【原】瑞士科学家将乳腺癌变成正常脂肪

收获脂肪，消灭转移

　　癌细胞的分化程度越高，可塑性越弱，越接近成熟的正常细胞，而分化程度越低，可塑性越强，越容易引起癌细胞的转移和治疗耐药。细胞分化的逆向过程，例如上皮→间质转化，将正常上皮细胞转化为低分化的间质细胞，能够增强细胞的可塑性。癌细胞可塑性与上皮→间质转化是动态过程，并且可以发生于癌细胞转移的各个步骤，被公认为癌细胞转移和治疗耐药的关键之一。

　　2019年1月14日，美国《细胞》旗下《癌细胞》正式发表瑞士巴塞尔大学的研究报告，巧妙利用癌细胞的可塑性，强制上皮→间质转化产生的乳腺癌细胞停止有丝分裂后转分化为功能正常的棕色脂肪细胞，从而有效抑制乳腺癌细胞的浸润和转移能力。

　　该研究首先阐明了上述转分化过程的潜在分子通路，随后将棕色脂肪细胞分化调控转录因子过氧化物酶体增殖物激活受体γ（PPARγ）激动剂（噻唑烷二酮类胰岛素增敏剂、糖尿病治疗药物罗格列酮）与促细胞有丝分裂原活化蛋白质激酶（MAPK）激酶（MEK）抑制剂（曲美替尼）联合，用于小鼠和人类乳腺癌细胞的各种临床前小鼠体内模型，将具备浸润和转移能力的癌细胞，转变为停止有丝分裂后功能正常的棕色脂肪细胞，从而有效抑制原发肿瘤形成浸润和转移。棕色脂肪负责分解引起肥胖的白色脂肪，将其转化成二氧化碳、水和热量，可以加快人体新陈代谢，促进白色脂肪消耗，而且不会变回癌细胞。

　　因此，该研究结果表明了癌细胞可塑性对于恶性肿瘤病情进展的关键作用，并且揭示了针对细胞可塑性的靶向治疗潜力，例如通过强制停止有丝分裂后形成脂肪，有望成为治疗乳腺癌的新方法。

Cancer Cell. 2019 Jan 14;35(1):17-32.e6.

Gain Fat—Lose Metastasis: Converting Invasive Breast Cancer Cells into Adipocytes Inhibits Cancer Metastasis.

Dana Ishay-Ronen, Maren Diepenbruck, Ravi Kiran Reddy Kalathur, Nami Sugiyama, Stefanie Tiede, Robert Ivanek, Glenn Bantug, Marco Francesco Morini, Junrong Wang, Christoph Hess, Gerhard Christofori.

University Hospital Basel, University of Basel, Basel, Switzerland.

HIGHLIGHTS

• EMT-derived breast cancer cells can differentiate into post-mitotic adipocytes

• Adipogenesis disconnects cancer cells from an invasive and oncogenic phenotype

• EMT/MET transcription factors and TGF-β signaling regulate cancer adipogenesis

• Adipogenesis-inducing drug combinations repress metastasis in preclinical models

Cancer cell plasticity facilitates the development of therapy resistance and malignant progression. De-differentiation processes, such as an epithelial-mesenchymal transition (EMT), are known to enhance cellular plasticity. Here, we demonstrate that cancer cell plasticity can be exploited therapeutically by forcing the trans-differentiation of EMT-derived breast cancer cells into post-mitotic and functional adipocytes. Delineation of the molecular pathways underlying such trans-differentiation has motivated a combination therapy with MEK inhibitors and the anti-diabetic drug Rosiglitazone in various mouse models of murine and human breast cancer in vivo. This combination therapy provokes the conversion of invasive and disseminating cancer cells into post-mitotic adipocytes leading to the repression of primary tumor invasion and metastasis formation.

Cancer cell plasticity and EMT are dynamic and can occur during different steps of cancer metastasis. We demonstrate that cellular plasticity acquired by EMT can be exploited to trans-differentiate breast cancer cells into post-mitotic and functional adipocytes. Notably, adipogenic differentiation therapy with a combination of Rosiglitazone and an MEK inhibitor efficiently inhibits cancer cell invasion, dissemination, and metastasis formation in various preclinical mouse models of breast cancer. The results underscore the pivotal role of cancer cell plasticity in malignant tumor progression and reveal the therapeutic potential that lies in the targeting of cellular plasticity, for example by forcing post-mitotic adipogenesis.

KEYWORDS: adipocyte; breast cancer; cell plasticity; EMT; invasion; metastasis; trans-differentiation; adipogenesis; TGFβ-signaling; differentiation therapy

DOI: 10.1016/j.ccell.2018.12.002