Cancer-associated fibroblasts (CAFs) display significant functional and molecular heterogeneity within the tumor microenvironment, playing diverse roles in cancer progression. Employing single-cell RNA sequencing data of colorectal cancer (CRC), we identified a subset of matrix CAFs (mCAFs) as a critical subtype that secretes THBS2, a molecule linked to advanced cancer stages and poor prognosis. Spatial transcriptomics and multiplex immunohistochemistry revealed clear spatial colocalization between THBS2-producing mCAFs and tumor cells. Mechanically, CAF-secreted THBS2 binds to CD47 on tumor cells, triggering the MAPK/ERK5 signaling pathway, which enhances tumor progression. The tumor-promoting role of THBS2 was further validated using fibroblast-specific THBS2 knockout mice, patient-derived organoids, and xenografts. Moreover, the transcription factor CREB3L1 was identified as a regulator of the transformation of normal fibroblasts into THBS2-producing mCAFs. These findings underscore the pivotal role of THBS2 in CRC progression and highlight the therapeutic potential of targeting the THBS2-CD47 axis and CREB3L1 in CRC.
The role of cancer-associated fibroblasts (CAFs) in the initiation and invasion phases of human lung adenocarcinoma (LUAD) development is not fully understood. In this study, we utilized single-cell RNA sequencing, spatial transcriptomics, and a combination of in vivo and in vitro models to decode the dynamics of tumor-stroma interactions during human LUAD progression, focusing primarily on adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (IAC). We identified a matrix CAF (mCAF) subtype characterized by high THBS2 expression, which was closely associated with poor clinical outcomes, tumor recurrence, and the invasive dynamics of LUAD. Spatial transcriptomics and multiplex immunohistochemistry analysis revealed that this CAF subpopulation was closely associated with tumor cells, with clear spatial colocalization. In vivo and in vitro experiments demonstrated that THBS2 secreted by these mCAFs directly binds to SDC4 on tumor cells, enhancing tumor epithelial-mesenchymal transition (EMT) programs. This study highlights THBS2+ mCAFs as key regulators of tumor-stroma interactions and identifies the THBS2-SDC4-EMT axis as a potential therapeutic target in LUAD.
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