An immunomechanical checkpoint PYK2 governs monocyte-to-macrophage differentiation in pancreatic cancer DOI Creative Commons
Wenyan Xie, Xin Yu, Qingxin Yang

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 21, 2024

Pancreatic ductal adenocarcinoma (PDAC) is a highly fibrotic and stiff tumor, tumor-associated macrophages (TAMs) are pivotal in driving ECM remodeling, PDAC progression immune evasion. The contribution of mechanical cues to monocyte differentiation into TAMs remains largely unexplored. Here we show that force required for monocyte-to-macrophage differentiation. PYK2, as an innovative immunomechanical checkpoint, de facto governs this process. We demonstrated PYK2 responds signals within the tumor microenvironment (TME) via Piezo1 integrins, leading its activation subsequent F-actin polymerization. Activated then translocates nucleus, where it engages with promoters genes governing mechanotransduction differentiation, including ACTR3 RELA. Targeted deletion impairs polarization monocyte-derived macrophages, reshapes microenvironment, enhances efficacy anti-PD-1 immunotherapy. These findings underscore critical role suggest targeting promising strategy modulate TAM function improve immunotherapy outcomes patients PDAC.

Language: Английский

Single-cell RNA Sequencing Reveals ECM Remodeling-Tumor Stiffness-FAK as a Key Driver of Vestibular Schwannoma Progression DOI
Yu Zhang, Jianfei Long, Jian Xu

et al.

Progress in Neurobiology, Journal Year: 2025, Volume and Issue: 247, P. 102730 - 102730

Published: Feb. 22, 2025

Language: Английский

Citations

0
PYK2 promotes cell proliferation and epithelial-mesenchymal transition in endometriosis by phosphorylating Snail1 DOI Creative Commons
Lu Liu,

Lan Liu,

Congbo Yue

et al.

Molecular Medicine, Journal Year: 2025, Volume and Issue: 31(1)

Published: April 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

Language: Английский

Citations

0
Integrin αVβ1-activated PYK2 promotes the progression of non-small-cell lung cancer via the STAT3-VGF axis DOI Creative Commons

Zhengyan Wu,

Min Jiao,

Chenying Shu

et al.

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: June 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.

Language: Английский

Citations

3
Focal adhesion kinase signaling – tumor vulnerabilities and clinical opportunities DOI Creative Commons
David D. Schlaepfer, Marjaana Ojalill, Dwayne G. Stupack

et al.

Journal of Cell Science, Journal Year: 2024, Volume and Issue: 137(14)

Published: July 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.

Language: Английский

Citations

3
Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes DOI Creative Commons
Ting Li,

Shichen Sun,

Yubing Li

et al.

Frontiers in Immunology, Journal Year: 2024, Volume and Issue: 15

Published: July 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.

Language: Английский

Citations

3
Preliminary study of the homeostatic regulation of osseointegration by nanotube topology DOI Creative Commons
Tao Chen, Mingxing Ren, Yuzhou Li

et al.

Materials Today Bio, Journal Year: 2024, Volume and Issue: 26, P. 101038 - 101038

Published: April 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.

Language: Английский

Citations

1
FAK family proteins regulatein vivobreast cancer metastasisviadistinct mechanisms DOI Open Access
Alessandro Genna, Joel Alter, Martina Poletti

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Oct. 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

Language: Английский

Citations

1
Targeting PYK2, entrectinib allays anterior subcapsular cataracts in mice by regulating TGFβ2 signaling pathway DOI Creative Commons
Xuefei Ding,

Xiaohe Li,

Rui Fang

et al.

Molecular Medicine, Journal Year: 2024, Volume and Issue: 30(1)

Published: Sept. 27, 2024

Language: Английский

Citations

0
The PTK2B gene is associated with obesity, adiposity and leptin levels in children and adolescents DOI Creative Commons

Eva Prida,

Raquel Pérez-Lois,

Pablo Jácome-Ferrer

et al.

iScience, Journal Year: 2024, Volume and Issue: 27(11), P. 111120 - 111120

Published: Oct. 9, 2024

Language: Английский

Citations

0
Inducible FAK Deletion but not FAK Inhibition in Endothelial Cells Activates p53 to Suppress Tumor Growth in PYK2-null Mice DOI Open Access
Xiao Lei Chen, Marjaana Ojalill, Christine Jean

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 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.

Language: Английский

Citations

0