这个新发现的生物标志物diaphanous- related formin-3（DIAPH3）参与蛋白质的相互作用，使细胞保持刚性。研究发现，当这种生物标志物丢失或降低时，细胞出现“变形”，在组织间隙中挤压，引起疾病的进展。这种现象被称为“变形虫样表型”（amoeboid phenotype）。
研究人员利用这一点，来确定接受紫杉醇化疗的患者的治疗灵敏度。紫杉醇的工作原理是破坏癌细胞的蛋白质结构，广泛用于治疗转移性前列腺癌和乳腺癌。DIAPH3的损失，经常与转移性乳腺癌和前列腺癌相关，同时增加细胞对紫杉醇的敏感性。DIAPH3与微管（microtubulies）相结合，其降低会改变的微管动力学的几个参数，并降低极化力（polarized force）产生、收缩性、和对基底刚度（substrate stiffness）的反应。研究人员沉默DIAPH3，发现前列腺和乳腺癌细胞系对紫杉醇的细胞毒性应答增强。在NCI-60细胞系中，研究人员分析了微管蛋白靶向药物的药物活性，发现DIAPH3表达降低与药物敏感性之间的均匀的正相关关系。同时DIAPH3的低表达显示与紫杉醇化疗方案治疗的乳腺癌患者无复发生存率增加有关联。这是第一次发现的针对有“变形虫样”表型的肿瘤细胞的定位策略。
研究人员计划未来开始发展这种生物标记物的工具，以方便在患者身上验证这些发现。通过确定癌症标志物，然后根据个人的遗传信息为基础定制治疗计划，可以大大提高癌症治疗的有效性。这种个性化的治疗计划或许成为癌症治疗的趋势。
PMC
PMID
Regulation of microtubule dynamics by DIAPH3 influences amoeboid tumor cell mechanics and sensitivity to taxanes
Samantha Morley, Sungyong You, Sara Pollan, Jiyoung Choi,Bo Zhou, Martin H. Hager Kenneth Steadman, Cristiana Spinelli, Kavitha Rajendran, Arkadiusz Gertych, Jayoung Kim Rosalyn M. Adam, Wei Yang, Ramaswamy Krishnan, Beatrice S. Knudsen, Dolores Di Vizio, Michael R. Freeman
Abstract
Taxanes are widely employed chemotherapies for patients with metastatic prostate and breast cancer. Here, we show that loss of Diaphanous-related formin-3 (DIAPH3), frequently associated with metastatic breast and prostate cancers, correlates with increased sensitivity to taxanes. DIAPH3 interacted with microtubules (MT), and its loss altered several parameters of MT dynamics as well as decreased polarized force generation, contractility, and response to substrate stiffness. Silencing of DIAPH3 increased the cytotoxic response to taxanes in prostate and breast cancer cell lines. Analysis of drug activity for tubulin-targeted agents in the NCI-60 cell line panel revealed a uniform positive correlation between reduced DIAPH3 expression and drug sensitivity. Low DIAPH3 expression correlated with improved relapse-free survival in breast cancer patients treated with chemotherapeutic regimens containing taxanes. Our results suggest that inhibition of MT stability arising from DIAPH3 downregulation enhances susceptibility to MT poisons, and that the DIAPH3 network potentially reports taxane sensitivity in human tumors.