WNT信号介导的肿瘤微环境调控在乳腺癌器官特异性转移中的作用和机制

A prominent phenomenon in tumor metastasis is the organ specificity, which argues the importance of tumor microenvironment in metastasis regulation. The difference in the metastasis proclivity of several breast cancer molecular subtypes has been observed; however, the underlying mechanism is yet to be elucidated. In this study, we found that compared to the luminal-type clinical breast tumors, the basal-type tumors tended to metastasize to lungs, but with lower risk of recurrence in the bone. Meanwhile, the WNT signaling was hyperactive in basal-type samples. Consistent with these observations, lung-tropic breast cancer cell lines secreted a higher level of the WNT ligand WNT8B than bone-tropic cells, and the latters were characterized by the enhanced concentration of the WNT inhibitor DKK1 in their exosomes. Therefore, we propose that the varied metastasis organ-tropism among breast cancer subtypes is due to their distinction in WNT signaling, which plays a bifurcated role in tissue-specific metastasis, i.e. promoting lung metastasis but supressing bone metastasis, by interacting with the local stromal components in these organs. This hypothesis was further supported by our preliminary functional assays of WNT signaling in metastasis. We will analyze the roles and mechanisms of WNT signaling in reshaping the tumor microenvironment during breast cancer metastasis, and will elucidate the reason for the metastasis difference of breast cancer subtypes. We will also assess the effeciency, and potential side effects, of WNT inhibitors to treat cancer metastasis using both cancer cell line xenograft and patient-derived xenograft models. Our study will help understand the molecular underpinning of breast cancer subtyping, and promote the development of effective anti-WNT therapeutics.

肿瘤转移的器官特异性提示肿瘤微环境在转移中有重要作用。乳腺癌不同分子亚型的转移倾向性存在很大差别，但是其具体分子机制尚不清楚。我们观察到乳腺癌临床标本中Luminal和Basal亚型分别倾向转移到骨和肺，而WNT信号在Basal亚型中活性更高。同时，肺转移性癌细胞高分泌WNT8B，而骨转移性细胞通过Exosome分泌大量的WNT拮抗分子DKK1。据此我们认为乳腺癌不同亚型间转移器官靶向性的差别可能源自它们分泌的不同WNT相关分子，而WNT信号作用于靶器官的不同微环境，分别对乳腺癌在骨、肺的定植发挥相反的作用。我们的初步功能分析支持了这一假设。本研究旨在分析肿瘤来源的WNT胞外信号在器官特异性转移中的“双面”作用及其微环境机制，阐明不同亚型乳腺癌转移性能差异的原因，并监测WNT靶向药物对转移的影响。本项目将有助于深入理解乳腺癌分子亚型之间的区别，并对开发有效的WNT靶向治疗方法有重要意义。

肿瘤微环境在转移中有重要作用。不同分子亚型的乳腺癌具有不同的转移器官选择性，但是其具体分子机制尚不清楚。在前期工作中我们观察到肺转移性乳腺癌中WNT信号被显著激活，而骨转移性细胞分泌大量的WNT拮抗分子DKK1。在本项目中我们发现肿瘤分泌的DKK1蛋白调控了癌细胞转移靶器官选择性。DKK1高分泌的肿瘤倾向转移到骨，而低分泌的肿瘤倾向转移到肺。在肺中DKK1抑制非经典WNT通路，减少巨噬细胞和中性粒细胞的招募并同时抑制癌细胞分泌生长因子TGFβ的水平，从而抑制肺转移。而在骨中DKK1通过抑制成骨细胞的经典WNT信号，从而促进骨转移形成。对肿瘤施用经典WNT信号通路抑制剂后，肺转移并未显著下降而骨转移情况恶化。相反的，联合使用JNK和TGFβR抑制剂能够同时抑制肺转移和骨转移。这项研究发现了一类在乳腺癌向不同靶器官转移过程中具有相反功能的基因，充分说明了微环境对癌细胞转移的重要调控作用，揭示了靶向经典WNT信号通路治疗肿瘤在临床应用中可能的副作用，并为乳腺癌晚期病人的多发转移提供了新的治疗策略。项目主要研究成果发表于Nat Cell Biol、Nat Commun等，并有相关专利申请2项。