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

项目概要/摘要： 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。的 PTEN缺失和MYC拷贝数增加的组合预测前列腺癌的不良结果。此外，委员会认为， 即使在低级别病变中，PTEN缺失也可以指示高级别侵袭性前列腺癌的存在。我们 发现Pten丢失与MYC结合在驱动侵袭性前列腺腺癌中的协同相互作用 在小鼠模型（BMPC小鼠）中的过表达。然而，MYC和PTEN的分子机制， 合作驾驶侵略性疾病是未知的。我们假设这种组合刺激了一种细胞 通过募集免疫抑制性骨髓细胞的非自主免疫逃避机制， 癌症相关的成纤维细胞。我们还假设这些微环境的改变 伴随着进展到侵袭性癌症的PTEN丢失可能已经在PIA中被调节 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道，表明：i）趋化因子Cxc 15在 高侵袭性前列腺癌前体细胞（BMPC PIN）中的Pten缺失， 多形核细胞髓源性抑制细胞（PMN-MDSC）的募集和M2 ii）BMPC侵袭性癌症中的骨髓细胞的这些增加与BMPC癌症中的巨噬细胞的增加平行; 高级别人前列腺癌中M2巨噬细胞增加的观察结果及其与PTEN的相关性 iii）具有PTEN缺失的侵袭性人前列腺癌病变，并且在BMPC动物中通常具有反应性的PTEN缺失。 间质，这是与FAP表达，并已牵连作为一个驱动程序， 免疫抑制和癌细胞侵袭;和iv）CXCL 5和FAP在基质中的表达， 与PIA病变的一个子集相关，表明这些特征可能已经在PIA中形成了条件反射 在进展为具有PTEN损失的侵袭性疾病的过程中，目标1： 假设BMPC PIN前体中Pten损失导致趋化因子Cxc 1 5的诱导，其募集 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， 观察到与PTEN缺失的人前列腺癌附近的FAP阳性反应性基质相关。 此外，FAP在来自BMPC小鼠的侵袭性癌症中上调。在目标2中，我们将确定 反应性基质和FAP介导BMPC小鼠免疫逃避和侵袭性前列腺癌。在 目的3，我们假设在PTEN缺失中观察到的变化类型，包括FAP激活和CXCL 5， 上调和髓样细胞浸润，已经在肿瘤细胞的“毕业”过程中发生。 巴基斯坦国际航空试验场的细胞因此，我们将定义上皮和微环境的改变， 与人前列腺癌中的PTEN缺失以及附近的PIA和PIN病变相关。

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.