Integrin αVβ1-activated PYK2 promotes the progression of non-small-cell lung cancer via the STAT3-VGF axis

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Июнь 6, 2024

Non-small-cell lung cancer (NSCLC) accounts for 80-85% of all and is the leading cause cancer-related deaths globally. Although various treatment strategies have been introduced, 5-year survival rate patients with NSCLC only 20-30%. Thus, it remains necessary to study pathogenesis develop new therapeutic drugs. Notably, PYK2 has implicated in progression many tumors, including NSCLC, but its detailed mechanism unclear. In this study, we aimed elucidate mechanisms through which promotes progression.

Язык: Английский

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Focal adhesion kinase signaling – tumor vulnerabilities and clinical opportunities

Journal of Cell Science, Год журнала: 2024, Номер 137(14)

Опубликована: Июль 15, 2024

Focal adhesion kinase (FAK; encoded by PTK2) was discovered over 30 years ago as a cytoplasmic protein tyrosine that is localized to cell sites, where it activated integrin receptor binding extracellular matrix proteins. FAK ubiquitously expressed and functions signaling scaffold for variety of proteins at adhesions in the cytoplasm, with transcription factors nucleus. expression intrinsic activity are essential mouse development, molecular connections motility, survival gene expression. Notably, elevated phosphorylation common tumors, including pancreatic ovarian cancers, associated decreased survival. Small molecule orally available inhibitors show on-target inhibition tumor stromal cells effects on chemotherapy resistance, fibrosis microenvironment immune function. Herein, we discuss recent insights regarding mechanisms activation signaling, its roles nuclear scaffold, tumor-intrinsic -extrinsic inhibitors. We also results from ongoing advanced clinical trials targeting low- high-grade serous acts master regulator drug resistance. Although not known be mutationally activated, preventing has revealed multiple vulnerabilities support expanding combinatorial possibilities.

Язык: Английский

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Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Июль 29, 2024

Brain metastatic cancer poses a significant clinical challenge, with limited treatment options and poor prognosis for patients. In recent years, immunotherapy has emerged as promising strategy addressing brain metastases, offering distinct advantages over conventional treatments. This review explores the evolving landscape of tumor in context cancer, focusing on intricate interplay between microenvironment (TME) immunotherapeutic approaches. By elucidating complex interactions within TME, including role immune cells, cytokines, extracellular matrix components, this highlights potential to reshape paradigm metastases. Leveraging checkpoint inhibitors, cellular immunotherapies, personalized strategies, holds promise overcoming challenges posed by blood-brain barrier immunosuppressive Through comprehensive analysis current research findings future directions, underscores transformative impact management new insights opportunities precise therapeutic interventions.

Язык: Английский

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Single-cell RNA Sequencing Reveals ECM Remodeling-Tumor Stiffness-FAK as a Key Driver of Vestibular Schwannoma Progression

Progress in Neurobiology, Год журнала: 2025, Номер 247, С. 102730 - 102730

Опубликована: Фев. 22, 2025

Язык: Английский

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PYK2 promotes cell proliferation and epithelial-mesenchymal transition in endometriosis by phosphorylating Snail1

Molecular Medicine, Год журнала: 2025, Номер 31(1)

Опубликована: Апрель 27, 2025

Abstract Background Endometriosis can lead to decreased endometrial receptivity, reduced rates of implantation, and diminished ovarian reserve. Currently, more than 50% infertile women are found suffer from endometriosis. However the etiology pathogenesis endometriosis still poorly understood. Epithelial-mesenchymal transition (EMT) has been confirmed be involved in PYK2 is a non-receptor tyrosine kinase that affects cell proliferation, survival, migration by regulating intracellular signaling pathways. plays regulatory role EMT process affecting expression genes associated with through influence transcription factors. Snail1 (Snail1) key highly expressed tissues. On other hand, invasive metastatic ability cells mainly process. However, upstream mechanisms regulate protein stability not clear. Methods We identified kinase, proline-rich 2 (PYK2 or PTK2B), examined The relevant plasmids were constructed. This study enrolled 20 patients laparoscopically meeting ASRM diagnostic criteria, collecting ectopic lesions (14 endometriotic cysts 6 deep infiltrating nodules) along matched eutopic tissues (15 proliferative phase, 5 secretory phase) as controls. All tissue specimens underwent immunohistochemical analysis. Human stromal (HESC) isolated normal endometrium 3 control for vitro meconium induction. Ectopic (EESC) obtained lesions. Protein extracts both subjected Western blot co-immunoprecipitation (Co-IP) interaction validation. Functional assays (proliferation/migration/invasion) performed using EESC 11Z lines triplicate biological replicates. Co-IP experiments verify between Snail1, well determine specific location this interaction. Additionally, we effect on whether VS-6063 inhibits functions cells. models established five-week-old female C57BL/6 mice, randomly allocated into experimental ( n = 10) groups. Statistical analyses conducted GraphPad Prism 7.0, employing parametric tests normally distributed data non-parametric methods otherwise, Benjamini-Hochberg correction multiple comparisons. Results It acts new binding partner enhances increasing phosphorylation Snail1. promotes migration, invasion while inhibiting decidualization. demonstrated inhibited vitro, growth vivo. Conclusions novel occurrence development up-regulating which could promising therapeutic target

