News Express: UM research team discovers new mechanism for anti-metastasis therapy in TNBC
新聞快訊：澳大研究團隊發現抵抗乳腺癌轉移新機制
通過與巨噬細胞相互作用，TNBC細胞獲得更強的細胞存活、腫瘤生長和癌症轉移能力
By interacting with macrophages, TNBC cells acquire stronger abilities in cell survival, tumour growth, and cancer metastasis
澳大研究團隊發現抵抗乳腺癌轉移新機制
澳門大學健康科學學院教授羅茜的研究團隊在腫瘤轉移機制研究上取得重大進展。研究發現，巨噬細胞和三陰性乳腺癌 （TNBC）細胞之間的相互作用可以誘導活性氧（ROS）介導的白細胞介素1α（IL1α）水平升高，進而促進腫瘤生長和癌症轉移，表明減少 ROS升高或下調IL1α 表達可以作為抵抗TNBC 轉移的新策略。相關研究成果已發表於國際知名期刊《先進科學》（Advanced Science）。
TNBC因更強的轉移能力比非TNBC的死亡率高。越來越多的研究顯示TNBC腫瘤比非TNBC腫瘤有更多的巨噬細胞浸潤，從而促進了TNBC細胞的轉移。然而，TNBC 細胞在與巨噬細胞相互作用後如何惡化的研究較少。因此，了解TNBC細胞和巨噬細胞如何相互作用以增強癌症轉移並確定有效的治療靶點對TNBC的治療具有重要意義。
該研究中，研究團隊觀察到當TNBC細胞與巨噬細胞共培養時，它們比非TNBC細胞表現出更強的生存和轉移能力。單培養和共培養TNBC細胞之間的轉錄組測序分析結果顯示，細胞因子IL1α、IL1β和IL8在共培養的TNBC細胞中的表達顯著上調。實驗結果表明，高水平的IL1α、IL1β和IL8使得TNBC細胞能在遇到巨噬細胞時更好地生存、獲得更強的轉移能力，以及將更多能夠幫助腫瘤細胞的M2型巨噬細胞招募到腫瘤部位。通過進一步的機制研究，團隊發現TNBC細胞在與巨噬細胞相互作用時，通過三個步驟獲得這些能力。首先，在與巨噬細胞共培養12小時內，一些TNBC細胞的ROS水平顯著升高。在24至48小時，通過ERK1/2-c-Jun和NF-κB信號通路上調IL1α表達。其次，分泌的IL1α與IL1R1結合，激活ERK1/2-ZEB1-VIM信號通路，從而促進轉移。第三，IL1α/IL1R1促進其自身合成，並通過MKK4-JNK-c-Jun和NF-κB信號通路在72至96小時誘導IL1β和IL8的表達。此外，乳腺癌患者中IL1α水平較高與巨噬細胞浸潤較多和總生存期較短呈正相關。因此，該研究表明ROS和IL1α可能作為TNBC抗轉移治療的新靶點。
是次研究的通訊作者為羅茜，博士畢業生郝夢為第一作者，博士畢業生黃斌、吳仁飛和彭征也對研究作出重要貢獻。該項目由澳門特別行政區科學技術發展基金（檔案編號：068/2017/A2，0147/2020/A3和0004/2021/AKP）、澳門大學精準腫瘤學前沿科學中心（檔案編號：SP2021-00001-FSCPO和SP2023-00001-FSCPO）資助。全文可瀏覽：http://doi.org/10.1002/advs.202302857。
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https://www.um.edu.mo/zh-hant/news-and-press-releases/campus-news/detail/56718/
UM research team discovers new mechanism for anti-metastasis therapy in TNBC
A research team led by Prof Kathy Luo Qian in the Faculty of Health Sciences (FHS) at the University of Macau (UM) has made significant advances in the study of tumour metastasis. The study found that the interaction between macrophages and triple-negative breast cancer (TNBC) cells induces reactive oxygen species (ROS)-mediated interleukin 1α (IL1α) upregulation, which in turn facilitates tumorigenesis and cancer metastasis. This discovery suggests that reducing ROS elevation or downregulating IL1α expression can serve as a new strategy to decrease metastasis of TNBC. The research results have been published in the internationally renowned journal Advanced Science.
TNBC has higher mortality than non-TNBC because of its stronger metastatic capacity. A growing number of studies reported that TNBC tumours had more macrophage infiltration than non-TNBC tumours, which promoted the metastasis of TNBC cells. However, how TNBC cells become more malignant after interacting with macrophages is less reported. Therefore, understanding how TNBC cells and macrophages interact to enhance cancer metastasis and identifying effective therapeutic targets are of great significance for the treatment of TNBC.
In the study, the researchers observed that when TNBC cells were co-cultured with macrophages, they displayed higher viability and stronger metastatic ability than non-TNBC cells. The results of RNA sequencing analysis between monocultured and co-cultured TNBC cells showed that the cytokines IL1α, IL1β and IL8 were highly expressed in co-cultured TNBC cells. High levels of IL1α, IL1β and IL8 are necessary for TNBC cells to better survive when encountering macrophages, achieve stronger metastatic ability, and recruit more tumour-helping M2 macrophages to tumour sites.
Through further mechanistic studies, the researchers discovered that TNBC cells acquire these abilities via interactions with macrophages in three phases. First, within 12 hours of co-culture with macrophages, some TNBC cells significantly elevate levels of ROS, which upregulate IL1α expression in ERK1/2-c-Jun- and NF-κB-dependent manners at 24 to 48 hours. Second, the secreted IL1α bound to IL1R1 activates the ERK1/2-ZEB1-VIM pathway which increases metastasis. Third, IL1α/IL1R1 facilitates its own synthesis and induces the expression of IL1β and IL8 at 72 to 96 hours through the MKK4-JNK-c-Jun and NF-κB signalling pathways. Moreover, a higher level of IL1α is positively correlated with more macrophage infiltration and shorter overall survival in breast cancer patients. Thus, the study suggests that ROS and IL1α may serve as new targets for anti-metastasis therapy in TNBC.
Prof Kathy Luo Qian is the corresponding author of the study and her PhD graduate Hao Meng is the first author. PhD graduates Huang Bin, Wu Renfei, and Peng Zheng also contributed to the study. The research project was supported by the Science and Technology Development Fund of the Macao SAR (File no: 068/2017/A2, 0147/2020/A3, and 0004/2021/AKP), and the Ministry of Education Frontiers Science Center for Precision Oncology of UM (SP2021-00001-FSCPO and SP2023-00001-FSCPO). The full version of the research article can be viewed at: http://doi.org/10.1002/advs.202302857.
To read the news on UM’s official website, please visit the following link:
https://www.um.edu.mo/news-and-press-releases/campus-news/detail/56718/