Mechanical factors driving cancer progression.

A fundamental step of tumor metastasis is tumor cell migration away from the primary tumor site. One mode of migration that is essential but still understudied is collective invasion, the process by which clusters of cells move in a coordinated fashion. In recent years, there has been growing interest to understand factors regulating collective invasion, with increasing number of studies investigating the biomechanical regulation of collective invasion. In this review we discuss the dynamic relationship between tumor microenvironment cues and cell response by first covering mechanical factors in the microenvironment and second, discussing the mechanosensing pathways utilized by cells in collective clusters to dynamically respond to mechanical matrix cues. Finally, we discuss model systems that have been developed which have increased our understanding of the mechanical factors contributing to tumor progression.

Three-dimensional models of breast cancer-fibroblasts interactions.

IMPACT STATEMENT: Tumor stroma plays an important role in progression of cancers to a fatal metastatic disease. Modern treatment strategies are considering targeting tumor stroma to improve outcomes for cancer patients. A current challenge to develop stroma-targeting therapeutics is the lack of preclinical physiologic tumor models. Animal models widely used in cancer research lack human stroma and are not amenable to screening of chemical compounds for cancer drug discovery. In this review, we outline in vitro three-dimensional tumor models that we have developed to study the interactions among cancer cells and stromal cells. We describe development of the tumor models in a modular fashion, from a spheroid model to a sophisticated organotypic model, and discuss the importance of using correct physiologic models to recapitulate tumor-stromal signaling. These biomimetic tumor models will facilitate understanding of tumor-stromal signaling biology and provide a scalable approach for testing and discovery of cancer drugs.

Organotypic breast tumor model elucidates dynamic remodeling of tumor microenvironment.

Fibroblasts are a critical component of tumor microenvironments and associate with cancer cells physically and biochemically during different stages of the disease. Existing cell culture models to study interactions between fibroblasts and cancer cells lack native tumor architecture or scalability. We developed a scalable organotypic model by robotically encapsulating a triple negative breast cancer (TNBC) cell spheroid within a natural extracellular matrix containing dispersed fibroblasts. We utilized an established CXCL12 - CXCR4 chemokine-receptor signaling in breast tumors to validate our model. Using imaging techniques and molecular analyses, we demonstrated that CXCL12-secreting fibroblasts have elevated activity of RhoA/ROCK/myosin light chain-2 pathway and rapidly and significantly contract collagen matrices. Signaling between TNBC cells and CXCL12-producing fibroblasts promoted matrix invasion of cancer cells by activating oncogenic mitogen-activated protein kinase signaling, whereas normal fibroblasts significantly diminished TNBC cell invasiveness. We demonstrated that disrupting CXCL12 - CXCR4 signaling using a molecular inhibitor significantly inhibited invasiveness of cancer cells, suggesting blocking of tumor-stromal interactions as a therapeutic strategy especially for cancers such as TNBC that lack targeted therapies. Our organotypic tumor model mimics native solid tumors, enables modular addition of different stromal cells and extracellular matrix proteins, and allows high throughput compound screening against tumor-stromal interactions to identify novel therapeutics.