Tumor‐On‐A‐Chip Model Incorporating Human‐Based Hydrogels for Easy Assessment of Metastatic Tumor Inter‐Heterogeneity

Abstract

The coordinated migration of invasive tumor cells is a complex and dynamic mechanism driven by diverse cellular and molecular events. Unfortunately, the inherent heterogeneity within tumors raises multiple challenges in deciphering key biomarkers and novel therapeutic approaches to prevent tumor metastasis. Here, a microengineered tumor‐on‐a‐chip system incorporating human platelet lysate hydrogels is proposed to recreate the early metastatic process of tumor invasion and drug response. By co‐culturing human bone marrow mesenchymal stem cells with two tumor cell lines with distinct metastatic capability, the developed model can emulate the 3D tumor microarchitecture and inter‐heterogeneity regarding its intrinsic metastatic ability. The recreated microenvironment supports tumor and stromal cell movement, evidencing the synergistic tumor‐stromal cell and cell‐extracellular matrix interactions of an invading tumor. Through gene and protein expression analysis and exometabolomic profiling, this tumor‐on‐a‐chip platform provides evidence for the role of a dynamic environment as a key regulator of tumor metastatic ability. Additionally, the effect of doxorubicin treatment on tumor invasiveness and biomarker profile highlights the suitability of the established models for therapy assessment. Overall, this study presents a tumor‐on‐a‐chip model useful to pursue mechanistic studies on early metastatic events in a fully human‐derived microenvironment, while contributing with fundamental insights into biomolecular profiling.

Human Platelet Lysate-Derived Nanofibrils as Building Blocks to Produce Free-Standing Membranes for Cell Self-Aggregation

“…Nonetheless, the interest in human-derived biomaterials has steadily evolved given the reduced risk of immunogenicity and the absence of ethical concerns related to animal welfare . Recent studies have proposed a human methacryloyl platelet lysate (PLMA)-based hydrogel as a bioactive and functional material to support stem cell and tumor spheroid viability and invasion. − In this line, PL- and PLMA-derived proteins were herein chosen as promising biomaterials to develop fibril-based 3D platforms for stem cell and tumor research.…”

“… 42 Recent studies have proposed a human methacryloyl platelet lysate (PLMA)-based hydrogel as a bioactive and functional material to support stem cell and tumor spheroid viability and invasion. 43 − 45 In this line, PL- and PLMA-derived proteins were herein chosen as promising biomaterials to develop fibril-based 3D platforms for stem cell and tumor research.…”

“…Based on previous reports, these cell types successfully adhered and proliferated in PLMA hydrogels, either as invading cell spheroids 43 or combined in a coculture 3D tumor model. 44 , 45 The great composition and biochemical properties of this human source of proteins were also evidenced by producing self-assembly PL microparticles that facilitated hBM-MSC adhesion and self-aggregation. 38 When seeded on the top of the fibril-derived membrane produced on a flat surface, both cell types exhibited adhesion within 4 h ( Figure S5A ).…”