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Traumatic brain injury (TBI), known as mechanical damage to the brain, impairs the normal function of the brain seriously. Its clinical symptoms manifest as behavioral impairment, cognitive decline, communication difficulties, etc. The pathophysiological mechanisms of TBI are complex and involve inflammatory response, oxidative stress, mitochondrial dysfunction, blood-brain barrier (BBB) disruption, and so on. Among them, oxidative stress, one of the important mechanisms, occurs at the beginning and accompanies the whole process of TBI. Most importantly, excessive oxidative stress causes BBB disruption and brings injury to lipids, proteins, and DNA, leading to the generation of lipid peroxidation, damage of nuclear and mitochondrial DNA, neuronal apoptosis, and neuroinflammatory response. Transcription factor NF-E2 related factor 2 (Nrf2), a basic leucine zipper protein, plays an important role in the regulation of antioxidant proteins, such as oxygenase-1(HO-1), NAD(P)H Quinone Dehydrogenase 1 (NQO1), and glutathione peroxidase (GPx), to protect against oxidative stress, neuroinflammation, and neuronal apoptosis. Recently, emerging evidence indicated the knockout (KO) of Nrf2 aggravates the pathology of TBI, while the treatment of Nrf2 activators inhibits neuronal apoptosis and neuroinflammatory responses via reducing oxidative damage. Phytochemicals from fruits, vegetables, grains, and other medical herbs have been demonstrated to activate the Nrf2 signaling pathway and exert neuroprotective effects in TBI. In this review, we emphasized the contributive role of oxidative stress in the pathology of TBI and the protective mechanism of the Nrf2-mediated oxidative stress response for the treatment of TBI. In addition, we summarized the research advances of phytochemicals, including polyphenols, terpenoids, natural pigments, and otherwise, in the activation of Nrf2 signaling and their potential therapies for TBI. Although there is still limited clinical application evidence for these natural Nrf2 activators, we believe that the combinational use of phytochemicals such as Nrf2 activators with gene and stem cell therapy will be a promising therapeutic strategy for TBI in the future.

Critical physical systems with large numbers of molecules can show universal and scaling behaviors. It is of interest to know whether human societies with large numbers of people can show the same behaviors. Here, we use network theory to analyze Chinese history in periods 209 BCE–23 CE and 515–618 CE) related to the Western Han–Xin Dynasty and the late Northern Wei–Sui Dynasty, respectively. Two persons are connected when they appear in the same historical event. We find that the historical networks from two periods separated about 500 years have interesting universal and scaling behaviors, and they are small-world networks; their average cluster coefficients as a function of degree are similar to the network of movie stars. In the historical networks, the persons with larger degrees prefer to connect with persons with a small degree; however, in the network of movie stars, the persons with larger degrees prefer to connect with persons with large degrees. We also find an interesting similar mechanism for the decline or collapse of historical Chinese dynasties. The collapses of the Xin dynasty (9–23 CE) and the Sui dynasty (581–618 CE) were initiated from their arrogant attitude toward neighboring states.

Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated, which results in a cytokine storm at the late stage of COVID-19. Autophagy regulation is involved in the infection and replication of SARS-CoV-2 at the early stage and the inhibition of NLRP3 inflammasome-mediated lung inflammation at the late stage of COVID-19. Here, we discuss the autophagy regulation at different stages of COVID-19. Specifically, we highlight the therapeutic potential of autophagy activators in COVID-19 by inhibiting the NLRP3 inflammasome, thereby avoiding the cytokine storm. We hope this review provides enlightenment for the use of autophagy activators targeting the inhibition of the NLRP3 inflammasome, specifically the combinational therapy of autophagy modulators with the inhibitors of the NLRP3 inflammasome, antiviral drugs, or anti-inflammatory drugs in the fight against COVID-19.

