趋化因子诱骗受体DARC通过清除微环境中CCL28抑制MSL型三阴性乳腺癌增殖侵袭的机制研究

Triple-negative breast cancer (TNBC), defined by the lack of expression of ER, PR, and the absence of amplification or over-expression of HER2, lacks known druggable targets and presents with relatively poor survival compared with other subtypes. Recently, six TNBC subtypes have been identified and one of them is a mesenchymal stem-like (MSL) subtype, which is heavily enriched in components and pathways involved in cancer stem cell. MSL subtype is demonstrated to be chemoresistant and has highly proliferative and invasive potential, which is the major cause of poor prognosis of general TNBC. Our previous investigations and preliminary experiments have demonstrated that, the inhibitory effect of the chemokine decoy receptor DARC on breast cancer growth and metastasis is mainly due to its ability to sequester pro-malignant chemokines. Furthermore, DARC could effectively decrease the concentration of CCL28, which is specifically up-regulated in MSL subtype and a higher expression of CCL28 is associated with significantly increased risk of relapse of TNBC. Taken together, we here propose a hypothesis that chemokine decoy receptor DARC could inhibit growth and invasion of the MSL subtype of TNBC via sequestrating CCL28 in tumor microenvironment. This project is based on the our previous Young Project of National Natural Science Foundation of China. The outcomes would be helpful to understand the biological basis of the aggressive behavior of MSL subtype and to find the treatment strategy for this subtype. The applicant has completed the tasks in the previous Young Project and has published 11 SCI papers of relevant achievement supported by the grant.

三阴性乳腺癌（TNBC）缺乏已知治疗靶点、预后较差，是乳腺癌治疗的难点。最新研究显示TNBC可进一步分为6个亚型，其中间质干细胞样（MSL）型有肿瘤干细胞特性，不仅抵抗化疗且易于增殖侵袭，是导致整组TNBC预后差的重要原因。我们前期研究和预实验发现：趋化因子诱骗受体DARC通过清除多种趋化因子抑制乳腺癌增殖转移；DARC还能有效降低微环境中CCL28浓度；而CCL28不仅在MSL型TNBC中高表达，也是复发转移的风险因素。由此，我们提出下一步研究假设：DARC可通过清除CCL28来抑制MSL型TNBC的增殖转移。本课题是在上个青年项目基础上的深入（从一般性乳腺癌聚焦到TNBC）与创新（探讨DARC-CCL28新通路），成果将确立MSL型TNBC易于增殖侵袭、预后不良的生物学基础，并为寻找其治疗策略提供参考。申请人已基本完成上个项目的任务，以第一作者发表标注自然基金资助的SCI论著11篇。

通过本课题实施，研究者聚焦“间质干细胞型三阴性乳腺癌的侵袭转移机制”开展基础研究，并进行临床转化，取得了如下系列成果：.1，确立宿主微环境中细胞趋化因子能够调控干细胞间质亚型三阴性乳腺癌的侵袭和转移。通过比对不同预后组的基因表达谱，发现CCL28在复发组三阴性乳腺癌的表达水平显著较高，进一步亚组分型揭示CCL28与间质干细胞亚型三阴性乳腺癌关系密切，而细胞趋化因子受体DARC可以清除包括CCL28在内的促肿瘤转移性趋化因子。DARC低表达导致间质干细胞亚型TNBC预后较差。研究确立了宿主微环境是乳腺癌转移的重要因素，相关论文发表于Clin Cancer Res上。.2，明确三阴性乳腺癌的分子本质。我们厘清了三阴性和非三阴性乳腺癌的关系，精确识别“具有三阴性生物学特性”的非三阴性乳腺癌。某些非三阴性肿瘤的生物学行为却呈三阴性特征，如ER-PR+HER2-这个亚类。与之相对，小部分三阴性肿瘤的HER2发生了胞内激酶域突变，HER2通路被持续激活，利用小分子酪氨酸激酶抑制剂能有效治疗此类患者。研究成果发表在BMC Med、Cancer Res等上。.3，揭示三阴性乳腺癌的化疗耐药和肿瘤逃逸新机制。通过深度测序技术比较化疗前后乳腺癌组织，发现化疗后癌组织中富集TEKT4基因变异。我们在临床标本、动物模型、细胞等多个层面系统论证了TEKT4变异通过降低微管稳定性来抵抗紫杉醇的微管稳定作用，导致紫杉醇抵抗。成果发表于Nat Comm、Cancer Res等国际主流学术期刊。. .本项目研究成果在Nat Commun、Cancer Res、Clin Cancer Res、BMC Med等权威学术刊物上共计发表论文9篇（均标注有本项目基金编号81370075），其中通讯（含共同）作者6篇，第一作者（含共同）1篇。成果获中国抗癌协会科技进步一等奖。在研期间，负责人继续受到以下项目资助：国家优秀青年科学基金项目（81722032），国家自然科学基金面上项目（81672600），上海市教育委员会曙光计划项目（2016004）。受邀在国际重要乳腺癌大会如第7届全球乳腺癌大会、上海国际乳腺癌论坛（连续3届）上发言，主编完成了《精准医学时代的乳腺肿瘤学》一部。