RAI2 as novel suppressor of cancer cell homing and survival in the bone microenvironment

RAI2作为骨微环境中癌细胞归巢和存活的新型抑制剂

• 批准号: 401186201
• 负责人: Professor Dr. Klaus Pantel
• 金额: --
• 依托单位: Institut für Tumorbiologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/401186201?language=en
• 关键词: RAI2; novel; suppressor; cancer; cell

Bone marrow (BM) is a common homing organ for disseminated tumor cells (DTCs, the seed of metastases) derived from various types of malignant epithelial tumors. We have shown that the presence of single DTCs in the BM is an independent predictor of metastatic relapse in many different solid tumors including breast cancer and identified genes, expression signatures and mechanisms associated with an early tumor cell dissemination to the BM. We identified retinoic acid–induced 2 (RAI2) as a novel metastasis suppressor gene significantly associated with both positive DTC status and poor prognosis in breast cancer. Furthermore, our functional studies showed that RAI2 sustains differentiation of ER-positive tumor cells, whereas loss of RAI2 induces hormone independent growth and activation of AKT signaling as an important mediator of dormancy control. Xenograft experiments performed during the first µBONE funding period showed an increased tumor dissemination (increased numbers of CTCs and DTCs) when RAI2 KO cells where injected orthotopically in Scid mice. Therefore, our results indicate that loss of RAI2 expression might represent a so far undiscovered key event for the onset of metastatic progression in the bone. The primary goal of this project is thus to better understand the precise role of RAI2 for the development of bone metastasis in breast cancer. Our recent drug screenings in the first project period identified a possible synthetic lethality associated with RAI2 expression in combination with drugs such as Aurora-A and AKT inhibitors. Thus, the role of RAI2 dependent AKT regulation in survival and dormancy will be analyzed in this application (WP1) as well as it suitability as a drug target in mouse models, including the suitability of Aurora-A kinase inhibition (WP2). We have also established a RAI2 KO (RAIKO) mouse, showing that RAI2 does not appear to be involved in initial tumor development. Here, we will cross RAIKO with a mouse model with spontaneous breast tumor formation (MMTV) to further analyze the involvement of RAI2 in early tumor dissemination and bone metastasis (WP2). Finally, we found that both the total conditioned media as well as the EV fraction from RAI2 KO cells was significantly increasing osteoclast differentiation. Thus, in the last WP3, we plan to analyze: (i) RAI2 dependent EV-related miRNA expression in bone modulation, and (ii) investigate of the role of RAI2 KO-derived secreted factors in tumor-bone crosstalk. In conclusion, the results obtained in this project will contribute to a better understanding of RAI2-mediated cancer dormancy and metastatic development in the BM microenvironment.

骨髓（BM）是源自各种类型恶性上皮肿瘤的播散性肿瘤细胞（DTC，转移的种子）的常见归巢器官。我们已经证明，BM 中单个 DTC 的存在是包括乳腺癌在内的许多不同实体瘤转移复发的独立预测因素，并确定了与早期肿瘤细胞扩散到 BM 相关的基因、表达特征和机制。 我们发现视黄酸诱导 2 (RAI2) 是一种新型转移抑制基因，与乳腺癌 DTC 阳性状态和不良预后显着相关。此外，我们的功能研究表明，RAI2 维持 ER 阳性肿瘤细胞的分化，而 RAI2 的缺失会诱导激素非依赖性生长和 AKT 信号激活，作为休眠控制的重要介质。在第一个 µBONE 资助期间进行的异种移植实验显示，当 RAI2 KO 细胞原位注射到 Scid 小鼠体内时，肿瘤扩散增加（CTC 和 DTC 数量增加）。因此，我们的结果表明，RAI2 表达的丧失可能代表了迄今为止尚未发现的骨转移进展发生的关键事件。因此，该项目的主要目标是更好地了解 RAI2 在乳腺癌骨转移发展中的确切作用。我们最近在第一个项目期间进行的药物筛选发现了与 RAI2 表达与 Aurora-A 和 AKT 抑制剂等药物联合使用可能产生的合成致死率。因此，本申请 (WP1) 将分析 RAI2 依赖性 AKT 调节在存活和休眠中的作用，以及它作为小鼠模型中药物靶点的适用性，包括 Aurora-A 激酶抑制的适用性 (WP2)。我们还建立了 RAI2 KO (RAIKO) 小鼠，表明 RAI2 似乎并不参与最初的肿瘤发展。在这里，我们将 RAIKO 与自发性乳腺肿瘤形成 (MMTV) 小鼠模型交叉，以进一步分析 RAI2 在早期肿瘤播散和骨转移 (WP2) 中的参与。最后，我们发现总条件培养基以及来自 RAI2 KO 细胞的 EV 部分均显着增加了破骨细胞的分化。因此，在最后一个 WP3 中，我们计划分析：（i）RAI2 依赖性 EV 相关 miRNA 在骨调节中的表达，以及（ii）研究 RAI2 KO 衍生的分泌因子在肿瘤骨串扰中的作用。总之，该项目获得的结果将有助于更好地了解 BM 微环境中 RAI2 介导的癌症休眠和转移发展。