Premetastatic niche mechanics and organotropism in breast cancer.

Numerous physical and mechanical changes occur in the premetastatic niche. Here, we review the mechanics of the premetastatic niche and how the altered extracellular matrix and cancer cell mechanics may play a role in organotropism in breast cancer. Future research into premetastatic niche development and organotropic cell behavior should address physical alterations and biomechanical effects to the same rigor that biochemical alterations are studied.

Inverse resolution of spatially varying diffusion coefficient using Physics-Informed neural networks.

Resolving the diffusion coefficient is a key element in many biological and engineering systems, including pharmacological drug transport and fluid mechanics analyses. Additionally, these systems often have spatial variation in the diffusion coefficient which must be determined, such as for injectable drug-eluting implants into heterogeneous tissues. Unfortunately, obtaining the diffusion coefficient from images in such cases is an inverse problem with only discrete data points.

The movement of mitochondria in breast cancer: internal motility and intercellular transfer of mitochondria.

As a major energy source for cells, mitochondria are involved in cell growth and proliferation, as well as migration, cell fate decisions, and many other aspects of cellular function. Once thought to be irreparably defective, mitochondrial function in cancer cells has found renewed interest, from suggested potential clinical biomarkers to mitochondria-targeting therapies. Here, we will focus on the effect of mitochondria movement on breast cancer progression.

Mitochondrial transfer from cancer-associated fibroblasts increases migration in aggressive breast cancer.

Cancer-associated fibroblasts (CAFs) have distinct roles within the tumor microenvironment, which can impact the mode and efficacy of tumor cell migration. CAFs are known to increase invasion of less-aggressive breast cancer cells through matrix remodeling and leader-follower dynamics. Here, we demonstrate that CAFs communicate with breast cancer cells through the formation of contact-dependent tunneling nanotubes (TNTs), which allow for the exchange of cargo between cell types.

Forces exerted and transduced by cancer-associated fibroblasts during cancer progression.

Although it is well-known that cancer-associated fibroblasts (CAFs) play a key role in regulating tumor progression, the effects of mechanical tissue changes on CAFs are understudied. Myofibroblastic CAFs (myCAFs), in particular, are known to alter tumor matrix architecture and composition, heavily influencing the mechanical forces in the tumor microenvironment (TME), but much less is known about how these mechanical changes initiate and maintain the myCAF phenotype. Additionally, recent studies have pointed to the existence of CAFs in circulating tumor cell clusters, indicating that CAFs may be subject to mechanical forces beyond the primary TME.

Tumor Cell-Autonomous SHP2 Contributes to Immune Suppression in Metastatic Breast Cancer.

Unlabelled: SH2 containing protein tyrosine phosphatase-2 (SHP2) is recognized as a druggable oncogenic phosphatase that is expressed in both tumor cells and immune cells. How tumor cell-autonomous SHP2 contributes to an immunosuppressive tumor microenvironment (TME) and therapeutic failure of immune checkpoint blockades in metastatic breast cancer (MBC) is not fully understood. Herein, we utilized systemic SHP2 inhibition and inducible genetic depletion of SHP2 to investigate immune reprogramming during SHP2 targeting.

Transglutaminase-2 mediates acquisition of neratinib resistance in metastatic breast cancer.

Acquisition of resistance to targeted therapies remains a major clinical obstacle for the HER2 subtype of breast cancer. Using an isogeneic progression series of HER2 breast cancer metastasis we demonstrate that metastatic cells have an increased capacity to acquire resistance to the covalent, pan-ErbB inhibitor, neratinib. RNA sequencing analyses comparing parental and metastatic cells identified upregulation of transglutaminase 2 (TG2).

High-Throughput Magnetic Actuation Platform for Evaluating the Effect of Mechanical Force on 3D Tumor Microenvironment.

Accurately replicating and analyzing cellular responses to mechanical cues is vital for exploring metastatic disease progression. However, many of the existing platforms for applying mechanical stimulation seed cells on synthetic substrates. To better recapitulate physiological conditions, a novel actuating platform is developed with the ability to apply tensile strain on cells at various amplitudes and frequencies in a high-throughput multi-well culture plate using a physiologically-relevant substrate.

A Bayesian approach to estimate the diffusion coefficient of Rhodamine 6G in breast cancer spheroids.

