Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche
Xi He, Sarah E. Smith, Shiyuan Chen, Hua Li, Di Wu, Paloma Meneses-Giles, Yongfu Wang, Mark Hembree, Kexi Yi, Xia Zhao, Fengli Guo, Jay R. Unruh, Lucinda Maddera, Zulin Yu, Allison Scott, Anoja Perera, Yan Wang, Chongbei Zhao, KyeongMin Bae, Andrew Box, Jeffrey S. Haug, Tao Fang, Deqing Hu, Darrick Hansen, Pengxu Qian, Subhrajit Saha, Dan A. Dixon, Shrikant Anant, Da Zhang, Edward H. Lin, Weijing Sun, Leanne M. Wiedemann, Linheng Li
Abstract
Tumor-initiating stem cells (TSCs) are critical for drug resistance and immune escape. However, the mutual regulations between TSC and tumor microenvironment (TME) remain unclear. Using DNA-label retaining, single-cell RNA sequencing (scRNA-seq), and other approaches, we investigated intestinal adenoma in response to chemoradiotherapy (CRT), thus identifying therapy-resistant TSCs (TrTSCs). We find bidirectional crosstalk between TSCs and TME using CellPhoneDB analysis. An intriguing finding is that TSCs shape TME into a landscape that favors TSCs for immunosuppression and propagation. Using adenoma-organoid co-cultures, niche-cell depletion, and lineaging tracing, we characterize a functional role of cyclooxygenase-2 (Cox-2)-dependent signaling, predominantly occurring between tumor-associated monocytes and macrophages (TAMMs) and TrTSCs. We show that TAMMs promote TrTSC proliferation through prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, which enhances β-catenin activity via AKT phosphorylation. Thus, our study shows that the bidirectional crosstalk between TrTSC and TME results in a pro-tumorigenic and immunosuppressive contexture.