蛋白激酶RIPK4诱导三阴性乳腺癌休眠逃逸的机制研究

Disseminated tumor cells often suffer an unfamiliar repressive microenvironment and kept dormant in distant organs. Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, and has a characteristic pattern of early metastasis, indicating that TNBC has high ability to escape from tumor dormancy; however, the mechanism remains unclear. Recently, we found that Receptor-interacting serine/threonine-protein kinase 4 (RIPK4) was specifically expressed in TNBC cells via gene amplification and hypoxia induction. Furthermore, we observed that: ① RIPK4 could abrogate the TGF-β-mediated cell cycle arrest via stabilization of c-Myc; ② Meanwhile, RIPK4 increased the cancer stem cell like-properties by simultaneous activation of Wnt/β-Catenin and NOTCH signaling pathways in TNBC; ③ Thus, RIPK4 was able to induce escape from dormancy and reactivate TNBC cells in distant organs, resulting in formation of overt metastases. In this project, we will combine both in vitro and in vivo experiment systems, as well as analysis of clinical samples, in order to investigate the pleiotropic functions of RIPK4 in TNBC distant colonization. Our work would provide novel prognostic markers and therapeutic targets against TNBC.

肿瘤细胞转移到远处器官后，通常会受远处微环境的抑制而产生近乎休眠的生长停滞。相比其它乳腺癌亚型，三阴性乳腺癌（TNBC）具有明显的早期转移特性，提示了TNBC具有逃逸休眠的能力；然而，其机制仍不清楚。近期，我们发现TNBC细胞由于基因扩增或者低氧诱导而特异高表达RIPK4激酶。进一步预实验结果显示：① RIPK4可通过磷酸化c-Myc而稳定其表达，解除TGF-β介导的肿瘤细胞生长停滞；② 同时，RIPK4可激活Wnt/β-Catenin和NOTCH信号通路，增强TNBC的肿瘤起始能力--干细胞样特性；③ 最终，RIPK4诱导TNBC细胞在远处器官的休眠逃逸，活化细胞并促进宏观转移灶的形成。然而，其详细的分子机制仍有待阐明。本项目将承前启后，深层次解析RIPK4激酶介导TNBC休眠逃逸的分子机制，为肿瘤转移提供新的理论依据；同时，与临床研究相结合，探讨RIPK4激酶在TNBC诊治中的意义。

肿瘤由于自身快速发展与外部环境供给不足和内部环境失衡之间的矛盾，以及外部药物作用，形成巨大的细胞压力。压力适应决定肿瘤细胞命运，在肿瘤恶性进展过程中发挥重要的作用。项目以RIPK4调控三阴乳腺癌休眠复发的机制研究为切入点，围绕“细胞压力适应与肿瘤恶性进展”这一主线展开研究，取得的主要成果：①发现RIPK4 结合并磷酸化c-Myc而稳定其表达，抵抗TGF-β等抗增殖因子的作用而诱发三阴性乳腺癌从休眠中活化，产生高效定植的机制，为抑制肿瘤复发提供了新的靶点。②发现支架蛋白HOMER3介导生长信号准确、高效传导，促进TNBC抵抗生长因子匮乏压力，诱导肿瘤转移的机制，为靶向生长信号通路抑制TNBC进展提供重要的科学依据。③发现乳腺癌细胞通过BAG2促进突变型p53蛋白聚集（aggregation）的形成，克服胞内蛋白错误折叠失衡压力的机制，为利用细胞内压力诱导肿瘤细胞死亡提供新的方法。④发现糖基化转移酶DPAGT1诱导HER2受体水解逃逸HER2靶向治疗的机制，为逆转HER2+乳腺癌耐药提供新的策略。⑤发现食管癌细胞利用烟草内含物压力诱导肿瘤转移和耐药的机制，为治疗重度烟瘾食管癌患者提供重要的科学依据。研究成果已发表论文5篇，这些研究探讨肿瘤细胞适应压力的动态调控机制，揭示肿瘤恶性进展的生物学规律并为改进肿瘤诊断和治疗方法提供科学依据。