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三阴性乳腺癌一线化疗药物紫杉类属于细胞微管蛋白稳定剂，可抑制肿瘤细胞有丝分裂。不过，化疗耐药可削弱其有效性。新辅助化疗前后肿瘤标本基因、转录与蛋白质分子分析可能有助于确定耐药相关基因。 2020年12月，常春藤旗下《治疗诊断学》第10卷第24期将正式发表复旦大学附属肿瘤医院刘西禹、马丁、葛丽萍、杨云松、苟宗超、徐晓恩、邵志敏、江一舟等学者的研究报告，根据新辅助化疗前后肿瘤标本的基因、转录与蛋白质分子分析，对三阴性乳腺癌紫杉类耐药相关基因进行了探索。 该研究首先对来自8例三阴性乳腺癌术前新辅助化疗患者的10个标本进行核糖核酸测序，其中3例术后病理完全缓解，其余5例术后非病理完全缓解。随后通过小分子干扰核糖核酸库进行体外功能筛选，选择能够预测化疗缓解的基因表达差异。最后通过体外体内实验进一步分析靶基因对于三阴性乳腺癌的临床意义和功能意义，通过生物化学和影像学进行机制分析。 结果，SYTL4被确定为首要功能候选基因，该基因编码的突触结合蛋白样蛋白主要功能为参与鸟苷三磷酸结合蛋白质将囊泡转运至靶细胞膜。多个三阴性乳腺癌队列的SYTL4高表达与低表达患者相比，生存结局显著较差，尤其经过紫杉类治疗的患者。利用三阴性乳腺癌细胞、小鼠模型、患者来源类器官，SYTL4被证实为新的化疗耐药基因。根据机制分析，SYTL4低表达可稳定细胞微管网络并减慢细胞微管生长速度。此外，SYTL4蛋白与细胞微管通过其连接蛋白和C2A结构域发生相互作用，SYTL4蛋白能够结合细胞微管并抑制其在体外聚合。 因此，该研究结果表明，SYTL4是三阴性乳腺癌紫杉类化疗耐药的关键基因之一，SYTL4蛋白可直接结合细胞微管并削弱其稳定性，从而引起紫杉类耐药，SYTL4表达水平有助于预测三阴性乳腺癌紫杉类化疗患者的生存结局。 相关链接 Theranostics. 2020;10(24):10940-10956. SYTL4 downregulates microtubule stability and confers paclitaxel resistance in triple-negative breast cancer. Liu XY, Jiang W, Ma D, Ge LP, Yang YS, Gou ZC, Xu XE, Shao ZM, Jiang YZ. Fudan University Shanghai Cancer Center; Shanghai Medical College, Fudan University, Shanghai, China; University of Chinese Academy of Sciences, Beijing, China. BACKGROUND: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. METHODS: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. RESULTS: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. CONCLUSION: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability. KEYWORDS: SYTL4; Triple-negative breast cancer; microtubule polymerization; paclitaxel resistance PMID: 33042263 PMCID: PMC7532662 DOI: 10.7150/thno.45207
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