美国科学家从血液破译乳腺癌转移线索
肿瘤细胞从原发灶脱落进入血液循环，成为循环肿瘤细胞。不过，只有少数特殊的循环肿瘤细胞能够形成远处转移灶，其分子特征和具体机制尚不明确。
2020年3月27日，全球自然科学三大旗舰期刊之一、美国科学促进会《科学》正刊发表哈佛大学医学院、麻省总医院、圣地兄弟会儿童医院、霍华德·休斯医学研究院的研究报告，探讨了乳腺癌循环肿瘤细胞形成远处转移灶的具体机制。
该研究将乳腺癌患者的循环肿瘤细胞植入小鼠体内，通过基因编辑技术对全基因组转录激活进行筛查，以确定促进远处转移的基因。核糖体蛋白质编码基因和基因翻译调节因子在筛查过程中被被富集。核糖体是催化蛋白质合成的细胞器，由一个沉降系数为40S的小亚基和一个沉降系数为60S的大亚基组成。
结果发现，编码核糖体60S大亚基成分的核糖体蛋白质L15基因过表达，可以增加多器官转移灶生长，并且选择性增强细胞周期调节因子以及其他核糖体蛋白质的基因翻译。
此外，通过对来自乳腺癌患者的新鲜循环肿瘤细胞进行核糖核酸测序，发现一组循环肿瘤细胞具备强大的核糖体和蛋白质合成能力。这些循环肿瘤细胞可以表达增殖和上皮的标志物，并且与不良临床结局密切相关。
因此，该研究结果表明，某些循环肿瘤细胞的核糖体蛋白质表达和基因翻译上调可以促进乳腺癌转移，针对这些循环肿瘤细胞的化疗＋靶向药物联合值得探索，例如基因翻译抑制剂高三尖杉＋细胞周期蛋白依赖型激酶抑制剂哌柏西利，有望成为乳腺癌转移的抑制剂，尤其对于缺乏靶向药物的三阴性乳腺癌。
对此，斯坦福大学医学院发表同期报道：从血液破译癌症线索。
Science. 2020 Mar 27;367(6485):1468-1473.
Deregulation of ribosomal protein expression and translation promotes breast cancer metastasis.
Ebright RY, Lee S, Wittner BS, Niederhoffer KL, Nicholson BT, Bardia A, Truesdell S, Wiley DF, Wesley B, Li S, Mai A, Aceto N, Vincent-Jordan N, Szabolcs A, Chirn B, Kreuzer J, Comaills V, Kalinich M, Haas W, Ting DT, Toner M, Vasudevan S, Haber DA, Maheswaran S, Micalizzi DS.
Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA, USA; Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA; Shriners Hospital for Children, Boston, MA, USA; Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA.
Metastasis: A matter of translation? Solid tumors shed a small number of cancer cells into the bloodstream, some of which are believed to contribute to metastasis. The molecular features that confer these circulating tumor cells (CTCs) with metastatic potential are poorly understood. Ebright et al. studied CTCs from breast cancer patients and found that cells with increased expression levels of certain ribosomal proteins and regulators of translation had greater metastatic capacity in a mouse model (see the Perspective by Ma and Jeffrey). Consistent with this finding, patients with higher levels of this subset of CTCs tended to have a poorer prognosis.
Circulating tumor cells (CTCs) are shed into the bloodstream from primary tumors, but only a small subset of these cells generates metastases. We conducted an in vivo genome-wide CRISPR activation screen in CTCs from breast cancer patients to identify genes that promote distant metastasis in mice. Genes coding for ribosomal proteins and regulators of translation were enriched in this screen. Overexpression of RPL15, which encodes a component of the large ribosomal subunit, increased metastatic growth in multiple organs and selectively enhanced translation of other ribosomal proteins and cell cycle regulators. RNA sequencing of freshly isolated CTCs from breast cancer patients revealed a subset with strong ribosome and protein synthesis signatures; these CTCs expressed proliferation and epithelial markers and correlated with poor clinical outcome. Therapies targeting this aggressive subset of CTCs may merit exploration as potential suppressors of metastatic progression.
DOI: 10.1126/science.aay0939
Science. 2020 Mar 27;367(6485):1424-1425.
Deciphering cancer clues from blood.
Ning Ma, Stefanie S. Jeffrey.
Stanford University School of Medicine, Stanford, CA, USA.
Cancer is associated with considerable morbidity and mortality, and despite therapeutic advances, it still represents the second leading cause of death worldwide. As cancers grow, evolve, and spread, they shed circulating tumor cells (CTCs), as well as other tumor-associated cells and products, into the bloodstream. Capturing and analyzing CTCs or other tumor-associated cells and products from a patient's blood sample can provide insight into a particular cancer's biology, response to treatment, and/ or potential therapeutic targets. CTCs are heterogeneous; a pressing question concerns which CTCs represent those directly involved in metastasis, the major cause of cancer-related death. On page 1468 of this issue, Ebright et al. identify genes in patient-derived CTCs encoding ribosomal proteins (RPs) that were associated with metastatic progression in mouse models, poor outcome in patients, and alterations in global translation. These findings could point to potential biomarkers or targets for future metastatic cancer therapies.
DOI: 10.1126/science.abb0736
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