Cells respond to physical stimuli, such as stiffness¹, fluid shear stress²and hydraulic pressure^3,4. Extracellular fluid viscosity is a key physical cue that varies under physiological and pathological conditions, such as cancer⁵. However, its influence on cancer biology and the mechanism by which cells sense and respond to changes in viscosity are unknown. Here we demonstrate that elevated viscosity counterintuitively increases the motility of various cell types on two-dimensional surfaces and in confinement, and increases cell dissemination from three-dimensional tumour spheroids. Increased mechanical loading imposed by elevated viscosity induces an actin-related protein 2/3 (ARP2/3)-complex-dependent dense actin network, which enhances Na⁺/H⁺exchanger 1 (NHE1) polarization through its actin-binding partner ezrin. NHE1 promotes cell swelling and increased membrane tension, which, in turn, activates transient receptor potential cation vanilloid 4 (TRPV4) and mediates calcium influx, leading to increased RHOA-dependent cell contractility. The coordinated action of actin remodelling/dynamics, NHE1-mediated swelling and RHOA-based contractility facilitates enhanced motility at elevated viscosities. Breast cancer cells pre-exposed to elevated viscosity acquire TRPV4-dependent mechanical memory through transcriptional control of the Hippo pathway, leading to increased migration in zebrafish, extravasation in chick embryos and lung colonization in mice. Cumulatively, extracellular viscosity is a physical cue that regulates both short- and long-term cellular processes with pathophysiological relevance to cancer biology.

Tumor cell extravasation is a key step during cancer metastasis, yet the precise mechanisms that regulate this dynamic process are unclear. We utilized a high-resolution time-lapse intravital imaging approach to visualize the dynamics of cancer cell extravasation in vivo. During intravascular migration, cancer cells form protrusive structures identified as invadopodia by their enrichment of MT1-MMP, cortactin, Tks4, and importantly Tks5, which localizes exclusively to invadopodia. Cancer cells extend invadopodia through the endothelium into the extravascular stroma prior to their extravasation at endothelial junctions. Genetic or pharmacological inhibition of invadopodia initiation (cortactin), maturation (Tks5), or function (Tks4) resulted in an abrogation of cancer cell extravasation and metastatic colony formation in an experimental mouse lung metastasis model. This provides direct evidence of a functional role for invadopodia during cancer cell extravasation and distant metastasis and reveals an opportunity for therapeutic intervention in this clinically important process.

Fluid shear sensing via TRPM7 limits tumor cell intravasation by activating RhoA/myosin and calmodulin/IQGAP1/Cdc42 pathways.

Multivalent nanoparticles have several key advantages in terms of solubility, binding avidity, and uptake, making them particularly well suited to molecular imaging applications. Herein is reported the stepwise synthesis and characterization of NIR viral nanoparticles targeted to gastrin‐releasing peptide receptors that are over‐expressed in human prostate cancers. The pan‐bombesin analogue, [β‐Ala11, Phe13, Nle14]bombesin‐(7–14), is conjugated to cowpea mosaic virus particles functionalized with an NIR dye (Alexa Fluor 647) and polyethylene glycol (PEG) using the copper(I)‐catalyzed azide‐alkyne cycloaddition reaction. Targeting and uptake in human PC‐3 prostate cells is demonstrated in vitro. Tumor homing is observed using human prostate tumor xenografts on the chicken chorioallantoic membrane model using intravital imaging. Further development of this viral nanoparticle platform may open the door to potential clinical noninvasive molecular imaging strategies.

Introduction: Metastatic cancers are extremely difficult to treat, and account for the vast majority of cancer-related deaths. The dissemination of tumor cells to distant sites is highly dynamic, asynchronous, and involves both tumor and host intrinsic factors. Effective therapeutic targets to block metastasis will need to disrupt key pathways that are required for multiple stages of metastasis. Areas covered: This review discusses the heterogeneity of cancers and metastasis, with an emphasis on motility as a key driver trait of metastasis. Recent metastatic cancer studies that identified either host or cancer cell intrinsic factors important for metastasis, using single gene-deficient animal models or 3D intravital imaging of avian embryo models, are also discussed. Potential metastatic blocking targets are listed as they relate to metastatic cancer therapy. Expert opinion: The development of metastatic disease is a complex interplay of genetic and epigenetic factors from the host and cancer cells acting in a patient-specific manner. Inhibiting key driver traits of metastasis should yield survival benefit at any stage of the disease, and we look forward to the next generation of personalized medicines for cancer therapy that target cancer cell motility for increased therapeutic efficacy.