卵巢肿瘤细胞通过积极降低微环境细胞的细胞适应性来获得竞争优势。
Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells.
作者信息
Madan Esha, Palma António M, Vudatha Vignesh, Kumar Amit, Bhoopathi Praveen, Wilhelm Jochen, Bernas Tytus, Martin Patrick C, Bilolikar Gaurav, Gogna Aenya, Peixoto Maria Leonor, Dreier Isabelle, Araujo Thais Fenz, Garre Elena, Gustafsson Anna, Dorayappan Kalpana Deepa Priya, Mamidi Narsimha, Sun Zhaoyu, Yekelchyk Michail, Accardi Davide, Olsen Amalie Lykke, Lin Lin, Titelman Asaf Ashkenazy, Bianchi Michael, Jessmon Phil, Farid Elnaz Abbasi, Pradhan Anjan K, Neufeld Lena, Yeini Eilam, Maji Santanu, Pelham Christopher J, Kim Hyobin, Oh Daniel, Rolfsnes Hans Olav, Marques Rita C, Lu Amy, Nagane Masaki, Chaudhary Sahil, Gupta Kartik, Gogna Keshav C, Bigio Ana, Bhoopathi Karthikeya, Mannangatti Padmanabhan, Achary K Gopinath, Akhtar Javed, Belião Sara, Das Swadesh, Correia Isabel, da Silva Cláudia L, Fialho Arsénio M, Poellmann Michael J, Javius-Jones Kaila, Hawkridge Adam M, Pal Sanya, Shree Kumari S, Rakha Emad A, Khurana Sambhav, Xiao Gaoping, Zhang Dongyu, Rijal Arjun, Lyons Charles, Grossman Steven R, Turner David P, Pillappa Raghavendra, Prakash Karanvir, Gupta Gaurav, Robinson Gary L W G, Koblinski Jennifer, Wang Hongjun, Singh Gita, Singh Sujay, Rayamajhi Sagar, Bacolod Manny D, Richards Hope, Sayeed Sadia, Klein Katherine P, Chelmow David, Satchi-Fainaro Ronit, Selvendiran Karuppaiyah, Connolly Denise, Thorsen Frits Alan, Bjerkvig Rolf, Nephew Kenneth P, Idowu Michael O, Kühnel Mark P, Moskaluk Christopher, Hong Seungpyo, Redmond William L, Landberg Göran, Lopez-Beltran Antonio, Poklepovic Andrew S, Sanyal Arun, Fisher Paul B, Church George M, Menon Usha, Drapkin Ronny, Godwin Andrew K, Luo Yonglun, Ackermann Maximilian, Tzankov Alexandar, Mertz Kirsten D, Jonigk Danny, Tsung Allan, Sidransky David, Trevino Jose, Saavedra Arturo P, Winn Robert, Won Kyoung Jae, Moreno Eduardo, Gogna Rajan
机构信息
Department of Surgery, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Massey Comprehensive Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
出版信息
Nat Biotechnol. 2024 Dec 9. doi: 10.1038/s41587-024-02453-3.
Cell competition and fitness comparison between cancer and tumor microenvironment (TME) cells determine oncogenic fate. Our previous study established a role for human Flower isoforms as fitness fingerprints, where the expression of Flower Win isoforms in tumor cells leads to growth advantage over TME cells expressing Lose isoforms. Here we demonstrate that the expression of Flower Lose and reduced microenvironment fitness is not a pre-existing condition but, rather, a cancer-induced phenomenon. Cancer cells actively reduce TME fitness by the exosome-mediated release of a cancer-specific long non-coding RNA, Tu-Stroma, which controls the splicing of the Flower gene in the TME cells and expression of Flower Lose isoform, which leads to reduced fitness status. This mechanism controls cancer growth, metastasis and host survival in ovarian cancer. Targeting Flower protein with humanized monoclonal antibody (mAb) in mice significantly reduces cancer growth and metastasis and improves survival. Pre-treatment with Flower mAb protects intraperitoneal organs from developing lesions despite the presence of aggressive tumor cells.
癌细胞与肿瘤微环境（TME）细胞之间的细胞竞争和适应性比较决定了致癌命运。我们之前的研究确定了人类Flower异构体作为适应性指纹的作用，其中肿瘤细胞中Flower Win异构体的表达导致其相对于表达Lose异构体的TME细胞具有生长优势。在此，我们证明Flower Lose的表达和微环境适应性降低并非预先存在的条件，而是一种癌症诱导的现象。癌细胞通过外泌体介导释放一种癌症特异性长链非编码RNA（Tu-Stroma）来主动降低TME适应性，该RNA控制TME细胞中Flower基因的剪接以及Flower Lose异构体的表达，从而导致适应性状态降低。这种机制控制卵巢癌中的癌症生长、转移和宿主存活。在小鼠中用人源化单克隆抗体（mAb）靶向Flower蛋白可显著降低癌症生长和转移并提高存活率。尽管存在侵袭性肿瘤细胞，但用Flower mAb进行预处理可保护腹腔器官不发生病变。
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