Cancer cells function as primary architects of the tumor microenvironment. Yet, the molecular features of cancer cells that govern stromal cell phenotypes remain unclear. Here, we show that cancer-associated fibroblasts (CAFs) are distinguishable on the basis of gene expression signatures they acquire in co-culture with epithelial- or mesenchymal-like lung adenocarcinoma (LUAD) cells. High expression of the EMT activator ZEB1 endows LUAD cells with the capacity to activate a soluble factor exchange that leads to CAF reprogramming, to generate CAF-led invasive projections in multicellular aggregates, and to respond to pro-metastatic signals from CAFs in mice. Thus, ZEB1-expressing LUAD cells are positioned at the apex of a signaling hierarchy in the tumor microenvironment.
Keywords: cancer associated fibroblasts, lung adenocarcinoma, Single Cell Sequencing, EMT, ZEB1
Bota-Rabassedas, Neus and Banerjee, Priyam and Cao, Wenjian and Sheng, Kuanwei and Xi, Yuanxin and Tan, Xiaochao and Niu, Yichi and Luo, Jiayi and Parra, Edwin Roger and Rodriguez-canales, Jaime and Albritton, Jacob and weiger, Michael and Liu, Xin and Guo, Hou-Fu and Yu, Jiang and Rodriguez, B. Leticia and Firestone, Joshua and Mino, Barbara and Creighton, Chad and Solis, Luisa and Villalobos, Pamela and Raso, Maria Gabriela and Sazer, Daniel and Gibbons, Don and William, Russell and Longmore, Gregory and Wistuba, Ignacio and Wang, Jing and Chapman, Harold and Miller, Jordan S. and Zong, Chenghang and Kurie, Jonathan, Contextual Cues from Cancer Cells Govern CAF Heterogeneity. Available at SSRN: https://ssrn.com/abstract=3570566 or http://dx.doi.org/10.2139/ssrn.3570566
This version of the paper has not been formally peer reviewed.
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