Cholangiocarcinoma is the most common primary malignant tumor of the bile duct. The current standard first-line treatment for advanced or metastatic cholangiocarcinoma is gemcitabine and cisplatin. However, few effective treatment choices exist for refractory cholangiocarcinoma, and additional therapeutic drugs are urgently required. Our previous work demonstrated that the ALDH isoform 1A3 plays a vital role in the malignant behavior of cholangiocarcinoma and may serve as a new therapeutic target. In this study, we found a positive correlation between ALDH1A3 protein expression levels and the cell migration abilities of three cholangiocarcinoma cell lines, which was verified using ALDH1A3-overexpressing and ALDH1A3-knockdown clones. We also used ALDH1A3-high and ALDH1A3-low populations of cholangiocarcinoma cell lines from the library of integrated network-based cellular signatures (LINCS) program and assessed the effects of ruxolitinib, a commercially available JAK2 inhibitor. Ruxolitinib had a higher cytotoxic effect when combined with gemcitabine. Furthermore, the nuclear translocation STAT1 and STAT3 heterodimers were markedly diminished by ruxolitinib treatment, possibly resulting in decreased ALDH1A3 activation. Notably, ruxolitinib alone or combined with gemcitabine led to significantly reduced tumor size and weight. Collectively, our studies suggest that ruxolitinib might suppress the ALDH1A3 activation through the JAK2/STAT1/3 pathway in cholangiocarcinoma, and trials should be undertaken to evaluate its efficacy in clinical therapy.

Intrahepatic cholangiocarcinoma (iCCA) is an adenocarcinoma arising from the intrahepatic bile duct and accounts for the second most cases of primary liver cancers after hepatocellular carcinoma. Lacking effective treatment leads to a poor prognosis for advanced iCCA so new targeted therapy is warranted. Impaired wild-type (WT) p53 tumor suppressor function by its negative regulators frequently occurs in iCCA. Therefore, restoration of WT p53 function by inhibiting its negative regulators is a therapeutic strategy being explored for cancer treatment. Both MDM2 inhibitor (MDM2i, RG7388) stabilizing p53 and WIP1 inhibitor (WIP1i, GSK2830371) increasing p53 phosphorylation lead to maximize p53 function. The combination of MDM2i/WIP1i has been reported in severe cancer types but no in vivo study has been done. In the current study, both liver adenocarcinoma cell lines, RBE and SK-Hep-1, were treated with the RG7388 alone and in combination with GSK2830371. Cell proliferation, clonogenicity, protein and mRNA expressions, and cell cycle distribution were performed to investigate the effect and mechanism of growth suppression. To evaluate the antitumor efficacy of RG7388 and GSK2830371 in vivo, xenografts with SK-Hep-1 cells were treated with combination therapy for two weeks in NOD-SCID mice. The combination of MDM2i and WIP1i significantly increased the growth inhibition, cytotoxic activity, increased p53 protein expression, and phosphorylation (Ser 15), leading to transactivation of downstream targets (p21 and MDM2). The in vivo test demonstrated that the combination treatment can significantly inhibit tumor growth. In this study, liver adenocarcinoma cell lines were inhibited by the combination via reactivation of p53 function evidenced by increased p53 expression, phosphorylation and its downstream targets. This efficacy was also validated by in vivo study. The current research provides a novel strategy for targeting the p53 pathway in liver adenocarcinoma. Citation Format: Chiao-Ping Chen, Chun-Nan Yeh, Yi-Ru Pan, Yu-Tien Hsiao, Chih-Hong Lo, Cai-Jhen Jhuang, Chiao-En Wu. Activating p53 through MDM2 and WIP1 inhibition effectively inhibits tumors in liver adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5289.

Cholangiocarcinoma (CCA) is a malignant tumor with aggressive biological behavior. Immune checkpoints such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and antiprogrammed death 1 (PD-1) are critical immune-checkpoint molecules that repress T-cell activation. The DNA vaccine potential against CTLA4 and PD-1 in CCA is unknown. We used a thioacetamide (TAA)-induced intrahepatic cholangiocarcinoma (iCCA) rat model to investigate the DNA vaccine potential against CTLA4, PD-1, and PD-L1. We detected PD-L1 expression in CCA and CD8+ T-cell infiltration during CCA progression in rats. We validated antibody production, carcinogenesis, and CD8+ T-cell infiltration in rats receiving DNA vaccination against PD-1, PD-L1, or CTLA4. In our TAA-induced iCCA rat model, the expression of PD-L1 and the infiltration of CD8+ T cells increased as in rat CCA tumorigenesis. PD-1 antibodies in rats were not increased after receiving PD-1 DNA vaccination, and CCA tumor growth was not suppressed. However, in rats receiving PD-L1&ndash, CTLA4 DNA vaccination, CCA tumor growth was inhibited, and the antibodies of PD-L1 and CTLA4 were produced. Furthermore, the number of CD8+ T cells was enhanced after PD-L1&ndash, CTLA4 DNA vaccination. DNA vaccination targeting CTLA4&ndash, PD-L1 triggered the production of specific antibodies and suppressed tumor growth in TAA-induced iCCA rats.

