Biology subjects

Zylka, M. M.

Publications and source records attributed to Zylka, M. M..

3 recordsLinked to original sources

bioRxiv2026

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. Massons 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.

cancer biology↗

bioRxiv2025

Mevalonate pathway activation in Ewing sarcoma reveals a 3D-specific synergy between statins and BCL-xL inhibition

Bone sarcomas are rare and aggressive pediatric cancers with limited progress in targeted therapy development, in part due to the poor physiological relevance of conventional two-dimensional (2D) culture systems used for preclinical testing. To address this gap, we developed a standardized three-dimensional (3D) culture and drug-testing platform for Ewing sarcoma (ES) and osteosarcoma (OS) that more accurately recapitulates in vivo tumor biology. Across 3D spheroids, bioprinted constructs, and patient-derived xenograft (PDX) cultures, we observed a consistent activation and dependency on the mevalonate pathway in ES. Leveraging this platform, we identified a selective therapeutic synergy between statins, which inhibit mevalonate pathway flux, and BCL-xL inhibitors, a vulnerability that was not detectable in 2D cultures. These findings highlight the mevalonate pathway as a targetable metabolic dependency in ES and demonstrate how physiologically grounded 3D models can uncover clinically actionable treatment strategies that remain hidden in traditional 2D systems. Our findings show that 3D tumor models can expose actionable metabolic vulnerabilities obscured by traditional approaches, supporting their use in rational combination therapy discovery for aggressive pediatric sarcomas.

cancer biology↗

bioRxiv2025

Small Particles, Big Problems: Polystyrene nanoparticles induce DNA damage, oxidative stress, migration, and mitogenic pathways predominantly in non-malignant lung cells

Polystyrene micro-and nanoplastics (PS-MNPs) are emerging environmental pollutants with potential implications for human health. In this study, we used two different sizes of PS-MNPs (0.25 {micro}m and 1 {micro}m) on non-small cell lung cancer (A549, H460), small cell lung cancer (DMS53, H372), and normal lung epithelial (BEAS-2B) cells, as well as on human-derived lung organoids, to investigate the cytotoxic effects of PS particles. At lower concentrations (< 30 {micro}g/cm2, equivalent to 50 {micro}g/ml), neither PS-MPs nor PS-NPs did not interfere with cell viability or proliferation. Intracellular kinetic assays revealed that non-malignant (BEAS-2B) lung cells showed the strongest turnover of PS-NPs compared to malignant cells. Since PS-NPs exhibited more pronounced cellular effects, we focused further analyses on their impact. Furthermore, we observed significantly increased migration, prolonged S-phase arrest along with induced DNA damage, and oxidative stress in non-malignant (BEAS-2B) lung cells. Thus, our data suggest that BEAS-2B cells exhibit the highest sensitivity to PS-NPs. We also demonstrate that after PS-NP treatment, these cells displayed decreased base excision repair capacity and increased activation of survival pathways, including AKT and ERK phosphorylation. PS-NP internalization and increase of signal pathways were validated in a more physiological lung organoid setting. Altogether, our findings suggest that PS-NPs do not significantly affect the malignant behavior of cancer cells. However, they could promote tumor-like features in normal lung cells by inducing survival pathways, migration, and alterations in stress response mechanisms. Environmental ImplicationsThis study investigates the effects of polystyrene micro-and nanoplastics (PS-MNPs) at environmentally relevant concentrations. The tested concentrations of PS-MNPs (0, 15, 30, and 60 {micro}g/cm2, equivalent to 0, 25, 50, and 100 {micro}g/ml) are commonly studied in the literature in lung cells. While these findings provide insights into cellular responses, the overall environmental impact of PS-MNPs remains limited at realistic exposure levels. HighlightsO_LIPS-MNPs are internalized into lung cells, with higher uptake in non-malignant cells. C_LIO_LIPS-NPs lead to increased migration, DNA damage, oxidative stress, and disturbed cell cycle progression. C_LIO_LIPS-NPs promote activation of survival pathways in non-malignant cells and lung organoids. C_LIO_LIExposure of PS-NPs may cause potential implications for lung cancer development and progression. C_LI

molecular biology↗