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

Area of Science:

• Oncology
• Cancer Stem Cell Biology
• Tumor Microenvironment Research

Background:

• Tumor-initiating stem cells (TSCs) are crucial for cancer drug resistance and immune evasion.
• The intricate relationship between TSCs and the tumor microenvironment (TME) is not fully understood.
• Investigating these interactions is key to overcoming therapeutic challenges.

Purpose of the Study:

• To elucidate the bidirectional crosstalk between TSCs and the TME in intestinal adenoma.
• To identify therapy-resistant TSCs (TrTSCs) and understand their role in shaping the TME.
• To uncover the molecular mechanisms driving TSC propagation and immune suppression within the TME.

Main Methods:

• Utilized DNA-label retaining and single-cell RNA sequencing (scRNA-seq) to study intestinal adenoma.
• Employed CellPhoneDB analysis to investigate TSC-TME crosstalk.
• Used adenoma-organoid co-cultures, niche-cell depletion, and lineage tracing to characterize signaling pathways.

Main Results:

• Identified therapy-resistant TSCs (TrTSCs) and demonstrated bidirectional communication between TSCs and the TME.
• Discovered that TSCs actively shape the TME to favor their own immunosuppression and proliferation.
• Characterized a key signaling axis involving cyclooxygenase-2 (Cox-2), tumor-associated monocytes and macrophages (TAMMs), and TrTSCs.

Conclusions:

• TAMMs promote TrTSC proliferation via prostaglandin E2 (PGE2)-PTGER4(EP4) signaling, enhancing beta-catenin activity.
• The bidirectional crosstalk between TrTSCs and the TME establishes a pro-tumorigenic and immunosuppressive environment.
• Targeting this crosstalk may offer novel therapeutic strategies against drug-resistant cancers.