TGF-ß downstream of Smad3 and MAPK signaling antagonistically regulate the viability and partial epithelial-mesenchymal transition of liver progenitor cells.

BACKGROUND: Liver progenitor cells (LPCs) are a subpopulation of cells that contribute to liver regeneration, fibrosis and liver cancer initiation under different circumstances. RESULTS: By performing adenoviral-mediated transfection, CCK-8 analyses, F-actin staining, transwell analyses, luciferase reporter analyses and Western blotting, we observed that TGF-ß promoted cytostasis and partial epithelial-mesenchymal transition (EMT) in LPCs. In addition, we confirmed that TGF-ß activated the Smad and MAPK pathways, including the Erk, JNK and p38 MAPK signaling pathways, and revealed that TGFß-Smad signaling induced growth inhibition and partial EMT, whereas TGFß-MAPK signaling had the opposite effects on LPCs. We further found that the activity of Smad and MAPK signaling downstream of TGF-ß was mutually restricted in LPCs. Mechanistically, we found that TGF-ß activated Smad signaling through serine phosphorylation of both the C-terminal and linker regions of Smad2 and 3 in LPCs. Additionally, TGFß-MAPK signaling inhibited the phosphorylation of Smad3 but not Smad2 at the C-terminus, and it reinforced the linker phosphorylation of Smad3 at T179 and S213. We then found that overexpression of mutated Smad3 at linker phosphorylation sites intensifies TGF-ß-induced cytostasis and EMT, mimicking the effects of MAPK inhibition in LPCs, whereas mutation of Smad3 at the C-terminus caused LPCs to blunt TGF-ß-induced cytostasis and partial EMT. CONCLUSION: These results suggested that TGF-ß downstream of Smad3 and MAPK signaling were mutually antagonistic in regulating the viability and partial EMT of LPCs. This antagonism may help LPCs overcome the cytostatic effect of TGF-ß under fibrotic conditions and maintain partial EMT and progenitor phenotypes.

A pair of primary colorectal cancer-derived and corresponding synchronous liver metastasis-derived organoid cell lines.

Proper preclinical models for the research of colorectal cancer (CRC) and CRC liver metastases (CLM) are a clear and unmet need. Patient-derived organoids have recently emerged as a robust preclinical model, but are not available to all scientific researchers. Here, we present paired 3D organoid cell lines of CWH22 (CRC-derived) and CLM22 (CLM-derived) with sound background information and the short tandem repeats are identical to those of the normal tissue. Morphological and immunohistochemical staining, along with whole-exome sequencing (WES), confirmed that the organoids exhibited the same differentiation, molecular expression, and mutation status as the corresponding tumor tissue. Both organoids possessed mutated APC/KRAS/SMAD4/CDKN1B/KMT2C genes and wild-type TP53 and PIK3CA; stably secreted the tumor markers CEA and CA19-9, and possessed sound proliferation rates in vitro, as well as subcutaneous tumorigenicity and liver metastatic abilities in vivo. IC50 assays confirmed that both cell lines were sensitive to 5-fluorouracil, oxaliplatin, SN-38, and sotorasib. WES and karyotype analyses revealed the genomic instability status as chromosome instability. The corresponding adherent cultured CWH22-2D/CLM22-2D cells were established and compared with commonly used CRC cell lines from the ATCC. Both organoids are publicly available to all researchers and will be useful tools for specific human CRC/CLM studies both in vitro and in vivo.

YTHDF2 Is a Therapeutic Target for HCC by Suppressing Immune Evasion and Angiogenesis Through ETV5/PD-L1/VEGFA Axis.

