Fibroblasts loss Lepr promote CRC progression
Cancer-associated fibroblasts (CAFs) are increasingly recognized as central stromal drivers of colorectal cancer (CRC) progression, yet their functional diversity and lineage origins remain incompletely defined. Here, we identify a previously unrecognized CAF population, Lepr^negMmp^high fibroblast, that specifically accumulates in CRC and exerts potent tumor-promoting effects. Using lineage-tracing and functional assays, we show that combined TNFa and TGFß signaling drives the transition from Lepr+ fibroblasts into Lepr^negMmp^high cells. This transition is mediated by TNFa and TGFß–induced downregulation of the transcription factor Tcf21, which in turn suppresses Lepr expression. Functionally, Lepr^negMmp^high cells enhance CRC progression by upregulating Csf3, thereby driving macrophage recruitment and establishing a pro-tumorigenic immune microenvironment. Importantly, genetic or pharmacological perturbation of relevant signaling attenuates CAF reprogramming and reduces macrophage infiltration. Together, our findings uncover a distinct fibroblast lineage trajectory in CRC, define the Tcf21–Lepr axis as a critical checkpoint of stromal plasticity, and highlight Lepr^negMmp^high fibroblasts as a promising target for stromal reprogramming strategies in CRC.
Cancer-associated fibroblasts (CAFs) are increasingly recognized as central stromal drivers of colorectal cancer (CRC) progression, yet their functional diversity and lineage origins remain incompletely defined. Here, we identify a previously unrecognized CAF population, Lepr^negMmp^high fibroblast, that specifically accumulates in CRC and exerts potent tumor-promoting effects. Using lineage-tracing and functional assays, we show that combined TNFa and TGFß signaling drives the transition from Lepr+ fibroblasts into Lepr^negMmp^high cells. This transition is mediated by TNFa and TGFß–induced downregulation of the transcription factor Tcf21, which in turn suppresses Lepr expression. Functionally, Lepr^negMmp^high cells enhance CRC progression by upregulating Csf3, thereby driving macrophage recruitment and establishing a pro-tumorigenic immune microenvironment. Importantly, genetic or pharmacological perturbation of relevant signaling attenuates CAF reprogramming and reduces macrophage infiltration. Together, our findings uncover a distinct fibroblast lineage trajectory in CRC, define the Tcf21–Lepr axis as a critical checkpoint of stromal plasticity, and highlight Lepr^negMmp^high fibroblasts as a promising target for stromal reprogramming strategies in CRC.