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Dissemination of cancer cells from the primary tumor into distant body tissues and organs is the leading cause of death in cancer patients. While most clinical strategies aim to reduce or impede the growth of the primary tumor, no treatment to eradicate metastatic cancer exists at present. Metastasis is mediated by feet-like cytoskeletal structures called invadopodia which allow cells to penetrate through the basement membrane and intravasate into blood vessels during their spread to distant tissues and organs. The non-receptor tyrosine kinase Pyk2 is highly expressed in breast cancer, where it mediates invadopodia formation and function via interaction with the actin-nucleation-promoting factor cortactin. Here, we designed a cell-permeable peptide inhibitor that contains the second proline-rich region (PRR2) sequence of Pyk2, which binds to the SH3 domain of cortactin and inhibits the interaction between Pyk2 and cortactin in invadopodia. The Pyk2-PRR2 peptide blocks spontaneous lung metastasis in immune-competent mice by inhibiting cortactin tyrosine phosphorylation and actin polymerization-mediated maturation and activation of invadopodia, leading to reduced MMP-dependent tumor cell invasiveness. The native structure of the Pyk2-PRR2:cortactin-SH3 complex was determined using nuclear magnetic resonance (NMR), revealing an extended class II interaction surface spanning the canonical binding groove and a second hydrophobic surface which significantly contributes to ligand affinity. Using structure-guided design, we created a mutant peptide lacking critical residues involved in binding that failed to inhibit invadopodia maturation and function and consequent metastatic dissemination in mice. Our findings shed light on the specific molecular interactions between Pyk2 and cortactin and may lead to the development of novel strategies for preventing dissemination of primary breast tumors predicted at the time of diagnosis to be highly metastatic, and of secondary tumors that have already spread to other parts of the body.

We develop a framework for two advanced trapped-ion cooling schemes, polarization-gradient and electromagnetically-induced-transparency cooling, for 88Sr+ ions using a visible-wavelength integrated-photonics platform and present the design of the key integrated devices.

Optical trapping using integrated optical phased arrays is demonstrated, enabling chip-based trapping at distances compatible with standard biological experimentation and opening the door to broader implementation of optical-trapping technology.

This work introduces an integrated photonic system that enables curing of a visible-light-curable resin for chip-based 3D printing. Curing of multiple mm-scale regions is achieved via an integrated optical phased array operating at 632.8 nm.

Integrated polarization rotators and splitters are designed for the first time at visible wavelengths. Specifically, an adiabatic polarization rotator, an off-axis polarization rotator, and a mode-coupling polarization splitter are designed in a silicon-nitride platform.

Focal adhesion kinase (FAK) is well established as a regulator of cell migration, but whether and how the closely related proline-rich tyrosine kinase 2 (Pyk2) regulates fibroblast motility is still under debate. Using mouse embryonic fibroblasts (MEFs) from Pyk2–/– mice, we show here, for the first time, that lack of Pyk2 significantly impairs both random and directed fibroblast motility. Pyk2–/– MEFs show reduced cell-edge protrusion dynamics, which is dependent on both the kinase and protein–protein binding activities of Pyk2. Using bioinformatics analysis of in vitro high- throughput screens followed by text mining, we identified CrkI/II as novel substrates and interactors of Pyk2. Knockdown of CrkI/II shows altered dynamics of cell-edge protrusions, which is similar to the phenotype observed in Pyk2–/– MEFs. Moreover, epistasis experiments suggest that Pyk2 regulates the dynamics of cell-edge protrusions via direct and indirect interactions with Crk that enable both activation and down-regulation of Crk-mediated cytoskeletal signaling. This complex mechanism may enable fine-tuning of cell-edge protrusion dynamics and consequent cell migration on the one hand together with tight regulation of cell motility, a process that should be strictly limited to specific time and context in normal cells, on the other hand.