N6-methyladenosine (m6A) modification orchestrates cancer formation and progression by affecting the tumor microenvironment (TME). For hepatocellular carcinoma (HCC), immune evasion and angiogenesis are characteristic features of its TME. The role of YTH N6-methyladenosine RNA binding protein 2 (YTHDF2), as an m6A reader, in regulating HCC TME are not fully understood. Herein, it is discovered that trimethylated histone H3 lysine 4 and H3 lysine 27 acetylation modification in the promoter region of YTHDF2 enhanced its expression in HCC, and upregulated YTHDF2 in HCC predicted a worse prognosis. Animal experiments demonstrated that Ythdf2 depletion inhibited spontaneous HCC formation, while its overexpression promoted xenografted HCC progression. Mechanistically, YTHDF2 recognized the m6A modification in the 5'-untranslational region of ETS variant transcription factor 5 (ETV5) mRNA and recruited eukaryotic translation initiation factor 3 subunit B to facilitate its translation. Elevated ETV5 expression induced the transcription of programmed death ligand-1 and vascular endothelial growth factor A, thereby promoting HCC immune evasion and angiogenesis. Targeting YTHDF2 via small interference RNA-containing aptamer/liposomes successfully both inhibited HCC immune evasion and angiogenesis. Together, this findings reveal the potential application of YTHDF2 in HCC prognosis and targeted treatment.

GRIN2A mutation is a novel indicator of stratifying beneficiaries of immune checkpoint inhibitors in multiple cancers.

Glutamate-NMDAR receptors (GRINs) have been reported to influence cancer immunogenicity; however, the relationship between GRIN alterations and the response to immune checkpoint inhibitors (ICIs) has not been determined. This study combined clinical characteristics and mutational profiles from multiple cohorts to form a discovery cohort (n = 901). The aim of this study was to investigate the correlation between the mutation status of the GRIN gene and the response to ICI therapy. Additionally, an independent ICI-treated cohort from the Memorial Sloan Kettering Cancer Center (MSKCC, N = 1513) was used for validation. Furthermore, this study explored the associations between GRIN2A mutations and intrinsic and extrinsic immunity using multiomics analysis. In the discovery cohort, patients with GRIN2A-MUTs had improved clinical outcomes, as indicated by a higher objective response rate (ORR: 36.8% vs 25.8%, P = 0.020), durable clinical benefit (DCB: 55.2% vs 38.7%, P = 0.005), prolonged progression-free survival (PFS: HR = 0.65; 95% CI 0.49 to 0.87; P = 0.003), and increased overall survival (OS: HR = 0.67; 95% CI 0.50 to 0.89; P = 0.006). Similar results were observed in the validation cohort, in which GRIN2A-MUT patients exhibited a significant improvement in overall survival (HR = 0.66; 95% CI = 0.49 to 0.88; P = 0.005; adjusted P = 0.045). Moreover, patients with GRIN2A-MUTs exhibited an increase in tumor mutational burden, high expression of costimulatory molecules, increased activity of antigen-processing machinery, and infiltration of various immune cells. Additionally, gene sets associated with cell cycle regulation and the interferon response were enriched in GRIN2A-mutated tumors. In conclusion, GRIN2A mutation is a novel biomarker associated with a favorable response to ICIs in multiple cancers.

Remarkable Off-On Tunable Solid-State Luminescence by the Regulation of Pyrene Dimer.

It is always a challenge to achieve "off-on" luminescent switch by regulating non-covalent interactions. Herein, we report a unique strategy for constructing high performance "off-on" tunable luminescent materials utilizing a novel molecule (TFPA) consist of pyrene and cyanostilbene. The pristine crystal of TFPA is almost non-emissive. Upon grinding/UV irradiation, an obvious luminescence enhancement is observed. Theoretical and experimental results revealed the underlying mechanism of this intriguing "off-on" switching behavior. The non-emissive crystal consists of ordered H-aggregates, with adjacent two molecules stacked in an anti-parallel manner and no overlapped area in pyrene moieties. When external force is applied by grinding or internal force is introduced through the photoisomerization, the dimer structures are facilitated with shorter intermolecular distances and better overlapping of pyrene moieties. In addition, the "on" state can recover to "off" state under thermal annealing, showing good reversibility and applicability in intelligence material. The present results promote an in-depth insight between packing structure and photophysical property, and offer an effective strategy for the construction of luminescence "off-on" switching materials, toward the development of stimuli-responsive luminescent materials for anti-counterfeiting.

