Invasion and Secondary Site Colonization as a Function of In Vitro Primary Tumor Matrix Stiffness: Breast to Bone Metastasis

• Published in: Advanced healthcare materials 2023-01, Vol.12 (3), p.e2201898-n/a
• Main Authors: Shah, Lekha, Latif, Ayşe, Williams, Kaye J., Mancuso, Elena, Tirella, Annalisa
• Format: Article
• Language: English
• Subjects: alginate hydrogels; Alginates; Alginic acid; Bone and Bones; Bone matrix; Bone Neoplasms; Bone tumors; Breast cancer; breast‐to‐bone metastasis; decellularized PCL scaffolds; Extracellular matrix; Gelatin; Humans; Hydrogels; in vitro models; Interleukin 6; invasive potential; matrix stiffness; Mechanical properties; Metastases; Metastasis; Osteolysis; Parathyroid hormone-related protein; Phenotypes; Scaffolds; Stiffness; Three dimensional printing; Tissue Scaffolds; Tumors
• ISSN: 2192-2640; 2192-2659; 2192-2659
• DOI: 10.1002/adhm.202201898

Increased breast tissue stiffness is correlated with breast cancer risk and invasive cancer progression. However, its role in promoting bone metastasis, a major cause of mortality, is not yet understood. It is previously identified that the composition and stiffness of alginate‐based hydrogels mimicking normal (1–2 kPa) and cancerous (6–10 kPa) breast tissue govern phenotype of breast cancer cells (including MDA‐MB‐231) in vitro. Here, to understand the causal effect of primary tumor stiffness on metastatic potential, a new breast‐to‐bone in vitro model is described. Together with alginate‐gelatin hydrogels to mimic breast tissue, 3D printed biohybrid poly‐caprolactone (PCL)‐composite scaffolds, decellularized following bone‐ECM deposition through Saos‐2 engraftment, are used to mimic the bone tissue. It is reported that higher hydrogel stiffness results in the increased migration and invasion capacity of MDA‐MB 231 cells. Interestingly, increased expression of osteolytic factors PTHrP and IL‐6 is observed when MDA‐MB‐231 cells pre‐conditioned in stiffer hydrogels (10 kPa, 3% w/v gelatin) colonize the bone/PCL scaffolds. The new breast‐to‐bone in vitro models herein described are designed with relevant tissue microenvironmental factors and could emerge as future non‐animal technological platforms for monitoring metastatic processes and therapeutic efficacy. This study delineates the importance of primary tumor stiffness in breast cancer invasion and bone metastasis using new in vitro models. Results suggests that stiffer hydrogels increase migration and invasive capability of MDA‐MB 231 cells. Moreover, preconditioning of cells in stiff breast‐mimicking hydrogel (10 kPa) is correlated with increased release of osteolytic factors while invading a bone‐like microenvironment.