Objective Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although the predictive tool is still unknown. Methods This study aimed to develop a novel gene panel by selecting DNA damage response (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) databank and validating them in previously reported cohorts. This association between DDR gene mutations and tumor mutation burden or microsatellite status was analysed from The Cancer Genome Atlas (TCGA) databank. Furthermore, we made the gene panel clinically accessible and predicted the response in clinical patients receiving ICIs by using cell‐free DNA. Results The top 20 mutated DDR genes in various cancers (total 37 genes) were taken from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in Van Allen's cohort were selected (Science, 350, 2015 and 207). Eighteen DDR genes were selected as the gene panel. The prevalence and predicted response rate were validated in the other three reported cohorts. Tumor mutational burden‐high was positively associated with mutations of the 18 DDR genes for most cancers. We used cell‐free DNA to test the DDR gene panel and validated by our patients receiving ICIs. This DDR gene panel accounted for approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients with a mutated gene panel receiving ICIs. Conclusion This gene panel is a novel and reliable tool for predicting the response to ICIs in cancer patients and guides the appropriate administration of ICIs in clinical practice., Immune checkpoint inhibitors (ICIs) have been widely used to treat various cancers and have achieved impressive success, resulting in a new era of anticancer therapy. However, only a subset of patients experienced lasting responses; therefore, exploring predictive biomarkers is critical to identify the patients who have benefit from ICIs. This gene panel using liquid biopsy is one of the best predictive biomarkers presently available and can help physicians to predict the response to ICIs and judge the utility of ICIs in clinical practice.

Simple Summary The inhibitors of BET proteins represent a promising class of therapeutic agents that target the oncogenic activity of MYC and repress DLBCL cell migration, but the mechanism of such repression remains elusive. Herein, we found that BET inhibitor JQ1 abrogated the amoeboid movement of DLBCL cells through a small GTPase-driven mechanism, including both restrained RAS signaling and MYC-mediated suppression of GTP-RhoA activity. BET inhibition drastically increased the expression of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3), in DLBCL. Proteomics-based re-stratification identified a specific subgroup of DLBCL patients whose tumors harbored an enhanced PI3K activity and had an inferior survival, whereas a lower IQGAP3 expression level further portended a very dismal outcome for those patients. The inhibitors of both BET and RAS (through attenuated PI3K signaling) activities effectively ameliorated the outspread of in vivo DLBCL tumors, indicating the potential of their synergism in the treatment of specific DLBCL subtypes. Abstract Phenotypic heterogeneity and molecular diversity make diffuse large B-cell lymphoma (DLBCL) a challenging disease. We recently illustrated that amoeboid movement plays an indispensable role in DLBCL dissemination and inadvertently identified that the inhibitor of bromodomain and extra-terminal (BET) proteins JQ1 could repress DLBCL migration. To explore further, we dissected the impacts of BET inhibition in DLBCL. We found that JQ1 abrogated amoeboid movement of DLBCL cells through both restraining RAS signaling and suppressing MYC-mediated RhoA activity. We also demonstrated that BET inhibition resulted in the upregulation of a GTPase regulatory protein, the IQ motif containing GTPase activating protein 3 (IQGAP3). IQGAP3 similarly exhibited an inhibitory effect on RAS activity in DLBCL cells. Through barcoded mRNA/protein profiling in clinical samples, we identified a specific subgroup of DLBCL tumors with enhanced phosphatidylinositol-3-kinase (PI3K) activity, which led to an inferior survival in these patients. Strikingly, a lower IQGAP3 expression level further portended those with PI3K-activated DLBCL a very dismal outcome. The inhibition of BET and PI3K signaling activity led to effective suppression of DLBCL dissemination in vivo. Our study provides an important insight into the ongoing efforts of targeting BET proteins as a therapeutic approach for DLBCL.

