Tumor-initiating stem cell shapes its microenvironment into an immunosuppressive barrier and pro-tumorigenic niche

• DOI: 10.1016/j.celrep.2021.109674
• Publication Date: 2021-09-07T14:33:18Z
• Authors: Xi He; Sarah E. Smith; Shiyuan Chen; Hua Li; Di Wu; Paloma I. Meneses...; Yongfu Wang; Mark Hembree; Kexi Yi; Xia Zhao; Fengli Guo; Jay R. Unruh; Lucinda E. Maddera; Zulin Yu; Allison Scott; Anoja Perera; Yan Wang; Chongbei Zhao; KyeongMin Bae; Andrew Box; Jeffrey S. Haug; Fang Tao; Deqing Hu; Darrick M. Hansen; Pengxu Qian; Subhrajit Saha; Dan Dixon; Shrikant Anant; Da Zhang; Edward H. Lin; Weijing Sun; Leanne M. Wiedemann; Linheng Li
• Keywords: 0301 basic medicine; Carcinogenesis; Article; Dinoprostone; Intestines; Organoids; Mice; 03 medical and health sciences; Cyclooxygenase 2; Neoplastic Stem Cells; Tumor Microenvironment; Animals; Humans; Cell Shape

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.