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

He, Xi; Smith, Sarah E.; Chen, Shiyuan; Li, Hua; Wu, Di; Meneses-Giles, Paloma I.; Wang, Yongfu; Hembree, Mark; Yi, Kexi; Zhao, Xia; Guo, Fengli; Unruh, Jay R.; Maddera, Lucinda E.; Yu, Zulin; Scott, Allison; Perera, Anoja; Wang, Yan; Zhao, Chongbei; Bae, KyeongMin; Box, Andrew; Haug, Jeffrey S.; Tao, Fang; Hu, Deqing; Hansen, Darrick M.; Qian, Pengxu; Saha, Subhrajit; Dixon, Dan; Anant, Shrikant; Zhang, Da; Lin, Edward H.; Sun, Weijing; Wiedemann, Leanne M.; Li, Linheng

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.