The motile characteristics and mechanisms that drive the dissemination of diffuse large B-cell lymphoma (DLBCL) are elusive. Here, we show that DLBCL initiates dissemination through activating STAT3-mediated amoeboid migration. Mechanistically, STAT3 activates RHOH transcription, which competes with the RhoGDP dissociation inhibitor RhoGDIγ to activate RhoA. In addition, activated STAT3 regulates microtubule dynamics and releases ARHGEF2 to activate RhoA. Both the JAK inhibitor ruxolitinib and the microtubule stabilizer Taxol suppress DLBCL cell dissemination in vivo. A clinical DLBCL sample analysis shows that STAT3-driven amoeboid movement is particularly important for the transition from stage I to stage II. This study elucidates the mechanism of DLBCL dissemination and progression and highlights the potential of combating advanced DLBCL with a JAK/STAT inhibitor or microtubule stabilizer to reduce DLBCL motility; these findings may have a great impact on the development of patient-tailored treatments for DLBCL., The mechanism underlying the dissemination of diffuse large B-cell lymphoma (DLBCL) is unclear. Here, the authors show that STAT3 controls amoeboid migration in DLBCL via the transcriptional activation of RHOH, which then releases RhoA from RhoGDIγ-mediated suppression, or via regulating microtubule dynamics to activate RhoA.

Patients with advanced biliary tract cancer (BTC) inevitably experience progression after first-line, gemcitabine-based chemotherapy, due to chemo-resistance. The genetic alterations of DNA damage repair (DDR) genes are usually determined in BTC tumors. In this study, we found that the POLQ mRNA levels are downregulated and the ataxia-telangiectasia mutated (ATM) inhibitor AZD0156 was more sensitive in gemcitabine-resistant BTC sublines than in the parental cell lines. The knockdown of DNA polymerase &theta, does not affect cell proliferation, but its combination with the ATM inhibitor facilitated cell death in gemcitabine-resistant and gemcitabine-intensive BTC cells. Moreover, in the DNA damage caused by photon, hydrogen peroxide, or chemotherapy drugs, synthetic lethal interactions were found in combination with ATM inhibition by AZD0156 and DNA polymerase &theta, depletion, resulting in increased DNA damage accumulation and micronucleus formation, as well as reduced cell survival and colony formation. Collectively, our results reveal that ATM acts as a potential target in gemcitabine-resistant and DNA polymerase &theta, deficient BTC.

e15052 Background: Immune checkpoint inhibitors (ICIs) have become the standard of care in various cancers, although predictive biomarkers for efficacy still remain largely unknown. Methods: This study aims to develop a novel gene panel by selecting DNA damage and repair (DDR) genes from the Catalogue of Somatic Mutations in Cancer (COSMIC) database and perform validation using publicly available cohorts. Association between the DDR gene panel and tumor mutation burden or microsatellite status were analyzed from The Cancer Genome Atlas (TCGA) database. To further improve the clinical accessibility of the DDR gene panel, we analyzed the feasibility of its predictive value using cell free DNA in from 64 patients receiving ICIs. Results: The 193 mutated DDR genes in various cancers were chosen from the COSMIC databank, and the DDR genes found to individually predict a response rate > 50% in publicly melanoma cohort (Van Allen, et al) were selected. Eighteen DDR genes were selected as the DDR gene panel. The prevalence of the DDR gene mutations and predicted response rate of ICIs were validated in other three publicly available cohorts (Hugo et al, Synder et al, and Rizvi et al.). Tumor mutational burden and high microsatellite instability were positively associated with mutations of the 18 DDR genes for most cancers. Further validation was performed using cell-free DNA from cancer patients receiving ICIs. This DDR gene panel was detected in approximately 30% of various cancers, achieving a predicted response rate of approximately 60% in patients receiving ICIs. Conclusions: Our developed DDR gene panel can serve as a novel and reliable biomarker that can provide critical information for predicting the response to ICIs in cancer patients and guide the appropriate administration of ICIs in clinical practice.

