美国弗吉尼亚联邦大学Rajan Gogna等研究人员合作发现，卵巢肿瘤细胞通过主动降低微环境细胞的细胞适应性获得竞争优势。相关论文于2024年12月9日在线发表于国际学术期刊《自然—生物技术》。

研究人员表示，细胞竞争和癌细胞与肿瘤微环境（TME）细胞之间的适应性比较，决定了癌变命运。研究人员之前的研究确立了人类Flower同种型作为适应性指纹的作用，其中肿瘤细胞中Flower Win同种型的表达，相较于表达Lose同种型的TME细胞具有生长优势。

研究人员展示了Flower Lose的表达和微环境适应性降低，并非一种先天条件，而是癌症诱导的现象。癌细胞通过外泌体介导释放癌症特异性长链非编码RNA Tu-Stroma，主动降低TME细胞的适应性，这种RNA调控TME细胞中Flower基因的剪接，导致Flower Lose同种型的表达，从而使微环境细胞的适应性降低。

这一机制控制了卵巢癌的生长、转移和宿主生存。通过人源化单克隆抗体（mAb）靶向Flower蛋白，可以显著减少小鼠的癌症生长和转移，并改善生存率。即使在存在侵袭性肿瘤细胞的情况下，预先用Flower mAb治疗仍能保护腹腔器官免受病变的发生。

附：英文原文

Title: Ovarian tumor cells gain competitive advantage by actively reducing the cellular fitness of microenvironment cells

Author: Madan, Esha, Palma, Antnio 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, Belio, Sara, Das, Swadesh, Correia, Isabel, da Silva, Cludia L., Fialho, Arsnio M., Poellmann, Michael J., Javius-Jones, Kaila, Hawkridge, Adam M., Pal, Sanya, Shree, Kumari S., Rakha, Emad A., Khurana, Sambhav, Xiao, Gaoping, Zhang, Dongyu

Issue&Volume: 2024-12-09

Abstract: 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.

DOI: 10.1038/s41587-024-02453-3

Source: https://www.nature.com/articles/s41587-024-02453-3