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.

authors

Cátia F. Monteiro, Inês A. Deus, Inês B. Silva, Iola F. Duarte, Catarina A. Custódio, João F. Mano

Groups

G5 - Biomimetic, Biological and Living Materials

Projects

CICECO - Aveiro Institute of Materials (UIDB/50011/2020)

CICECO - Aveiro Institute of Materials (UIDP/50011/2020)

Associated Laboratory CICECO-Aveiro Institute of Materials (LA/P/0006/2020)

Full human-based multi-scale constructs with jammed regenerative pockets for bone engineering. (REBORN)

Human based bioinks to engineer physiologically relevant tissues (HumanINK)

Rede Nacional de Ressonância Magnética Nuclear (PTNMR)

acknowledgements

This work was developed within the scope of the project CICECO-Aveiro Institute of Materials, UIDB/50011/2020 (DOI 10.54499/UIDB/50011/2020), UIDP/50011/2020 (DOI 10.54499/UIDP/50011/2020) & LA/P/0006/2020 (DOI 10.54499/LA/P/0006/2020), financed by national funds through the FCT/MCTES (PIDDAC). The authors would like to acknowledge the European Research Council for the Advanced Grant Agreement number H2020-ERC-AdG–883370 for the project REBORN and for the Proof-of-Concept Grant Agreement number ERC-2022-PoC-101082210 for the project HumanINK. This work was also supported by the Foundation for Science and Technology through the individual contract 2020.01647.CEECIND of Dr. Catarina A. Custódio and the doctoral grant SFRH/BD/144640/2019 of Cátia F. Monteiro. The NMR spectrometer is part of the National NMR Network (PTNMR), partially supported by Infrastructure Project No. 022161 (co-financed by FEDER through COMPETE 2020, POCI, and PORL and FCT through PIDDAC).