Podosomes are dynamic actin-based membrane protrusions that are important for extracellular matrix degradation and invasive cell motility. Individual podosomes are often found to organize into large rosette-like structures in some types of cells, such as osteoclasts, endothelial cells, Src-transformed fibroblasts, and certain highly invasive cancer cells. In this study, we show that new podosome rosettes arise through one of two mechanisms; de novo assembly or fission of a pre-existing podosome rosette in Src-transformed fibroblasts. Fission is a more efficient way than de novo assembly to generate new podosome rosettes in these cells. Podosome rosettes undergoing fission possess higher motility and a stronger matrix-degrading capability. Podosome rosette fission may be the result of polarized myosin II-mediated contractility of these structures, which is coordinately regulated by myosin light chain kinase and Rho-associated kinase II. Collectively, this study unveils a previously unknown mechanism—fission for the biogenesis of podosome rosettes.

To investigate the relationship of muscle mass and muscle function with age.The study including 415 participants (aged 60-99 years). Upper (UMM) and lower (LMM) limbs muscle mass and whole body fat free mass (FFM) were measured by bioelectrical impedance analysis. The appendicular skeletal muscle mass (ASM) index (ASM/height2) was calculated. Muscle function was assessed by measuring hand grip strength (HGS) and gait speed.Using ASM index cutoff values we found that higher prevalence of sarcopenia in women than in men (33.5% vs 23.6%, p=0.025). In the upper limb, HGS (β=-0.809) declined more rapidly with age than did UMM (β=-0.592) in men, but not in women (β=-0.389 and β=-0.486 respectively). In the lower limb, gait speed declined more rapidly than LMM in both men (β=-0.683 vs β=-0.442) and women (β=-1.00 vs β=-0.461). The variance of UMM explained 28-29% of the variance of HGS, and LMM explained 7-8% of the variance of gait speed in women and men respectively. In addition to the common predictors (BMI and age), the specific predictors were smoking, exercise and education for FFM and ASM, and smoking, drinking and exercise for HGS (p0.05).Loss of muscle function is greater than the decline of muscle mass particularly in the upper limbs in men. However, women are more prone to have low muscle mass than the men. Exercise programs need to be designed gender specifically.目的：探讨与年龄相关的骨骼肌肌量与功能之间的关系。方法：本研究包括 415 名年龄在6099 岁之间的受试者。采用人体成分仪测量上肢和下肢骨骼肌 肌量、去脂组织。四肢骨骼肌肌量指数=四肢骨骼肌肌量/身高平方。采用握力 与步速评价骨骼肌功能。结果：老年男性、女性骨骼肌肌量低于切点值的比 例分别是（ 23.6% vs 33.5% ， p=0.025 ） 。老年男性随年龄的增加握力 （β=0.809）下降快于上肢骨骼肌肌量（β=-0.592），但在老年女性中不存在 同样的情况（β=0.389 和β=0.486）。在老年男性（β=0.683 vs β=0.442） 与女性（β=1.00 vs β=0.461）中，步速下降快于下肢骨骼肌肌量。老年男性 与女性上肢骨骼肌肌量与握力的决定系数是2829%，下肢骨骼肌肌量与步速 的决定系数是（78%）。除体重指数与年龄外，吸烟、运动和受教育情况与 四肢骨骼肌肌量、去脂组织相关。吸烟、饮酒与握力呈负相关（p0.05）。结 论：老年男性上肢骨骼肌功能下降快于骨骼肌肌量。然而，老年女性骨骼肌 肌量低于切点值的百分比大于男性。运动方案的制定需要考虑性别的因素。.

FAK opposes Rho activity and vimentin intermediate filament formation to promote podosome rosette assembly., Podosomes are dynamic actin-enriched membrane structures that play an important role in invasive cell motility and extracellular matrix degradation. They are often found to assemble into large rosettelike structures in highly invasive cells. However, the mechanism of this assembly remains obscure. In this study, we identified focal adhesion kinase (FAK) as a key molecule necessary for assembly. Moreover, phosphorylation of p130Cas and suppression of Rho signaling by FAK were found to be important for FAK to induce the assembly of podosome rosettes. Finally, we found that suppression of vimentin intermediate filaments by FAK facilitates the assembly of podosome rosettes. Collectively, our results strongly suggest a link between FAK, podosome rosettes, and tumor invasion and unveil a negative role for Rho signaling and vimentin filaments in podosome rosette assembly.

