复旦发现三阴性乳腺癌肺转移突变

　　三阴性乳腺癌是最致命的乳腺癌亚型，远处转移倾向高，治疗选择有限，但是其分子学基础尚不明确。MORC家族CW型锌指蛋白2（MORC2）是一种新发现的染色质重塑蛋白，其突变与若干神经系统疾病存在因果关系，其突变对三阴性乳腺癌的影响尚不明确。

　　2018年10月15日，美国癌症研究学会《癌症研究》将正式发表复旦大学附属肿瘤医院肿瘤研究所乳腺癌研究所生物医学研究院李大强、邵志敏等学者的研究报告，发现MORC2残基第276位的甲硫氨酸→异亮氨酸突变（M276I）可以调节异质性细胞核核糖核蛋白M（hnRNPM）引起细胞表面黏附分子CD44蛋白剪接转换，从而促进三阴性乳腺癌的迁移、浸润和肺转移。

　　该研究发现，MORC2突变型与其野生型相比，表达于三阴性乳腺癌细胞可以增加细胞迁移、浸润和肺转移，而不影响细胞增殖和原发肿瘤生长。M276I突变增强MORC2与hnRNPM（剪接体机制组成部分）结合，该相互作用促进hnRNPM引起CD44由上皮同种型（CD44v）剪接转换为间质同种型（CD44s），最终导致上皮→间质转化。

　　阻止hnRNPM基因转录产物正常剪接，可以减少突变型MORC2与CD44前mRNA的结合，并且逆转突变型MORC2诱发的CD44剪接转换和上皮→间质转化，从而削弱突变型MORC2表达细胞的迁移、浸润和肺转移能力。

　　因此，该研究结果为M276I突变促进三阴性乳腺癌进展提供了首个功能证据，还建立了MORC2与RNA剪接之间的首个机制联系，并且突显了破译独特患者衍生突变以优化该高度异质性疾病临床结局的重要性。

相关阅读

Cancer Res. 2018 Oct 1. [Epub ahead of print]

Cancer-Associated MORC2-Mutant M276I Regulates an hnRNPM-Mediated CD44 Splicing Switch to Promote Invasion and Metastasis in Triple-Negative Breast Cancer.

Zhang FL, Cao JL, Xie HY, Sun R, Yang LF, Shao ZM, Li DQ.

Cancer Institute, Fudan University; Fudan University; Shanghai Cancer Center and Institutes of Biomedical Sciences, Fudan University; Institutes of Biomedical Sciences, Fudan University; Breast Cancer Institution, Cancer Hospital, Fudan University; Cancer Institute and Institute of Biomedical Sciences, Fudan University.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with a high propensity for distant metastasis and limited treatment options, yet its molecular underpinnings remain largely unknown. Microrchidia family CW-type zinc finger 2 (MORC2) is a newly identified chromatin remodeling protein whose mutations have been causally implicated in several neurologic disorders. Here, we report that a cancer-associated substitution of methionine to isoleucine at residue 276 (M276I) of MORC2 confers gain-of-function properties in the metastatic progression of TNBC. Expression of mutant MORC2 in TNBC cells increased cell migration, invasion, and lung metastasis without affecting cell proliferation and primary tumor growth compared with its wild-type counterpart. The M276I mutation enhanced binding of MORC2 to heterogeneous nuclear ribonucleoprotein M (hnRNPM), a component of the spliceosome machinery. This interaction promoted an hnRNPM-mediated splicing switch of CD44 from the epithelial isoform (CD44v) to the mesenchymal isoform (CD44s), ultimately driving epithelial-mesenchymal transition (EMT). Knockdown of hnRNPM reduced the binding of mutant MORC2 to CD44 pre-mRNA and reversed the mutant MORC2-induced CD44 splicing switch and EMT, consequently impairing the migratory, invasive, and lung metastatic potential of mutant MORC2-expressing cells. Collectively, these findings provide the first functional evidence for the M276I mutation in promoting TNBC progression. They also establish the first mechanistic connection between MORC2 and RNA splicing and highlight the importance of deciphering unique patient-derived mutations for optimizing clinical outcomes of this highly heterogeneous disease.

SIGNIFICANCE: A gain-of-function effect of a single mutation on MORC2 promotes metastasis of triple-negative breast cancer by regulating CD44 splicing.

PMID: 30093560

PII: canres.1394.2017

DOI: 10.1158/0008-5472.CAN-17-1394

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