A human lung organoid co-culture model of early bone sarcoma metastasis reveals contact-dependent epithelial remodeling at the metastatic interface

Lung metastasis drives mortality across cancer types, yet how infiltrating tumor cells remodel the lung epithelium to establish metastatic niches remains poorly understood. Here we establish MESCUL (MEtastatic Sarcoma Co-CULture), a co-culture platform combining human lung organoids with patient-derived bone sarcoma cells to model early tumor-lung epithelial interactions in a physiologically relevant 3D system. MESCUL reveals that direct tumor-epithelial contact induces rapid, reproducible lung epithelial remodeling across Ewing sarcoma (ES) and osteosarcoma (OS) models and multiple organoid donor backgrounds, which is contact-dependent and not recapitulated by paracrine signaling. Single-cell RNA sequencing identifies LIMES (Lung Interface Metastasis Signature), a shared transcriptional program encompassing focal adhesion assembly, matrix metalloprotease (MMP) upregulation, and emergence of a damage-associated transitional cell state, in both ES and OS. Mechanistically, tumor-derived fibronectin (FN1) engages epithelial integrin receptors to activate focal adhesion kinase (FAK), driving amphiregulin (AREG) induction and MMP-mediated remodeling; FN1 alone phenocopies this response, and FAK inhibition attenuates it, nominating the FN1-integrin-FAK-AREG axis as a candidate therapeutic vulnerability. The LIMES program, identified through the MESCUL co-culture model, is spatially confined to the tumor-lung interface in patient metastases of both ES and OS, as demonstrated by spatial transcriptomics across nine patients. Masson's trichrome staining of matched patient sections reveals pronounced collagen deposition in the peri-tumoral lung parenchyma, consistent with LIMES acting upstream of a wound-healing cascade that proceeds to structural fibrotic remodeling in patient tissue. Together, these findings establish the lung epithelium as an active participant in metastatic colonization, characterize a pharmacologically targetable, spatially restricted epithelial remodeling response at the bone sarcoma-lung interface across OS and ES, and introduce MESCUL as a tractable 3D platform for investigating lung metastasis, with possible implications for tumor types beyond bone sarcomas.

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