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Lactylation has been recently identified as a new type of posttranslational modification occurring widely on lysine residues of both histone and nonhistone proteins. The acetyltransferase p300 is thought to mediate protein lactylation, yet the cellular concentration of the proposed lactyl-donor, lactyl-coenzyme A, is about 1,000 times lower than that of acetyl-CoA, raising the question of whether p300 is a genuine lactyltransferase. Here, we report that alanyl-tRNA synthetase 1 (AARS1) moonlights as a bona fide lactyltransferase that directly uses lactate and ATP to catalyze protein lactylation. Among the candidate substrates, we focused on the Hippo pathway, which has a well-established role in tumorigenesis. Specifically, AARS1 was found to sense intracellular lactate and translocate into the nucleus to lactylate and activate the YAP-TEAD complex; and AARS1 itself was identified as a Hippo target gene that forms a positive-feedback loop with YAP-TEAD to promote gastric cancer (GC) cell proliferation. Consistently, the expression of AARS1 was found to be upregulated in GC, and elevated AARS1 expression was found to be associated with poor prognosis for patients with GC. Collectively, this work found AARS1 with lactyltransferase activity in vitro and in vivo and revealed how the metabolite lactate is translated into a signal of cell proliferation.

Summary TSPAN family of proteins are generally considered to assemble as multimeric complexes on the plasma membrane. Our previous work uncovered that TSPAN8 can translocate into the nucleus as a membrane-free form, a process that requires TSPAN8 palmitoylation and association with cholesterol to promote its extraction from the plasma membrane and subsequent binding with 14-3-3θ and importin-β. However, what upstream signal(s) regulate(s) the nuclear translocation of TSPAN8, the potential function of TSPAN8 in the nucleus, and the underlying molecular mechanisms all remain unclear. Here, we demonstrate that, epidermal growth factor receptor (EGFR) signaling induces TSPAN8 nuclear translocation by activating the kinase AKT, which in turn directly phosphorylates TSPAN8 at Ser129, an event essential for its binding with 14-3-3θ and importin ß1. In the nucleus, phosphorylated TSPAN8 interacts with STAT3 to enhance its chromatin occupancy and therefore regulates transcription of downstream cancer-promoting genes, such as MYC, BCL2, MMP9 , etc. The EGFR–AKT–TSPAN8–STAT3 axis was found to be hyperactivated in multiple human cancers, and associated with aggressive phenotype and dismal prognosis. We further developed a humanized monoclonal antibody hT8 Ab4 that specifically recognizes the large extracellular loop of TSPAN8 (TSPAN8-LEL), thus being able to block the extraction of TSPAN8 from the plasma membrane and consequently its nuclear localization. Importantly, both in vitro and in vivo studies demonstrated an antitumor effect of hT8 Ab4 . Collectively, we discovered an unconventional function of TSPAN8 and dissected the underlying molecular mechanisms, which not only showcase a new layer of biological complexity of traditional membrane proteins, but also shed light on TSPAN8 as a novel therapeutic target for refractory cancers.

Chemotherapy represents a major type of clinical treatment against colorectal cancer (CRC). Aberrant drug efflux mediated by transporters acts as a key approach for tumor cells to acquire chemotherapy resistance. Increasing evidence implies that tumor-associated macrophages (TAMs) play a pivotal role in both tumorigenesis and drug resistance. Nevertheless, the specific mechanism through which TAMs regulate drug efflux remains elusive. Here, we discovered that TAMs endow CRC cells with resistance to 5-fluorouracil (5-FU) treatment via a cell-cell interaction-mediated MRP1-dependent drug efflux process. Mechanistically, TAM-secreted C-C motif chemokine ligand 17 (CCL17) and CCL22, via membrane receptor CCR4, activated the PI3K/AKT pathway in CRC tumor cells. Specifically, phosphorylation of AKT inactivated IP3R and induced calcium aggregation in the ER, resulting in the activation of ATF6 and upregulation of GRP78. Accordingly, excessive GRP78 can interact with MRP1 and promote its translocation to the cell membrane, causing TAM-induced 5-FU efflux. Taken together, our results demonstrated that TAMs promote CRC chemotherapy resistance via elevating the expression of GRP78 to promote the membrane translocation of MRP1 and drug efflux, providing direct proof for TAM-induced drug resistance.