Язык: Английский

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Preliminary study of the homeostatic regulation of osseointegration by nanotube topology

Materials Today Bio, Год журнала: 2024, Номер 26, С. 101038 - 101038

Опубликована: Апрель 4, 2024

The ideal implant surface plays a substantial role in maintaining bone homeostasis by simultaneously promoting osteoblast differentiation and limiting overactive osteoclast activity to certain extent, which leads satisfactory dynamic osseointegration. However, the rational search for materials with an structure is challenging hot research topic field of tissue engineering. In this study, we constructed titanium dioxide nanotubes (TNTs) anodic oxidation found that significantly promoted inhibited formation function while inhibiting total protein levels proline-rich tyrosine kinase 2 (PYK2) focal adhesion (FAK). Knockdown PYK2 gene siRNA suppressed number osteoclastic mouse marrow mononuclear cells (BMMs), overexpression osteogenesis increased activity. Surprisingly, first time neither knockdown nor FAK alone caused changes or function. More importantly, compared deletion PYK2/FAK alone, coexpression cosilencing two kinases accelerated effects TNTs on osteogenic cells. Furthermore, vivo experiments revealed significant increase positiveexpression-PYK2 TNTs, but no change positiveexpression -FAK was observed. summary, key effector molecule osteoblasts sense nanotopological mechanical signals maintain around implants. These results provide referable molecular mechanism future development design homeostasis-based regulatory biomaterials.

Язык: Английский

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FAK family proteins regulatein vivobreast cancer metastasisviadistinct mechanisms

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Окт. 29, 2023

ABSTRACT Breast cancer is the most commonly diagnosed malignancy and major leading cause of tumor-related deaths in women. It estimated that majority breast are a consequence metastasis, to which no cure exists at present. The FAK family proteins Proline-rich tyrosine kinase (PYK2) focal adhesion (FAK) highly expressed cancer, but exact cellular signaling mechanisms by they regulate vivo tumor cell invasiveness consequent metastatic dissemination mostly unknown. Using PYK2 knockdown xenograft model we show here, for first time, ablation either or decreases primary size significantly reduces Tumor MicroEnvironment Metastasis (TMEM) doorway activation, decreased intravasation reduced spontaneous lung metastasis. Intravital imaging analysis further demonstrates PYK2, not FAK, regulates motility phenotype switch between adhesion-mediated fast invadopodia-dependent, ECM-degradation associated slow within tumor. Furthermore, validate our intravital results with integrated transcriptomic proteomic data from tumors reveal new distinct pathways these two homologous kinases dissemination. Our findings identify as novel mediators mammary progression metastasis candidate therapeutic targets

Язык: Английский

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Targeting PYK2, entrectinib allays anterior subcapsular cataracts in mice by regulating TGFβ2 signaling pathway

Molecular Medicine, Год журнала: 2024, Номер 30(1)

Опубликована: Сен. 27, 2024

Язык: Английский

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The PTK2B gene is associated with obesity, adiposity and leptin levels in children and adolescents

iScience, Год журнала: 2024, Номер 27(11), С. 111120 - 111120

Опубликована: Окт. 9, 2024

Язык: Английский

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Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 6, 2024

Abstract Focal adhesion kinase (FAK) functions as a signaling and scaffolding protein within endothelial cells (ECs) impacting blood vessel function tumor growth. Interpretations of EC FAK-null phenotypes are complicated by related PYK2 (protein tyrosine 2) expression, to test this, we created -/- FAK fl/fl mice with tamoxifen-inducible EC-specific Cre recombinase expression. At 11 weeks age, inactivation resulted in increased heart lung mass vascular leakage only on background. Surprisingly, ∼90% survived 75 age. Syngeneic melanoma, breast, or carcinoma tumors did not grow mice, but grew normally lacking Cre. This inhibitory phenotype was associated abortive sprouting, enhanced p53 suppressor p21CIP1 (cyclin-dependent inhibitor 1) alterations serum cytokine levels. To discern the role versus activity ECs, generated defective (FAK K454R, KD) fl/KD fl/WT (WT, wildtype) mice. Hemizygous -/KD expression supported primary growth metastasis, implicating dissemination. In vitro , hemizygous either WT KD suppressed levels cell death observed ECs. Combined knockdown also PARP1 (poly ADP-ribose polymerase p53-associated manner anchorage-independent Together, these results underscore linkage between loss activation Impact Statement PYK2-null combined cell-specific transgenic mouse models show that limits spread genetic chemical degradation preventing FAK-PYK2 may be an approach induce anti-tumor response.

Язык: Английский

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