Multicellular spheroids have emerged as a robust platform to model tumor growth and are widely used for studying drug sensitivity. Diffusion is the main mechanism for transporting nutrients and chemotherapeutic drugs into spheroids, since they are typically avascular. In this study, the Bayesian inference was used to solve the inverse problem of determining the light attenuation coefficient and diffusion coefficient of Rhodamine 6G (R6G) in breast cancer spheroids, as a mock drug for the tyrosine kinase inhibitor, Neratinib.

In Vitro Magnetic Techniques for Investigating Cancer Progression.

Worldwide, there are currently around 18.1 million new cancer cases and 9.6 million cancer deaths yearly.

Design and validation of a modular micro-robotic system for the mechanical characterization of soft tissues.

The mechanical properties of tissues are critical design parameters for biomaterials and regenerative therapies seeking to restore functionality after disease or injury. Characterizing the mechanical properties of native tissues and extracellular matrix throughout embryonic development helps us understand the microenvironments that promote growth and remodeling, activities critical for biomaterials to support. The mechanical characterization of small, soft materials like the embryonic tissues of the mouse, an established mammalian model for development, is challenging due to difficulties in handling minute geometries and resolving forces of low magnitude.

Epigenetic targeting of neuropilin-1 prevents bypass signaling in drug-resistant breast cancer.

Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers are treated using targeted antibodies and kinase inhibitors, but resistance to these therapies leads to systemic tumor recurrence of metastatic disease. Herein, we conducted gene expression analyses of HER2 kinase inhibitor-resistant cell lines as compared to their drug-sensitive counterparts. These data demonstrate the induction of epithelial-mesenchymal transition (EMT), which included enhanced expression of fibroblast growth factor receptor 1 (FGFR1) and axonal guidance molecules known as neuropilins (NRPs).

SHP2 is a multifunctional therapeutic target in drug resistant metastatic breast cancer.

Metastatic breast cancer (MBC) is an extremely recalcitrant disease capable of bypassing current targeted therapies via engagement of several growth promoting pathways. SH2 containing protein tyrosine phosphatase-2 (SHP2) is an oncogenic phosphatase known to facilitate growth and survival signaling downstream of numerous receptor inputs. Herein, we used inducible genetic depletion and two distinct pharmacological inhibitors to investigate the therapeutic potential of targeting SHP2 in MBC.

Fibronectin-Expressing Mesenchymal Tumor Cells Promote Breast Cancer Metastasis.

Tumor metastasis is connected to epithelial-mesenchymal heterogeneity (EMH) and the extracellular matrix (ECM) within the tumor microenvironment. Mesenchymal-like fibronectin (FN) expressing tumor cells enhance metastasis within tumors that have EMH. However, the secondary tumors are primarily composed of the FN null population.

The Dynamic Relationship of Breast Cancer Cells and Fibroblasts in Fibronectin Accumulation at Primary and Metastatic Tumor Sites.

In breast cancer (BC), tissue stiffening via fibronectin (FN) and collagen accumulation is associated with advanced disease progression at both the primary tumor and metastatic sites. Here, we evaluate FN production in 15 BC cell lines, representing a variety of subtypes, phenotypes, metastatic potentials, and chemotherapeutic sensitivities. We demonstrate that intracellular and soluble FN is initially lost during tumorigenic transformation but is rescued in all lines with epithelial-mesenchymal plasticity (EMP).

Transglutaminase-2 facilitates extracellular vesicle-mediated establishment of the metastatic niche.

The ability of breast cancer cells to interconvert between epithelial and mesenchymal states contributes to their metastatic potential. As opposed to cell autonomous effects, the impact of epithelial-mesenchymal plasticity (EMP) on primary and metastatic tumor microenvironments remains poorly characterized. Herein we utilize global gene expression analyses to characterize a metastatic model of EMP as compared to their non-metastatic counterparts.

Autocrine Fibronectin Inhibits Breast Cancer Metastasis.

Both epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are linked to metastasis via their ability to increase invasiveness and enhance tumor-initiating capacity. Growth factors, cytokines, and chemotherapies present in the tumor microenvironment (TME) are capable of inducing EMT, but the role of the extracellular matrix (ECM) in this process remains poorly understood. Here, a novel tessellated three-dimensional (3D) polymer scaffolding is used to produce a fibrillar fibronectin matrix that induces an EMT-like event that includes phosphorylation of STAT3 and requires expression of β1 integrin.