Tumor metastasis might be evoked in response to microenvironmental stress, such as a shortage of oxygen. Although the cellular response to hypoxia has been well established, we know little about how tumors adapt themselves to deprivation of growth factor. Protein kinase Cdelta (PKCdelta), a stress-sensitive protein kinase, has been implicated in tumor progression. In this study, we demonstrate that elevated expression of PKCdelta in Madin-Darby canine kidney cells induces a scatter response upon serum starvation, a condition that mimics growth-factor deprivation. Serum starvation stimulates the catalytic activity and Y311 phosphorylation of PKCdelta through reactive oxygen species (ROS) and the Src family kinases. Mutation of PKCdelta at Y311 and Y322, both of which are phosphorylation sites for Src, impairs its activation and ability to promote cell scattering upon serum deprivation. Once activated by ROS, PKCdelta itself activates ROS production at least partially through NADPH oxidase. In addition, the c-Jun N-terminal kinase is identified as a crucial downstream mediator of ROS and PKCdelta for induction of cell scattering upon serum deprivation. We demonstrate that the C1B domain of PKCdelta is essential not only for its localization at the Golgi complex, but also for its activation and ability to induce cell scattering upon serum deprivation. Finally, depletion of PKCdelta in human bladder carcinoma T24 cells restores their cell-cell contacts, which thereby reverses a scattered growth pattern to an epithelial-like growth pattern. Collectively, our results suggest that elevated expression of PKCdelta might facilitate the scattering of cells in order to escape stress induced by growth-factor deprivation.

Podosomes are actin-based membrane protrusions that facilitate extracellular matrix degradation and invasive cell motility. Podosomes can self-organize into large rosette-like structures in Src-transformed fibroblasts, osteoclasts, and some highly invasive cancer cells. However, the mechanism of this assembly remains obscure. In this study, we show that the suppression of c-Jun N-terminal kinase (JNK) by the JNK inhibitor SP600125 or short-hairpin RNA inhibited podosome rosette formation in SrcY527F-transformed NIH3T3 fibroblasts. In addition, SrcY527F was less potent to induce podosome rosettes in JNK1-null or JNK2-null mouse embryo fibroblasts than in their wild-type counterparts. The kinase activity of JNK was essential for promoting podosome rosette formation but not for its localization to podosome rosettes. Moesin, a member of the ERM (ezrin, radixin, and moesin) protein family, was identified as a substrate of JNK. We show that the phosphorylation of moesin at Thr558 by JNK was important for podosome rosette formation in SrcY527F-transformed NIH3T3 fibroblasts. Taken together, our results unveil a novel role of JNK in podosome rosette formation by phosphorylating moesin.

Summary Podosomes are actin-enriched membrane protrusions that play important roles in extracellular matrix degradation and invasive cell motility. Podosomes undergo self-assembly into large rosette-like structures in Src-transformed fibroblasts, osteoclasts and certain highly invasive cancer cells. Several protein tyrosine kinases have been shown to be important for the formation of podosome rosettes, but little is known regarding the role of protein tyrosine phosphatases in this process. We found that knockdown of the Src homolog domain-containing phosphatase 2 (SHP2) significantly increased podosome rosette formation in Src-transformed fibroblasts. By contrast, SHP2 overexpression suppressed podosome rosette formation in these cells. The phosphatase activity of SHP2 was essential for the suppression of podosome rosette formation. SHP2 selectively suppressed the tyrosine phosphorylation of Tks5, a scaffolding protein required for podosome formation. The inhibitory effect of SHP2 on podosome rosette formation was associated with the increased activation of Rho-associated kinase (ROCK) and the enhanced polymerization of vimentin filaments. A higher content of polymerized vimentin filaments was correlated with a lower content of podosome rosettes. Taken together, our findings indicate that SHP2 serves as a negative regulator of podosome rosette formation through the dephosphorylation of Tks5 and the activation of ROCK-mediated polymerization of vimentin in Src-transformed fibroblasts.