收獲脂肪，消滅轉(zhuǎn)移

　　癌細(xì)胞的分化程度越高，可塑性越弱，越接近成熟的正常細(xì)胞，而分化程度越低，可塑性越強(qiáng)，越容易引起癌細(xì)胞的轉(zhuǎn)移和治療耐藥。細(xì)胞分化的逆向過程，例如上皮→間質(zhì)轉(zhuǎn)化，將正常上皮細(xì)胞轉(zhuǎn)化為低分化的間質(zhì)細(xì)胞，能夠增強(qiáng)細(xì)胞的可塑性。癌細(xì)胞可塑性與上皮→間質(zhì)轉(zhuǎn)化是動(dòng)態(tài)過程，并且可以發(fā)生于癌細(xì)胞轉(zhuǎn)移的各個(gè)步驟，被公認(rèn)為癌細(xì)胞轉(zhuǎn)移和治療耐藥的關(guān)鍵之一。

　　2019年1月14日，美國(guó)《細(xì)胞》旗下《癌細(xì)胞》正式發(fā)表瑞士巴塞爾大學(xué)的研究報(bào)告，巧妙利用癌細(xì)胞的可塑性，強(qiáng)制上皮→間質(zhì)轉(zhuǎn)化產(chǎn)生的乳腺癌細(xì)胞停止有絲分裂后轉(zhuǎn)分化為功能正常的棕色脂肪細(xì)胞，從而有效抑制乳腺癌細(xì)胞的浸潤(rùn)和轉(zhuǎn)移能力。

　　該研究首先闡明了上述轉(zhuǎn)分化過程的潛在分子通路，隨后將棕色脂肪細(xì)胞分化調(diào)控轉(zhuǎn)錄因子過氧化物酶體增殖物激活受體γ（PPARγ）激動(dòng)劑（噻唑烷二酮類胰島素增敏劑、糖尿病治療藥物羅格列酮）與促細(xì)胞有絲分裂原活化蛋白質(zhì)激酶（MAPK）激酶（MEK）抑制劑（曲美替尼）聯(lián)合，用于小鼠和人類乳腺癌細(xì)胞的各種臨床前小鼠體內(nèi)模型，將具備浸潤(rùn)和轉(zhuǎn)移能力的癌細(xì)胞，轉(zhuǎn)變?yōu)?/span>停止有絲分裂后功能正常的棕色脂肪細(xì)胞，從而有效抑制原發(fā)腫瘤形成浸潤(rùn)和轉(zhuǎn)移。棕色脂肪負(fù)責(zé)分解引起肥胖的白色脂肪，將其轉(zhuǎn)化成二氧化碳、水和熱量，可以加快人體新陳代謝，促進(jìn)白色脂肪消耗，而且不會(huì)變回癌細(xì)胞。

　　因此，該研究結(jié)果表明了癌細(xì)胞可塑性對(duì)于惡性腫瘤病情進(jìn)展的關(guān)鍵作用，并且揭示了針對(duì)細(xì)胞可塑性的靶向治療潛力，例如通過強(qiáng)制停止有絲分裂后形成脂肪，有望成為治療乳腺癌的新方法。

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