Integrins regulate stemness in solid tumor: an emerging therapeutic target.

Integrins are the adhesion molecules and transmembrane receptors that consist of α and ß subunits. After binding to extracellular matrix components, integrins trigger intracellular signaling and regulate a wide spectrum of cellular functions, including cell survival, proliferation, differentiation and migration. Since the pattern of integrins expression is a key determinant of cell behavior in response to microenvironmental cues, deregulation of integrins caused by various mechanisms has been causally linked to cancer development and progression in several solid tumor types. In this review, we discuss the integrin signalosome with a highlight of a few key pro-oncogenic pathways elicited by integrins, and uncover the mutational and transcriptomic landscape of integrin-encoding genes across human cancers. In addition, we focus on the integrin-mediated control of cancer stem cell and tumor stemness in general, such as tumor initiation, epithelial plasticity, organotropic metastasis and drug resistance. With insights into how integrins contribute to the stem-like functions, we now gain better understanding of the integrin signalosome, which will greatly assist novel therapeutic development and more precise clinical decisions.

Development of polyvinyl alcohol-based carbon nano fiber sheet for thermal interface material.

Polyvinyl alcohol (PVA)-based carbon nanofiber (CNF) sheets are fabricated as an innovative thermal interface material (TIM), which is a potential substitute for traditional TIMs. Five types of PVA-based CNF sheets were fabricated at different mass ratios of PVA:vapor-grown carbon fiber (VGCF) (1:0.100, 1:0.070, 1:0.050, 1:0.030, 1:0.025). The thickness of the PVA-based CNF sheets was 30-50 µm, which was controlled by the amount of VGCF. The microstructure of the CNF sheets indicated that VGCFs were arranged in random directions inside the sheet, and PVA was formed as a membrane between two VGCFs. However, many pores were found to exist between the VGCFs. The porosity of the PVA-based CNF sheets decreased from 25 to 13% upon decreasing the mass ratio of VGCF from 43.38 to 16.13%. The density and Shore hardness of all CNF sheets were 1.03-1.15 × 106 g m-3 and 82.4-85.0 HS, respectively. The highest thermal conductivity, measured as the mass ratio of PVA:VGCF, was achieved at 1:0.05, with the in-plane thermal conductivity of the fabricated sheet being 14.3 W m-1 k-1.

SYK is a candidate kinase target for the treatment of advanced prostate cancer.

Improved targeted therapies are needed to combat metastatic prostate cancer. Here, we report the identification of the spleen kinase SYK as a mediator of metastatic dissemination in zebrafish and mouse xenograft models of human prostate cancer. Although SYK has not been implicated previously in this disease, we found that its expression is upregulated in human prostate cancers and associated with malignant progression. RNAi-mediated silencing prevented invasive outgrowth in vitro and bone colonization in vivo, effects that were reversed by wild-type but not kinase-dead SYK expression. In the absence of SYK expression, cell surface levels of the progression-associated adhesion receptors integrin α2ß1 and CD44 were diminished. RNAi-mediated silencing of α2ß1 phenocopied SYK depletion in vitro and in vivo, suggesting an effector role for α2ß1 in this setting. Notably, pharmacologic inhibitors of SYK kinase currently in phase I-II trials for other indications interfered similarly with the invasive growth and dissemination of prostate cancer cells. Our findings offer a mechanistic rationale to reposition SYK kinase inhibitors for evaluation in patients with metastatic prostate cancer.

ß1 integrin inhibition elicits a prometastatic switch through the TGFß-miR-200-ZEB network in E-cadherin-positive triple-negative breast cancer.

Interactions with the extracellular matrix (ECM) through integrin adhesion receptors provide cancer cells with physical and chemical cues that act together with growth factors to support survival and proliferation. Antagonists that target integrins containing the ß1 subunit inhibit tumor growth and sensitize cells to irradiation or cytotoxic chemotherapy in preclinical breast cancer models and are under clinical investigation. We found that the loss of ß1 integrins attenuated breast tumor growth but markedly enhanced tumor cell dissemination to the lungs. When cultured in three-dimensional ECM scaffolds, antibodies that blocked ß1 integrin function or knockdown of ß1 switched the migratory behavior of human and mouse E-cadherin-positive triple-negative breast cancer (TNBC) cells from collective to single cell movement. This switch involved activation of the transforming growth factor-ß (TGFß) signaling network that led to a shift in the balance between miR-200 microRNAs and the transcription factor zinc finger E-box-binding homeobox 2 (ZEB2), resulting in suppressed transcription of the gene encoding E-cadherin. Reducing the abundance of a TGFß receptor, restoring the ZEB/miR-200 balance, or increasing the abundance of E-cadherin reestablished cohesion in ß1 integrin-deficient cells and reduced dissemination to the lungs without affecting growth of the primary tumor. These findings reveal that ß1 integrins control a signaling network that promotes an epithelial phenotype and suppresses dissemination and indicate that targeting ß1 integrins may have undesirable effects in TNBC.

Integrin signaling in control of tumor growth and progression.

Interactions with the extracellular matrix (ECM) provide cells with physical and chemical cues that act in concert with growth factors to support survival and proliferation. Transmembrane receptors of the integrin family mediate ECM attachment and play important roles in sensing and responding to ECM properties. Integrin signaling involves large integrin-associated intracellular protein complexes that act as anchors for the cytoskeleton and as signaling hotspots where enzymes and substrates are concentrated. Moreover, many different growth factor signaling cascades are amplified when cells are attached to the ECM. Integrins are involved in many pathologies; here we focus on their roles in cancer. Although "anchorage-independence" is a hallmark of cancer cells, genetic studies clearly show that integrins and associated proteins provide essential support for early tumor development and growth. Integrins also provide support during later stages of tumor progression but in some scenarios they appear to have suppressive activity, which is currently not understood.

Automated microinjection of cell-polymer suspensions in 3D ECM scaffolds for high-throughput quantitative cancer invasion screens.

Cell spheroids (CS) embedded in 3D extracellular matrix (ECM) serve as in vitro mimics for multicellular structures in vivo. Such cultures, started either from spontaneous cell aggregates or single cells dispersed in a gel are time consuming, applicable to restricted cell types only, prone to high variation, and do not allow CS formation with defined spatial distribution required for high-throughput imaging. Here, we describe a method where cell-polymer suspensions are microinjected as droplets into collagen gels and CS formation occurs within hours for a broad range of cell types. We have automated this method to produce CS arrays in fixed patterns with defined x-y-z spatial coordinates in 96 well plates and applied automated imaging and image analysis algorithms. Low intra- and inter-well variation of initial CS size and CS expansion indicates excellent reproducibility. Distinct cell migration patterns, including cohesive strand-like - and individual cell migration can be visualized and manipulated. A proof-of-principle chemical screen is performed identifying compounds that affect cancer cell invasion/migration. Finally, we demonstrate applicability to freshly isolated mouse breast and human sarcoma biopsy material - indicating potential for development of personalized cancer treatment strategies.