, which recruit PMN-MDSC and M2 macrophages to engender an immunosuppressive phenotype. In our preliminary data, we observed an association with FAP-positive reactive stroma in the vicinity of PTEN-lost human prostate cancer. Furthermore, FAP was upregulated in aggressive cancers from BMPC mice. In Aim 2, we will determine the role of reactive stroma and FAP in mediating immune evasion and aggressive prostate cancer in BMPC mice. In Aim 3, we hypothesize that the types of changes seen with PTEN loss, including FAP activation and CXCL5 upregulation, and myeloid cell infiltration, were already conditioned to occur during “graduation” of the neoplastic cells from the PIA proving ground. Thus, we will define the epithelial and microenvironmental alterations associated with PTEN loss in human prostate cancer, and nearby PIA and PIN lesions.

项目摘要/摘要： 目前迫切需要了解侵袭性前列腺癌与惰性前列腺癌的发病机制。这个 PTEN缺失和MYC拷贝数增加相结合预示前列腺癌预后不良。此外， PTEN的缺失，即使在低级别病变中，也可能预示着高级别侵袭性前列腺癌的存在。我们 发现Pten Lost和MYC在驱动侵袭性前列腺癌中的协同作用 在小鼠模型(BMPC小鼠)中过表达。然而，MYC和PTEN的分子机制 合作驾驶攻击性疾病尚不清楚。我们假设这种组合刺激了一个细胞 免疫抑制髓系细胞的非自主免疫逃逸机制 癌症相关的成纤维细胞。我们还假设这些微环境的改变 伴有PTEN缺失的侵袭性癌症的进展可能已经在PIA中形成条件 这些肿瘤细胞最初出现的试验场内的病变。这些假设是 基于强有力的初步数据和先前的报告，表明：i)趋化因子CXCL5上调 高侵袭性前列腺癌前体(BMPC PIN)中PTEN缺失与 多形核髓系衍生抑制细胞(PMN-MDSCs)的募集和M2的增加 巨噬细胞在BMPC浸润性癌中的作用；II)BMPC癌中髓系细胞的这些增加是平行的 高级别前列腺癌M2巨噬细胞增多及其与PTEN关系的观察 丢失；iii)侵袭性人类前列腺癌病变伴PTEN缺失，在BMPC动物中经常存在反应性 基质，它与FAP的表达相关，并被认为是 免疫抑制和癌细胞侵袭；以及iv)CXCL5和FAP在间质中的表达 与PIA病变的子集相关，表明这些特征可能已经在PIA中受到限制 试验场地，并在进展为侵袭性疾病时再次觉醒，PTEN丢失。在目标1中，我们 假设BMPC PIN前体中Pten缺失导致趋化因子CXCL5的诱导，该趋化因子可招募 PMN-MDSC和M2巨噬细胞产生免疫抑制表型。在我们的初步数据中，我们 观察到在PTEN缺失的人前列腺癌附近与FAP阳性反应间质有关。 此外，FAP在BMPC小鼠侵袭性肿瘤中上调。在目标2中，我们将确定 反应性间质和FAP在介导BMPC小鼠免疫逃避和侵袭性前列腺癌中的作用。在……里面 目的3，我们假设PTEN缺失的变化类型包括FAP激活和CXCL5 在肿瘤的“毕业”期间，上调和髓样细胞的渗透已经有了条件。 来自PIA试验场的细胞。因此，我们将定义上皮和微环境的改变 与前列腺癌及邻近的PIA和PIN病变中的PTEN缺失有关。