Lung-mimicking click alginate-dECM model of breast cancer lung metastasis reveals the role of ECM mechanics in tumor growth dynamics and genomic instability

Abstract Metastatic breast cancer (BC) is the main cause of cancer-related death in women. Accumulating evidence highlights the prominent changes within the lung metastatic niche, resulting in stiffening of the extracellular matrix (ECM). The prevailing concept of cancer evolution encompasses the acquisition of beneficial traits as a consequence of genomic instability, yet it remains elusive to what extend altered lung ECM mechanics feed into this. To investigate this, a tunable 3D bioengineered model, capturing the biophysical and biochemical characteristics of the BC metastatic lung niche is developed. Porcine derived lung decellularized ECM (dECM), combined with norbornene and tetrazine modified click-crosslinkable alginate, recapitulates composition and mechanics of healthy soft (3 kPa) and metastatic stiff (13 kPa) lung niches. Label-free optical microscopy further validates the microarchitectural resemblance between resulting matrices and human lung metastasis samples. Encapsulation of MDA-MB-231 and MCF7 cells reveals that stiffer matrices promote BC cluster growth and DNA damage, indicated by yH2AX, independent of BC subtype. Moreover, this platform is compatible with patient derived cells, which remain viable for 14 days. These findings underscore the critical role of tissue mechanics in regulating BC metastasis progression and demonstrate the utility of the herein developed tunable, physiologically relevant platform for patient-based models. Table of ContentFabrication of 3D bioengineered breast cancer (BC) lung metastasis niche to investigate how tissue mechanics modulate cancer evolution. Tunable hybrid biomaterials recapitulate the mechanical and biochemical characteristics of healthy soft and diseased stiff lung. Within these niches, stiffness promotes enhanced BC cluster growth and genomic instability. Biocompatibility with patient-derived BC cells, opens opportunities for drug testing platforms for personalized medicine. Competing Interest Statement The authors have declared no competing interest.