Engineering confining microenvironment for studying cancer metastasis

Abstract

The physical microenvironment of cells plays a fundamental role in regulating cellular behavior and cell fate, especially in the context of cancer metastasis. For example, capillary deformation can destroy arrested circulating tumor cells while the dense extracellular matrix can form a physical barrier for invading cancer cells. Understanding how metastatic cancer cells overcome the challenges brought forth by physical confinement can help in developing better therapeutics that can put a stop to this migratory stage of the metastatic cascade. Numerous in vivo and in vitro assays have been developed to recapitulate the metastatic processes and study cancer cell migration in a confining microenvironment. In this review, we summarize some of the representative techniques and the exciting new findings. We critically review the advantages, as well as challenges associated with these tools and methodologies, and provide a guide on the applications that they are most suited for. We hope future efforts that push forward our current understanding on metastasis under confinement can lead to novel and more effective diagnostic and therapeutic strategies against this dreaded disease.

Circulating Tumor Cells in Cancer Diagnostics and Prognostics by Single-Molecule and Single-Cell Characterization

“…Cell–cell and cell–ECM interactions through biochemical and biophysical mechanisms contribute to the key steps of the metastatic cascade. 3D (bio)­printing allows, to some extent, the arrangement of cancer cells and tissue-like materials in a way that more faithfully reproduces the spatial organization of the tumor microenvironment. , As a consequence, the scaffolds obtained through bioprinting act as relevant models for the study of cancer cell migration and metastatic processes as reported by Jung et al The generation of 3D matrixes with specific porosity and topography, coupled to the hierarchical features of the ECM, could further improve the physiological/pathological relevance of in vitro 3D tumor models to study both confining and fluid environments for CTCs. , Despite the numerous freeze-cast scaffolds that can be applied to 3D cell culture and bioengineering, to the best of our knowledge, the sole scaffold used as an in vitro tumor model was reported by Campbell et al, whose radially anisotropic cross-linked collagen scaffold was able to separate BrCa cell lines based on their invasiveness and could serve as a potential tool for in vitro assays for cancer cell invasion …”

Optical manipulation and assembly of micro/nanoscale objects on solid substrates

“…Precise manipulation of micro/nanoscale objects plays an important role in a variety of fields, such as microrobotics ( Palima and Glückstad, 2013 ; Zhang et al., 2019 ), biomedical engineering ( Ding et al., 2012 , 2014 ; Jiang et al., 2021 ; Zhong et al., 2019 ), and nanofabrication ( Lin et al., 2017b ; Ozin et al., 2009 ). Among the different manipulation methods, such as microfluidic ( Farahi et al., 2004 ), optical ( Grier, 2003 ), acoustic ( Ding et al., 2012 ), electric ( Fan et al., 2011 ), and magnetic manipulation ( Snezhko and Aranson, 2011 ), optical manipulation is appealing for its remote and noninvasive control of objects with nanoscale resolution ( Chen et al., 2022 ).…”

Intolerance of profligacy: an aptamer concentration gradient-tailored unicellular array for high-throughput biologics-mediated phenotyping

“…High shear stress can induce cellular migration and uncontrollable deformability, making it impossible to conduct proper assays on single cells. 26,27 For dynamically carrying out drug-mediated phenotype profiling in single cells with the minimal utilization of Aptprobe, we proposed an integrated microfluidic platform consisting of Apt-CGG and D-SCA (Mi-Apt-SCA), as illustrated in Scheme 1. It facilitated the accurate construction of an Apt-gradient microenvironment, the high-throughput capture/culturing of individual cells, stimulation with agents, and unicellular fluorescence imaging.…”

“…High shear stress can induce cellular migration and uncontrollable deformability, making it impossible to conduct proper assays on single cells. 26,27…”