Extracellular vesicles (EVs) are known to mediate cell communications and shape tumor microenvironment. Compared to the well-studied small EVs, the function of large microvesicles (MVs) during tumorigenesis is poorly understood. Here we show the proteome of MVs in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), and identify olfactomedin 4 (OLFM4) is induced by EBV infection and secreted via MVs to promote tumor progression through Hippo signaling. Specifically, OLFM4 is a target gene of the cGAS-STING pathway, and EBV infection activates cGAS-STING pathway and increases OLFM4 expression. Moreover, MV-carried OLFM4 binds with the extracellular cadherin domain of FAT1, thereby impairing its intracellular interaction with MST1 and leading to YAP activation in recipient cells. Together, our study not only reveals a regulatory mechanism though which viral infection is coupled via MVs with intercellular control of the Hippo signaling, but also highlights the OLFM4-Hippo axis as a therapeutic target for EBV-associated cancers. The functions of microvesicles (MVs) in gastric cancer are less studied compared to other types of extracellular vesicles. Here, the authors report that in Epstein-Barr virus (EBV)-associated gastric cancer (EBVaGC), Olfactomedin 4 protein is enriched in secreted MVs to promote EBVaGC progression by inhibiting the Hippo signaling in tumor cells.

Dysregulation of SMAD4 (i.e. somatic mutation) is strongly associated with poor pancreatic ductal adenocarcinoma (PDAC) prognosis, yet the molecular mechanisms remain underlying this relationship obscure. Previously, we discovered that SMAD4 mutation renders pancreatic cancer resistant to radiotherapy via promotion of autophagy. In the current work, we observed a downregulation of the protein level of SMAD4 in PDAC as compared with adjacent normal tissue, and that such SMAD4 low PDAC failed to benefit from chemotherapy. Furthermore, we observed that SMAD4 depletion dramatically enhanced DNA repair capacity in response to irradiation (IR) or a radiomimetic chemical. Interestingly, we found the radiomimetic chemical having induced a robust translocation of SMAD4 into the nucleus, where a direct interaction was shown to occur between the MH1 domain of SMAD4 and the DBD domain of PARP1. Functionally, the SMAD4-PARP1 interaction was found to perturb the recruitment of PARP1 to DNA damage sites. Accordingly, the combination of olaparib and radiotherapy was indicated in vivo and in vitro to specifically reduce the growth of SMAD4-deficient PDAC by attenuating PARP1 activity. Collectively, our results revealed a novel molecular mechanism for the involvement of the SMAD4-PARP1 interaction in DNA repair with a vital role in radiotherapy response in PDAC. Based on our set of findings, our findings offer a new combined therapeutic strategy for SMAD4 deficient PDAC that can significantly reduce pancreatic cancer radiotherapy resistance.

The striatin-interacting phosphatase and kinase (STRIPAK) complexes integrate extracellular stimuli that result in intracellular activities. Previously, we discovered that STRIPAK is a key machinery responsible for loss of the Hippo tumor suppressor signal in cancer. Here, we identified the Hippo-STRIPAK complex as an essential player in the control of DNA double-stranded break (DSB) repair and genomic stability. Specifically, we found that the mammalian STE20-like protein kinases 1 and 2 (MST1/2), independent of classical Hippo signaling, directly phosphorylated zinc finger MYND type-containing 8 (ZMYND8) and hence resulted in the suppression of DNA repair in the nucleus. In response to genotoxic stress, the cyclic GMP-AMP synthase/stimulator of IFN genes (cGAS/STING) pathway was determined to relay nuclear DNA damage signals to the dynamic assembly of Hippo-STRIPAK via TANK-binding kinase 1-induced (TBK1-induced) structural stabilization of the suppressor of IKBKE 1- sarcolemma membrane-associated protein (SIKE1-SLMAP) arm. As such, we found that STRIPAK-mediated MST1/2 inactivation increased the DSB repair capacity of cancer cells and endowed these cells with resistance to radio- and chemotherapy and poly(ADP-ribose)polymerase (PARP) inhibition. Importantly, targeting the STRIPAK assembly with each of 3 distinct peptide inhibitors efficiently recovered the kinase activity of MST1/2 to suppress DNA repair and resensitize cancer cells to PARP inhibitors in both animal- and patient-derived tumor models. Overall, our findings not only uncover what we believe to be a previously unrecognized role for STRIPAK in modulating DSB repair but also provide translational implications of cotargeting STRIPAK and PARP for a new type of synthetic lethality anticancer therapy.

Multi-robot systems (MRSs) are widely applied in the fields of joint search and rescue, exploration, and carrying. To achieve cooperative tasks and guarantee physical safety, the robots should avoid inter-robot collisions as well as robot–obstacle collisions. However, the collision/obstacle avoidance task usually conflicts with the given cooperative task, which poses a significant challenge for the achievement of multi-robot cooperative tasks. This paper provides a review of the state-of-the-art results in the collision/obstacle avoidance cooperative control of MRSs. Specifically, the latest developments of collision/obstacle avoidance cooperative control are summarized according to different planning strategies and classified into three categories: (1) offline planning; (2) receding horizon planning; and (3) reactive control. Furthermore, specific design solutions for existing reference/command governors are highlighted to demonstrate the latest research advances. Finally, several challenging issues are discussed to guide future research.