Targeting MMP9 in CTNNB1 mutant hepatocellular carcinoma restores CD8+ T cell-mediated antitumour immunity and improves anti-PD-1 efficacy.

OBJECTIVE: The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC. DESIGN: RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9. RESULTS: MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of ß-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC. CONCLUSIONS: CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.

CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1.

The centromere proteins (CENPs), a critical mitosis-related protein complexes, are involved in the kinetochore assembly and chromosome segregation. In this study, we identified that CENPA was significantly up-regulated in HCC and highly expressed CENPA correlated with poor prognosis for HCC patients. Knockdown of CENPA inhibited HCC cell proliferation and tumor growth in vitro and in vivo. Mechanistically, CENPA transcriptionally activated and cooperated with YY1 to drive the expression of cyclin D1 (CCND1) and neuropilin 2 (NRP2). Moreover, we identified that CENPA can be lactylated at lysine 124 (K124). The lactylation of CENPA at K124 promotes CENPA activation, leading to enhanced expression of its target genes. In summary, CENPA function as a transcriptional regulator to promote HCC via cooperating with YY1. Targeting the CENPA-YY1-CCND1/NRP2 axis may provide candidate therapeutic targets for HCC.

Case Report: Successful conversion and salvage resection of huge hepatocellular carcinoma with portal vein tumor thrombosis and intrahepatic metastasis via sequential hepatic arterial infusion chemotherapy, lenvatinib plus PD-1 antibody followed by simultaneous transcatheter arterial chemoembolization, and portal vein embolization.

Background: Advanced hepatocellular carcinoma (HCC) shows poor prognosis. Combined hepatic artery infusion chemotherapy (HAIC) and lenvatinib and PD-1 antibody therapy show promising effects in treating advanced HCC, and salvage hepatectomy further promotes the overall survival in patients who were successfully converted after combined therapy. However, salvage major hepatectomy is not always amenable due to insufficient future liver remnant volume (FLV). Case presentation: We report the case of a 59-year-old man with a huge HCC as well as multiple intrahepatic foci and portal vein tumor thrombosis at his right hemi-liver. Genomic and pathologic analyses of HCC tissue revealed a TMB-high, TPS, and CPS-high cancer, with mutated DNA damage repair gene FANCC. These results suggested that this patient may benefit from chemotherapy and immunotherapy. Thus, he received combined HAIC, lenvatinib, and PD-1 antibody treatment and showed a quick and durable response. After successful downstaging, this patient was evaluated as not suitable for salvage hepatectomy due to the low FLV. He then received simultaneous transcatheter arterial chemoembolization (TACE) and portal vein embolization (PVE). The FLV increased to meet the criteria of salvage hepatectomy. Finally, this patient underwent right hemi-hepatectomy without any severe perioperative complications. In addition, no tumor recurrence occurred during the 9-month follow-up period after surgery. Conclusion: Combined HAIC, lenvatinib, and PD-1 antibody therapy, followed by simultaneous TACE and PVE, is a safe and effective conversion therapy that promotes tumor necrosis and increase FLV in patients with advanced HCC.

Case Report: Durable complete response of metastatic hepatocellular carcinoma with asymptomatic hyperamylasemia to combined immunotherapy of anti-cytotoxic T lymphocyte-associated antigen 4 plus anti-programmed cell death-1 antibodies.

