A biomimetic 3D model of hypoxia-driven cancer progression

Abstract

The fate of tumors depends both on the cancer cells’ intrinsic characteristics and on the environmental conditions where the tumors reside and grow. Engineered in vitro models have led to significant advances in cancer research, allowing the investigation of cells in physiological environments and the study of disease mechanisms and processes with enhanced relevance. Here we present a biomimetic cancer model based on a collagen matrix synthesized through a biologically inspired process. We compared in this environment the responses of two breast tumor lineages characterized by different molecular patterns and opposite clinical behaviors: MCF-7 that belong to the luminal A subtype connected to an indolent course, and basal-like MDA-MB-231 connected to high-grade and aggressive disease. Cancer cells in the biomimetic matrix recreate a hypoxic environment that affects their growth dynamics and phenotypic features. Hypoxia induces apoptosis and the selection of aggressive cells that acquire expression signatures associated with glycolysis, angiogenesis, cell-matrix interaction, epithelial to mesenchymal transition and metastatic ability. In response to hypoxia MDA-MB-231 migrate on the collagen fibrils and undergo cellular senescence, while MCF-7 do not exhibit these behaviors. Our biomimetic model mimics the evolution of tumors with different grade of aggressiveness fostered by a hypoxic niche and provides a relevant technology to dissect the events involved in cancer progression.

Trends in Bone Metastasis Modeling

“…There are two different types of BC cell lines examined here by the authors: MCF-7 (estrogen-positive BC cells, linked to good prognosis), and MDA-MB-231 (triple negative and aggressive BC cells) [109]. Their discovery shows in this experimental scenario that cells are able to build a hypoxic core niche, with modified growth dynamics, and that more aggressive cancer cells are selected, similarly to what happens during the in vivo disease progression [108].…”

“…Liverani and colleagues presented a biomimetic 3D tumor model based on macroporous scaffolds, which resembles the hierarchically organized structure of extracellular collagen [107,108]. There are two different types of BC cell lines examined here by the authors: MCF-7 (estrogen-positive BC cells, linked to good prognosis), and MDA-MB-231 (triple negative and aggressive BC cells) [109].…”

Intrinsic and Extrinsic Modulators of the Epithelial to Mesenchymal Transition: Driving the Fate of Tumor Microenvironment

“…The authors identified ADAM19 and its epigenetic regulation as a robust new biomarker of EMT in vitro and in vivo (136). With another experimental approach using 3D biomimetic scaffolds, Liverani et al (137) demonstrated that metastatic breast tumors have a higher capability to alter the extracellular collagen structures, affecting the mechanobiology of cell-ECM in metastatic tumors. Moreover, the modification in collagen hydroxylation state was associated with pyruvate metabolism in metastatic breast cancer cell lines (138).…”

Targeting Mechanotransduction in Osteosarcoma: A Comparative Oncology Perspective

“…For example, a 3D collagen scaffold model created by Liverani and colleagues (2019), allowed for the culture of breast cancer cells in an environment that mimics the hierarchically organised structure of extracellular collagen in actual tissue. Furthermore, this model permits the study of hypoxia effects on cell fate and metabolism, as tissue-like cellular structures are able to establish realistic oxygen gradients, which contributes to their overall phenotype [ 79 ]. Another invaluable tool in the study of mechanobiology is atomic force microscopy, which permits the mechanical profiling of matrices and individual cells on a nanometre scale.…”