A series of LiFePO4/C composites with Ti in-situ doped has been synthesized by a combination of wet ball-milling, spray drying, and carbothermal reduction. The test result shows that the composite ion doping can significantly improve the electrochemical performance of the material. The discharge specific capacity of the button cell at 0.2C is 160.2 mAh g−1. After 500 cycles, the battery capacity remained 96.8% of the initial discharge capacity, which shows an excellent rate discharge performance and cycle performance. The study found that the appropriate amount of Ti doping does not much affect the crystal structure, but the particle size of the primary particles exhibits a trend of nanocrystallization, which could effectively shorten the deintercalation distance of Li+. Especially the low-temperature performance of the Ti doping LiFePO4, there was the highest discharge capacity of 122.3 mAh g−1 at 1C and − 20 °C. But the excessive doping of Ti could cause the deformation and blockage of lithium-ion channels, which reduced the lithium-ion diffusion coefficient. Besides, the 14,500 cylindrical batteries were performed to verify the effectiveness of application, which could reach a 148.8 mAh g−1 at 1C rate.

Background Serine/threonine kinase 3 (STK3) is recognized as a key regulator in Hippo pathway and a tumor-suppressing gene in various cancer types. However, its non-canonical role has been gradually revealed in cancer development. Methods Our objective is to elucidate the upregulation pattern and molecular mechanisms of STK3 in advancing gastric cancer (GC) progression. The regulation of YAP1 on STK3 was assessed through a combination of bulk and single-cell RNA-sequencing, Western blot, ChIP-qPCR, gene knockout mouse models, and functional rescue assays. The oncogenic roles of STK3 were confirmed through subcutaneous xenograft formation models and functional assays including spheroid formation and organoid growth. The phosphorylated target of STK3 was revealed by co-immunoprecipitation and in vitro kinase assays. STK3-targeted drugs were screened out by molecular docking and cellular thermal shift assay (CETSA). Results Reduction of YAP1 significantly impaired STK3 expression at both mRNA and protein levels, and deletion of STK3 partially attenuated the oncogenic activity of YAP1. Notably, MNNG-induced tumors in Yap1 −/− Taz −/− mice exhibited decreased STK3 expression. Knockdown of STK3 led to reduced expression of stemness markers and xenograft growth, while sensitizing GC organoids and xenografts to 5-fluorouracil treatment. Mechanistically, the direct interaction between STK3 and GSK-3β promoted GSK-3β phosphorylation and β-catenin nuclear accumulation, and thus the activation of Wnt signaling. Furthermore, aminopterin demonstrates as a promising STK3-targeted small molecule with remarkable effectiveness in inhibiting GC cell malignance and xenograft growth. Conclusions STK3 was identified as a transcriptional target of YAP1, leading to enhanced DNA repair ability and stemness acquisition during GC progression by activating Wnt/β-catenin activity through GSK-3β degradation. Moreover, STK3-targeted therapy offered a novel approach to concur acquired chemo-resistance in GC patients. Graphical Abstract

Background The mammalian STE20-like kinase 4 (MST4) has been implicated as a potential oncogene in various cancers, including pancreatic cancer (PC). However, the precise mechanisms through which MST4 promotes PC malignancy remain incompletely understood. Methods A Biotin identification (BioID)-based proximity labeling approach was employed to identify key MST4-interacting molecules in human PANC-1 pancreatic cancer (PC) cells, followed by cell migration assay to validate the synergistic promotional effect of the MST4-interacting complex on PC cell migration. Direct binding between MST4 and its interacting partners was confirmed via microscale thermophoresis (MST) and isothermal titration calorimetry (ITC), with further validation through X-ray crystallographic structural analysis. The efficacy of rationally designed peptides targeting this interaction was evaluated in both in vitro cell models and in vivo xenograft mouse models. Results In this study, we demonstrate that MST4 forms a phosphorylation-dependent complex with 14-3-3ζ, leading to Yes-associated protein (YAP) activation and synergistic enhancement of PC cell migration. We observed significant upregulation of both MST4 and 14-3-3ζ in PC patient samples, which correlated strongly with YAP activation and poor prognosis. Structural analysis revealed the detailed interface of the MST4–14-3-3ζ complex, facilitating the rational design of peptide inhibitors that disrupt this interaction. These peptides effectively suppressed YAP activation and exhibited potent anti-tumor effects both in vitro and in vivo. Conclusions Our findings establish the MST4–14-3-3ζ complex as a critical regulator of YAP signaling that synergistically promotes PC cell migration. Furthermore, rationally designed peptides targeting this MST4–14-3-3ζ interaction represent a promising therapeutic strategy for pancreatic cancer and warrant further clinical exploration. Graphical Abstract