Background: Combined immunotherapy has shown promising results in the treatment of advanced HCC, whereas the priority population that would respond to the combined immunotherapy is still elusive. In addition, HCC with asymptomatic hyperamylasemia was not reported previously. Case presentation: An aged patient was diagnosed as HCC with BCLC stage C (bone metastasis). Notably, this patient showed asymptomatic hyperamylasemia. The patient was then enrolled in a trial evaluating combined immunotherapy of anti-PD-1 antibody sintilimab (IBI308) plus anti-CTLA-4 antibody (IBI310) in advanced HCC. After being treated with combined immunotherapy, this patient rapidly achieved complete response (CR) according to mRECIST criteria or immune partial response (iPR) according to iRECIST criteria and maintain the CR state for more than 12 months. Interestingly, serum levels of amylase and lipase in this patient were reduced after treatment. Conclusion: We reported, for the first time, a case of metastatic HCC with asymptomatic hyperamylasemia, and suggested that HCC patients with asymptomatic hyperamylasemia may benefit from combined immunotherapy of anti-CTLA-4 and PD-1 antibodies.

IMOPAC: A web server for interactive multiomics and pharmacological analyses of patient-derived cancer cell lines.

Large-scale multidimensional cancer genomic and pharmacological profiles have been created by several large consortium projects, including NCI-60, GDSC and DepMap, providing novel opportunities for data mining and further understanding of intrinsic therapeutic response mechanisms. However, it is increasingly challenging for experimental biologists, especially those without a bioinformatic background, to integrate, explore, and analyse these tremendous pharmacogenomics. To address this gap, IMOPAC, an interactive and easy-to-use web-based tool, was introduced to provide rapid visualizations and customizable functionalities on the basis of these three publicly available databases, which may reduce pharmacogenomic profiles from cell lines into readily understandable genetic, epigenetic, transcriptionomic, proteomic, metabolomic, and pharmacological events. The user-friendly query interface together with customized data storage enables users to interactively investigate and visualize multiomics alterations across genes and pathways and to link these alterations with drug responses across cell lines from diverse cancer types. The analyses in our portal include pancancer expression, drug-omics/pathway correlation, cancer subtypes, omics-omics (cis-/trans-regulation) correlation, fusion query analysis, and drug response prediction analysis. The comprehensive multiomics and pharmacogenomic analyses with simple clicking through IMOPAC will significantly benefit cancer precision medicine, contribute to the discoveries of potential biological mechanisms and facilitate pharmacogenomics mining in the identification of clinically actionable biomarkers for both basic researchers and clinical practitioners. IMOPAC is freely available at http://www.hbpding.com/IMOPAC.

Tubular cell transcriptional intermediary factor 1γ deficiency exacerbates kidney injury-induced tubular cell polyploidy and fibrosis.

Tubulointerstitial fibrosis is considered the final convergent pathway of progressive chronic kidney diseases (CKD) regardless of etiology. However, mechanisms underlying kidney injury-induced fibrosis largely remain unknown. Recent studies have indicated that transcriptional intermediary factor 1γ (TIF1γ) inhibits the progression of fibrosis in other organs. Here, we found that TIF1γ was highly expressed in the cytoplasm and nucleus of the kidney proximal tubule. Interestingly, we found tubular TIF1γ expression was decreased in patients with CKD, including those with diabetes, hypertension, and IgA nephropathy, and in mouse models with experimental kidney fibrosis (unilateral ureteral obstruction [UUO], folic acid nephropathy [FAN], and aristolochic acid-induced nephrotoxicity). Tubule-specific knock out of TIF1γ in mice exacerbated UUO- and FAN-induced tubular cell polyploidy and subsequent fibrosis, whereas overexpression of kidney TIF1γ protected mice against kidney fibrosis. Mechanistically, in tubular epithelial cells, TIF1γ exerted an antifibrotic role via transforming growth factor-ß (TGF-ß)-dependent and -independent signaling. TIF1γ hindered TGF-ß signaling directly by inhibiting the formation and activity of the transcription factor Smad complex in tubular cells, and we discovered that TIF1γ suppressed epidermal growth factor receptor (EGFR) signaling upstream of TGF-ß signaling in tubular cells by ubiquitylating EGFR at its lysine 851/905 sites thereby promoting EGFR internalization and lysosomal degradation. Pharmacological inhibition of EGFR signaling attenuated exacerbated polyploidization and the fibrotic phenotype in mice with tubule deletion of TIF1γ. Thus, tubular TIF1γ plays an important role in kidney fibrosis by suppressing profibrotic EGFR and TGF-ß signaling. Hence, our findings suggest that maintaining homeostasis of tubular TIF1γ may be a new therapeutic option for treating tubulointerstitial fibrosis and subsequent CKD.

