Regulation of Metastatic Development by Heritable Variants in the Tumor Microenvironment

项目摘要 转移性前列腺癌是无法治愈的。定义原发性肝癌中转移性进展的关键因素 肿瘤将对临床上可翻译的靶点产生广泛的影响， 转移性癌症的风险和癌症的治疗。在基于患者的数据中，我们已经确定了生殖系 Asporin（ASPN）的天冬氨酸（D）重复结构域长度的变异，其与（D14）相关， 或保护（D13）转移发展。我们报道说，与在癌细胞中表达相反， ASPN表达在癌相关成纤维细胞（CAF）中高度富集，并且其表达在癌相关成纤维细胞（CAF）中显著增加。 与通过Gleason分级测量的局部癌症侵袭性相关。符合基于患者的 数据，肿瘤-基质相互作用的体内模型，支持在肿瘤微环境中表达 ASPN D14驱动而ASPN D13限制转移发展。我们的数据表明，ASPN有潜力 临床实用性，以更好地分层疾病的侵略性，治疗决策，也可能是一个潜在的 由于其在肿瘤微环境中的细胞外表达，因此是治疗靶点。尽管它的潜力很大， 临床意义，ASPN在局部肿瘤侵袭性或转移性发展中的作用尚未被证实。 完全确定。此外，ASPN调节转移的细胞和分子机制， 进展也不完全确定。然而，我们的初步数据表明，ASPN可能调节 多能性和自我更新的CAF祖细胞，这可能是一个关键机制，如何ASPN调节局部 进展和转移潜力。基于这些新发现，我们的目标是确定 ASPN调节肿瘤进展。我们的中心假设是ASPN维持CAF祖细胞， 因此，ASPN增强了CAF诱导的侵袭和向转移的进展。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， 最终影响转移性发展。我们的目标是：1）确定ASPN对 原发性肿瘤生长和转移性发展在本地动物模型，并描绘2） ASPN D14促进和ASPN D13限制肿瘤的细胞和3）分子机制 前列腺癌的进展和转移-侵袭。我们建议全面研究 ASPN在局部癌症侵袭性和转移性发展中的作用，使用新型体内动物模型，切割 边缘体外分析和基于患者的数据。成功完成这些目标将提供关键信息， 关于ASPN如何调节转移性发展，因此将提供机会， 预后和治疗的发现。

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.