The formation and recovery of gaps in the vascular endothelium governs a wide range of physiological and pathological phenomena, from angiogenesis to atherosclerosis and tumor cell extravasation. However, the interplay between the mechanical and signaling processes that drive dynamic behavior in vascular endothelial cells is not well understood. In this study, we propose a chemo-mechanical model to investigate the maintenance of endothelial junctions as dependent on the crosstalk between actomyosin contractility, VE-cadherin bond turnover, and actin polymerization, which mediate the forces exerted on the cell-cell interface. Our theoretical model reveals that active cell tension can stabilize cadherin bonds within an adhesion, but excessive RhoA signaling can drive bond dissociation and junction failure. While Rac1-mediated actin polymerization aids gap closure, high levels of Rac1 may also facilitate junction weakening. Combining the modeling framework with novel experiments, we identify how dynamic rupture and heal cycles emerge and, further, describe why gaps tend to localize at multi-cell contacts. Beyond, our analysis also indicates that a critical balance between RhoA and Rac1 expression is required to maintain junction stability and limit endothelial dysfunction. The model predicts how pharmacological modulation of actin polymerization and cell contractility impacts junction stability, with predictions subsequently validated experimentally. Our proposed framework can help guide the development of therapeutics that target the Rho family of GTPases and downstream active mechanical processes.

Neuroblastoma is the most frequent extracranial malignant solid tumor in children, and the 5 year OS of high risk neuroblastoma patients was less than 15%. This study aimed to identify biomarkers for risk stratification and prognosis prediction in neuroblastoma.149 low risk samples, 108 intermediate risk samples and 619 high risk samples were included in our study, and NBPF1 gene was found to be significantly correlated with risk levels and OS. Significant negative correlations between NBPF1 and the expression of MYCN and AKT1S1, and positive correlations between NBPF1 and KIF1B expression were found, but only NBPF1 was an independent biomarker based on the construct of PPI for MYCN, NBPF1, KIF1B and AKT1S1 by STRING enrichment.

Osteosarcoma is a primary malignant tumor with a high tendency to form metastasis and poor prognosis. Consequently, finding effective early indicators of metastases is crucial for identifying and treating high-risk patients. CXCR4 and MMP-2 have been found to strongly correlate with invasion and metastasis of malignant tumors, including osteosarcoma.Our study evaluated CXCR4 in conjunction with MMP-2 as an important clinicopathological prognostic predictor for metastasis and overall survival of osteosarcoma. 73 patients' clinical data and pathological samples were retrieved for the study. A median time of 36 months follow-up was performed to evaluate for tumor metastasis and patient survival. CXCR4 and MMP-2 proteins in tumor tissues were detected by immunohistochemistry on paraffin-embedded tissue sections.The positive expression rate of CXCR4 and MMP-2 was 68.5% and 54.8% respectively, and of the 45 patients who developed distal metastasis, 33 and 28 patients had positive expression of CXCR4 and MMP-2 respectively. The median metastasis-free survival was 72.00 months in the CXCR4-negative group and 14.00 months in the CXCR4 positive group. Furthermore, median overall survival was 73.77 and 24.00 months in these same two groups. Further, the median metastasis-free survival was 66.51 months in the MMP-2 negative group and 9.00 months in the MMP-2 positive group. The median overall survival was 75.07 and 19.00 months in these same two groups. MMP2 and metastasis remained the significant and independent prognostic factors for metastasis-free survival and overall survival by using the COX regression model adjusted for the multivariate predictors of survival.Our results suggest that metastasis and MMP-2 are both independent prognostic indicators for metastasis-free and overall survival of osteosarcoma patients.

Chemotherapy is an indispensable method in treatment of Soft tissue sarcomas (STS), but variability in sensitivity as a result of tumor heterogeneity is a key factor in determining patient outcome. Several studies have investigated the phenomenon of chemotherapy resistance in STS, while its precise complex mechanism is still unknown. This study aims to identify potential biomarkers for predicting the STS chemosensitivity, with the goal of both aiding patient treatment determination in the clinic and providing insight into key parts of the underlying mechanism. Gene expression profiles of 265 patients were obtained from The Cancer Genome Atlas dataset and differentially expressed genes (DEGs) associated with chemosensitivity were identified in groups of varying chemosensitivity, including 177 upregulated and 21 downregulated genes (P 0.05). Then, DEGs were found to be enriched in complement and coagulation cascades and the osteoclast differentiation pathway. Protein-protein interaction analysis showed 15 genes (52 edges) enriched in the complement and coagulation cascades while 11 genes (28 edges) enriched in the osteoclast differentiation pathway. Notably, all the genes that significantly correlated to disease-free survival (DFS) and overall survival (OS), such as C1QC, C3AR1, C7, CFI and SERPINE1, are enriched in complement and coagulation cascades pathway. The differential expression of these genes was further verified by using the GSE database. Our findings support that C1QC, C3AR1, C7, CFI and SERPINE1 in the complement and coagulation cascade pathway are potential biomarkers for chemotherapy resistance and survival of STS patients.