Casanova Alexandre G, Roth Gael S, Hausmann Simone, Lu Xiaoyin, Bischoff Ludivine J M, Froeliger Emilie M, Belmudes Lucid, Bourova-Flin Ekaterina, Flores Natasha M, Benitez Ana Morales, Chasan Tourkian, Caporicci Marcello, Vayr Jessica, Blanchet Sandrine, Ielasi Francesco, Rousseaux Sophie, Hainaut Pierre, Gozani Or, Le Romancer Muriel, Couté Yohann, Palencia Andres, Mazur Pawel K, Reynoird Nicolas
Grenoble Alpes University, CNRS UMR 5309, INSERM U 1209, Institute for Advanced Biosciences, Grenoble, France.
Clinique Universitaire d'Hépato-gastroentérologie et Oncologie digestive, CHU Grenoble Alpes, Grenoble, France.
Cell Discov. 2024 Jan 31;10(1):12. doi: 10.1038/s41421-023-00644-x.
Malignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.
对现有疗法难治的恶性乳腺癌形式仍然是一个主要的未满足的健康问题，主要是由于转移扩散。更好地理解其中的作用机制将为预防乳腺癌细胞扩散的替代治疗提供更好的见解。在这里，我们确定赖氨酸甲基转移酶SMYD2是乳腺癌转移的一种具有临床可操作性的主要调节因子。虽然SMYD2在侵袭性乳腺癌中过表达，但我们注意到它对原发性肿瘤生长不是必需的。然而，乳腺上皮特异性SMYD2缺失通过阻断原发性肿瘤细胞的转移能力来提高小鼠的总体生存率。从机制上讲，我们确定BCAR3是乳腺癌细胞中SMYD2真正的生理底物。在赖氨酸K334处单甲基化的BCAR3（K334me1）被FMNLs蛋白中存在的一个新的甲基结合域识别。这些肌动蛋白细胞骨架调节因子通过SMYD2甲基化信号被招募到细胞边缘，并调节片状伪足的特性。BCAR3甲基化受损的乳腺癌细胞在体外失去迁移和侵袭能力，并且在体内促进转移方面无效。值得注意的是，SMYD2的药物抑制有效地损害了乳腺癌细胞、人源肿瘤异种移植模型（PDX）以及基因工程小鼠侵袭性乳腺肿瘤的转移扩散。这项研究为通过靶向SMYD2-BCAR3-FMNL轴创新治疗性预防恶性乳腺癌转移进展提供了理论依据。
