Embracing Mechanobiology in Next Generation Organ-On-A-Chip Models of Bone Metastasis

Abstract

Bone metastasis in breast cancer is associated with high mortality. Biomechanical cues presented by the extracellular matrix play a vital role in driving cancer metastasis. The lack of in vitro models that recapitulate the mechanical aspects of the in vivo microenvironment hinders the development of novel targeted therapies. Organ-on-a-chip (OOAC) platforms have recently emerged as a new generation of in vitro models that can mimic cell-cell interactions, enable control over fluid flow and allow the introduction of mechanical cues. Biomaterials used within OOAC platforms can determine the physical microenvironment that cells reside in and affect their behavior, adhesion, and localization. Refining the design of OOAC platforms to recreate microenvironmental regulation of metastasis and probe cell-matrix interactions will advance our understanding of breast cancer metastasis and support the development of next-generation metastasis-on-a-chip platforms. In this mini-review, we discuss the role of mechanobiology on the behavior of breast cancer and bone-residing cells, summarize the current capabilities of OOAC platforms for modeling breast cancer metastasis to bone, and highlight design opportunities offered by the incorporation of mechanobiological cues in these platforms.

Oncologic necessity for the complete removal of residual microcalcifications after neoadjuvant chemotherapy for breast cancer

“…Complete removal of microcalcifications may be necessary to confirm the actual pCR, and complete removal of residual cancer may help reduce the local recurrence rate. Furthermore, malignant microcalcifications that remain even after NAC contain larger www.nature.com/scientificreports/ hydroxyapatite particles, which upregulate MMP-1 and promote the aggressiveness of breast cancer by decreasing the elasticity of the extracellular matrix [18][19][20] .…”

“…However, malignant microcalcifications containing larger hydroxyapatite particles, even if detected as an early finding in breast cancer, are associated with more invasive breast carcinomas 18 . Because hydroxyapatite upregulates the expression of matrix metalloproteinase 1 (MMP-1) and promotes the migration of breast cancer cells through decreased elasticity of the extracellular matrix, augmented gene expression of MMP-1 predicts worse metastasis-free survival 19 , 20 .…”

Three-Dimensional Cell Cultures: The Bridge between In Vitro and In Vivo Models

“…Advances in additive manufacturing, bioprinting, and microfluidics have led to a surge in the development and manufacturing of microfluidic cell culture platforms and organ-ona-chip devices, such as the bone chip system [291] and bone metastasis models [292], to create bone structure for pharmaceutical pre-clinical testing [293]. Mandatari et al tested the effect of vitamin K2 on a human osteoblasts/osteoclasts 3D dynamic co-culture system that reproduced the bone microenvironment, observing how this vitamin improved the functions of osteoblasts isolated from osteoporotic patients.…”

Organ-on-a-Chip and Microfluidic Platforms for Oncology in the UK

“…Mechanical stimulation is now thought to be a crucial element of organchip models, and the standardisation of biomechanical cues is of critical importance when developing these systems (reviewed elsewhere by researchers at Queen Mary University of London [29]). The unique opportunities provided by organ chips to manipulate cancer cell mechanobiology has been highlighted for some specific cancers [30], but will be discussed here in general terms.…”