Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering ...biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido5,4-bthieno3,2-e1,4diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.
Highlights • The protective effect of galangin against carbon tetrachloride-induced liver fibrosis in rats was investigated. • Galangin inhibited lipid peroxidation, HSCs proliferation and collagen ...gene expression. • For the first time, we confirmed that galangin can ameliorate liver fibrosis.
More than 60% of nonsmall cell lung cancer (NSCLC) patients show a positive response to the first ALK inhibitor, crizotinib, which has been used as the standard treatment for newly diagnosed patients ...with ALK rearrangement. However, most patients inevitably develop crizotinib resistance due to acquired secondary mutations in the ALK kinase domain, such as the gatekeeper mutation L1196M and the most refractory mutation, G1202R. Here, we develop XMU‐MP‐5 as a new‐generation ALK inhibitor to overcome crizotinib resistance mutations, including L1196M and G1202R. XMU‐MP‐5 blocks ALK signaling pathways and inhibits the proliferation of cells harboring either wild‐type or mutant EML4‐ALK in vitro and suppresses tumor growth in xenograft mouse models in vivo. Structural analysis provides insights into the mode of action of XMU‐MP‐5. In addition, XMU‐MP‐5 induces significant regression of lung tumors in two genetically engineered mouse (GEM) models, further demonstrating its pharmacological efficacy and potential for clinical application. These preclinical data support XMU‐MP‐5 as a novel selective ALK inhibitor with high potency and selectivity. XMU‐MP‐5 holds great promise as a new therapeutic against clinically relevant secondary ALK mutations.
Synopsis
Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.
XMU‐MP‐5 is a new ALK inhibitor with high potency and selectivity.
XMU‐MP‐5 overcomes acquired resistance to first and second generation ALK inhibitors, including ALKL1196M and ALKG1202R.
XMU‐MP‐5 induces significant regression of lung tumors in ALK wild‐type and L1196M GEM models.
Despite the clinical success of ALK inhibitors in NSCLC, multiple drug‐resistant mutations in ALK are inevitably reported. XMU‐MP‐5 overcomes resistance to first and second generation ALK inhibitors in vitro and in vivo, thus holds great promise for the therapeutic use against ALK‐positive NSCLC.
Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet ...therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.
The analysis of nanoparticles’ biocompatibility and immunogenicity is mostly performed under a healthy condition. However, more clinically relevant evaluation conducted under pathological condition ...is less known. Here, the immunogenicity and bio–nano interactions of porous silicon nanoparticles (PSi NPs) are evaluated in an acute liver inflammation mice model. Interestingly, a new mechanism in which PSi NPs can remit the hepatocellular damage and inflammation activation in a surface dependent manner through protein corona formation, which perturbs the inflammation by capturing the pro‐inflammatory signaling proteins that are inordinately excreted or exposed under pathological condition, is found. This signal sequestration further attenuates the nuclear factor κB pathway activation and cytokines production from macrophages. Hence, the study proposes a potential mechanism for elucidating the altered immunogenicity of nanomaterials under pathological conditions, which might further offer insights to establish harmonized standards for assessing the biosafety of biomaterials in a disease‐specific or personalized manner.
The inflammation attenuation capability of porous silicon nanoparticles (PSi NPs) under an acute liver inflammation condition is positively correlated with the protein corona formation process. The detailed composition of protein corona composition of each type of PSi NPs is identified and confirmed by both proteomic and R‐language analyses, highlighting the role of PSi NPs in the prognosis of the disease.
The store-operated calcium (Ca2+) entry (SOCE) is the Ca2+ entry mechanism used by cells to replenish depleted Ca2+ store. The dysregulation of SOCE has been reported in metastatic cancer. It is ...believed that SOCE promotes migration and invasion by remodeling the actin cytoskeleton and cell adhesion dynamics. There is recent evidence supporting that SOCE is critical for the spatial and the temporal coding of Ca2+ signals in the cell. In this review, we critically examined the spatiotemporal control of SOCE signaling and its implication in the specificity and robustness of signaling events downstream of SOCE, with a focus on the spatiotemporal SOCE signaling during cancer cell migration, invasion and metastasis. We further discuss the limitation of our current understanding of SOCE in cancer metastasis and potential approaches to overcome such limitation.
Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, ...invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacologic inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared with MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and to drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and to prevent metastasis.
Elevated mitochondrial calcium uptake in PDAC promotes metastasis but exposes cystine addiction and ferroptosis sensitivity that could be targeted to improve pancreatic cancer treatment.
•Proposed a one-six network for phase calculation.•This article proposes for the first time a one-six network combined with binocular fringe projection for 3D reconstruction.•The method proposed in ...this article can effectively reduce the drawback of requiring a large number of fringe patterns in binocular fringe projection, achieving high-speed and high-precision measurement.•The network proposed in this article can fuse more feature information and achieve better and faster fitting by setting appropriate drop values.•This article uses composite color fringe patterns, which have more feature information and can provide a better learning for the network.
At present, deep learning plays a crucial role in structured light 3D reconstruction. Further, in the field of fringe projection profilometry, learning 3D features from fringes and performing 3D reconstruction are being studied by many researchers. This paper combines deep learning with binocular fringe projection, uses three channels to form a single-composite-color fringe pattern for three different frequencies as the input, and predicts the numerator and denominator required to solve the wrapped phase of the object. The wrapped phase is calculated using an arctangent function. The absolute phase is obtained by unwrapping the multi-frequency heterodyne method, and the absolute phase of the left and right cameras is matched to obtain a disparity map. The parameters obtained through camera calibration can restore the 3D shape of the object, which greatly reduces the number of fringes required; accuracy close to the phase of the training set is achieved. Finally, the experimental results demonstrate the feasibility of this approach.
Fascin is a pro-metastatic actin-bundling protein that is upregulated in all metastatic carcinomas. Fascin promotes cancer cell migration and invasion by facilitating membrane protrusions, such as ...filopodia and invadopodia. Aerobic glycolysis is a key feature of cancer metabolism and provides critical intermediate metabolites for tumor growth. Here, we report that fascin increases glycolysis in lung cancer to promote tumor growth and metastasis. Fascin promotes glycolytic flux by increasing the expression and activities of phosphofructose-kinases 1 and 2 (PFK1 and 2). Fascin mediates glycolytic functions via activation of yes-associated protein 1 (YAP1) through its canonical actin-bundling activity by promoting the binding of YAP1 to a TEAD1/4 binding motif located 30 bp upstream of the PFKFB3 transcription start site to activate its transcription. Examination of the TCGA database suggests that the fascin-YAP1-PFKFB3 axis is likely conserved across different types of cancers. Importantly, pharmacological inhibitors of fascin suppressed YAP1-PFKFB3 signaling and glycolysis in cancer cell lines, organoid cultures, and xenograft metastasis models. Taken together, our data reveal that the glycolytic function of fascin is essential for the promotion of lung cancer growth and metabolism, and suggest that pharmacological inhibitors of fascin may be used to reprogram cancer metabolism in lung and potentially other cancers with fascin upregulation.
•Fascin promotes glycolysis in lung cancer through its canonical actin bundling activities.•Fascin promotes the binding of YAP1 to a TEAD1/4 binding site to activate the transcription of PFKFB3.•PFKFB3 is required for fascin to increase glycolysis, tumor growth and metastasis in lung cancer.•Fascin inhibitors could be used to suppress the fascin-YAP1-PFKFB3 circuit in lung cancer.
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