biostudies-literatureUnknown132(8)Tang F<h4>Background</h4>The heterogeneity of tumors significantly impacts on colorectal cancer (CRC) progression. However, the influence of this heterogeneity on the spatial architecture of CRC remains largely unknown.<h4>Methods</h4>Spatial transcriptomic (ST) analysis of AOM/DSS-induced colorectal cancer (CRC), integrated with single-cell RNA sequencing, generated a comprehensive spatial atlas of CRC. Pseudotime trajectory, stemness evaluation, and cell-cell communication analyses explored how CD44⁺ tumor cells at the leading edge remodel the tumor microenvironment (TME). In vitro experiments and immunofluorescence staining of clinical samples validated pleiotrophin (PTN) signaling in promoting cancer-associated fibroblasts (CAFs) phenotypic transition and CRC progression.<h4>Results</h4>Our findings revealed a distinctive layered ring-like structure within CRC tissues, where CD44⁺ tumor cells exhibiting high stemness were positioned at the tumor's leading edge. Inflammatory CAFs (iCAFs)-like, myofibroblastic CAFs (myCAFs)-like cells and pro-tumorigenic neutrophils primarily located at the tumor edge, in proximity to CD44⁺ tumor cells. CD44⁺ tumor cells then triggered the phenotypic transition of CAFs into iCAF-like and myCAF-like cells through PTN signaling.<h4>Conclusions</h4>Our results provide distinctive insights into how tumor heterogeneity reshapes the TME at the leading edge of tumor, thereby promoting CRC progression.British journal of cancer703-715https://www.ebi.ac.uk/biostudies/studies/S-EPMC11997037biostudies-literatureCD44&lt;sup&gt;+&lt;/sup&gt; cells enhance pro-tumor stroma in the spatial landscape of colorectal cancer leading edge.PMC11997037Sun LShen JZhu YYuan BHe XTian YWeng LTang FfalseCD44&lt;sup&gt;+&lt;/sup&gt; cells enhance pro-tumor stroma in the spatial landscape of colorectal cancer leading edge.<h4>Background</h4>The heterogeneity of tumors significantly impacts on colorectal cancer (CRC) progression. However, the influence of this heterogeneity on the spatial architecture of CRC remains largely unknown.<h4>Methods</h4>Spatial transcriptomic (ST) analysis of AOM/DSS-induced colorectal cancer (CRC), integrated with single-cell RNA sequencing, generated a comprehensive spatial atlas of CRC. Pseudotime trajectory, stemness evaluation, and cell-cell communication analyses explored how CD44⁺ tumor cells at the leading edge remodel the tumor microenvironment (TME). In vitro experiments and immunofluorescence staining of clinical samples validated pleiotrophin (PTN) signaling in promoting cancer-associated fibroblasts (CAFs) phenotypic transition and CRC progression.<h4>Results</h4>Our findings revealed a distinctive layered ring-like structure within CRC tissues, where CD44⁺ tumor cells exhibiting high stemness were positioned at the tumor's leading edge. Inflammatory CAFs (iCAFs)-like, myofibroblastic CAFs (myCAFs)-like cells and pro-tumorigenic neutrophils primarily located at the tumor edge, in proximity to CD44⁺ tumor cells. CD44⁺ tumor cells then triggered the phenotypic transition of CAFs into iCAF-like and myCAF-like cells through PTN signaling.<h4>Conclusions</h4>Our results provide distinctive insights into how tumor heterogeneity reshapes the TME at the leading edge of tumor, thereby promoting CRC progression.2025-01-01T00:00:00Z2025 May2026-06-03T01:17:28.313Z2025-07-03T03:06:43.381ZS-EPMC119970374006957410.1038/s41416-025-02968-9