Regulation of Metastatic Development by Heritable Variants in the Tumor Microenvironment

项目摘要 转移性前列腺癌是不治之症。确定原发肿瘤内转移进展的关键因素 肿瘤将对临床上可翻译的靶点具有广泛的意义，对于早期识别谁是 转移癌症和癌症治疗的风险。在基于患者的数据中，我们已经确定了生殖系 Asporin的天冬氨酸(D)重复结构域(ASPN)长度的变体与(D14) 或对(D13)转移发展有保护作用。我们报告说，与在癌细胞中表达相反， ASPN在肿瘤相关成纤维细胞(CAF)中的表达高度丰富，并且其表达显著 与Gleason分级测量的局部癌症侵袭性相关。与以患者为基础的做法一致 肿瘤-间质相互作用的体内模型数据支持这种表达在肿瘤微环境中的表达。 ASPN D14驱动，而ASPN D13限制转移发展。我们的数据表明ASPN具有潜在的 更好地将疾病侵袭性分层用于治疗决策的临床效用，也可能是一种潜在的 由于其在肿瘤微环境中的细胞外表达而成为治疗的靶点。尽管它有很高的潜力 临床意义：ASPN在局部肿瘤侵袭或转移中的作用尚未得到证实 完全下定决心。此外，ASPN调控转移的细胞和分子机制 级数的定义也不完全。然而，我们的初步数据表明，ASPN可能调节 CAF前体细胞的多能性和自我更新，这可能是ASPN调节局部的关键机制 进展和转移潜能。基于这些新的发现，我们的目标是确定 ASPN调节肿瘤的进展。我们的中心假设是ASPN维持CAF前体细胞，并且 因此，ASPN增强了CAF诱导的侵袭和进展到转移。我们进一步假设 ASPN中D-重复结构域的长度影响其机制和细胞功能 归根结底，它对转移性发展的影响。我们的目标是1)确定ASPN对 原发肿瘤生长和转移的原发动物模型，并勾画2) 3)ASPN D14促进和抑制肿瘤的分子机制 前列腺癌的进展和转移-侵袭。我们建议全面研究 用新的体内动物模型研究ASPN在局部肿瘤侵袭和转移发展中的作用 EDGE体外分析，以及基于患者的数据。成功完成这些目标将提供关键信息 关于ASPN如何调节转移发育，因此将提供机会来翻译这些 对预后和治疗的研究结果。

Project Summary Metastatic prostate cancer is incurable. Defining the key contributors to metastatic progression within the primary tumor will have broad implications for clinically translatable targets for both the early identification of who is at risk for metastatic cancer and for the treatment of cancer. In patient based data, we have identified germline variants in the length of the aspartate (D) repeat domain of Asporin (ASPN) that are either associated with (D14) or are protective of (D13) metastatic development. We reported that opposed to being expressed in cancer cells, ASPN expression is highly enriched in cancer associated fibroblasts (CAFs), and its expression is significantly associated with local cancer aggressiveness as measured by Gleason grade. Consistent with patient-based data, in vivo models of tumor-stromal interactions, support that expression in the tumor microenvironment of ASPN D14 drives while ASPN D13 restricts metastatic development. Our data suggest that ASPN has potential clinical utility to better stratify disease aggressiveness for treatment decision making and may also be a potential therapeutic target due to its extracellular expression in the tumor microenvironment. Despite its high potential for clinical significance, the role of ASPN in local tumor aggressiveness or metastatic development has not been fully determined. Furthermore, the cellular and molecular mechanisms by which ASPN regulates metastatic progression are also incompletely defined. However, our preliminary data suggest that ASPN may regulate pluripotency and self-renewal of CAF progenitors, which may be a key mechanism for how ASPN regulates local progression and metastatic potential. Based on these new findings, we aim to identify the mechanisms by which ASPN regulates tumor progression. Our central hypothesis is that ASPN maintains CAF progenitors, and thereby ASPN potentiates CAF-induced invasion and progression to metastasis. We further hypothesize that the length of the D-repeat domain in ASPN affects its mechanistic and cellular functions and ultimately its impact on metastatic development. Our goals are 1) to determine the contribution of ASPN to primary tumor growth and metastatic development in autochthonous animal models, and to delineate the 2) cellular and 3) molecular based mechanisms by which ASPN D14 promotes and ASPN D13 restricts tumor progression and metastatic-invasion of prostate cancer. We propose to comprehensively examine the role of ASPN in local cancer aggressiveness and metastatic development using novel in vivo animal models, cutting edge in vitro assays, and patient-based data. Successful completion of these aims will provide critical information on how ASPN regulates metastatic development, and will therefore provide opportunities for translating these findings for prognosis and therapy.