Bone Lesion-Derived Extracellular Vesicles Fuel Prometastatic Cascades in Hepatocellular Carcinoma by Transferring ALKBH5-Targeting miR-3190-5p.

Bone is the second leading metastatic site for hepatocellular carcinoma (HCC). Patients with HCC and bone metastasis suffer poor quality of life and reduced survival time. Extracellular vesicles (EVs) are widely involved in HCC formation and metastasis. However, the communication between primary HCC and bone lesions mediated by EVs remains unclear and the possible effect of bone metastasis on the progression of HCC remains largely unknown. Here, bone-metastasized HCC-derived EVs (BM-EVs) are found to localize to orthotropic HCC cells and promote HCC progression. Mechanistically, miR-3190-5p (miR-3190) is upregulated in intracellular HCC cells isolated from bone lesions as well as in their derived EVs. miR-3190 in BM-EVs is transferred into orthotopic tumor cells and enhances their metastatic capacity by downregulating AlkB homolog 5 (ALKBH5) expression. Decreased level of ALKBH5 exacerbates the prometastatic characteristics of HCC by modulating gene expression in N6-methyladenosine-dependent and -independent ways. Finally, antagomir-miR-3190-loaded liposomes with HCC affinity successfully suppress HCC progression in mice treated with BM-EVs. These findings reveal that BM-EVs initiate prometastatic cascades in orthotopic HCC by transferring ALKBH5-targeting miR-3190 and miR-3190 is serving as a promising therapeutic target for inhibiting the progression of HCC in patients with bone metastasis.

Hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals for cancer therapy.

Cancer stem cells (CSCs) have been recognized as the culprit for tumor progression, treatment resistance, metastasis, and recurrence while redox homeostasis represents the Achilles' Heel of CSCs. However, few drugs or formulations that are capable of elevating oxidative stress have achieved clinical success for eliminating CSCs. Here, we report hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanoparticles (CuET@HES NPs), which conspicuously suppress CSCs not only in vitro but also in numerous tumor models in vivo. Furthermore, CuET@HES NPs effectively inhibit CSCs in fresh tumor tissues surgically excised from hepatocellular carcinoma patients. Mechanistically, we uncover that hydroxyethyl starch stabilized copper-diethyldithiocarbamate nanocrystals via copper­oxygen coordination interactions, thereby promoting copper-diethyldithiocarbamate colloidal stability, cellular uptake, intracellular reactive oxygen species production, and CSCs apoptosis. As all components are widely used in clinics, CuET@HES NPs represent promising treatments for CSCs-rich solid malignancies and hold great clinical translational potentials. This study has critical implications for design of CSCs targeting nanomedicines.

A novel lonidamine derivative targeting mitochondria to eliminate cancer stem cells by blocking glutamine metabolism.

Cancer stem cells (CSCs) have been blamed as the main culprit of tumor initiation, progression, metastasis, chemoresistance, and recurrence. However, few anti-CSCs agents have achieved clinical success so far. Here we report a novel derivative of lonidamine (LND), namely HYL001, which selectively and potently inhibits CSCs by targeting mitochondria, with 380-fold and 340-fold lower IC50 values against breast cancer stem cells (BCSCs) and hepatocellular carcinoma stem cells (HCSCs), respectively, compared to LND. Mechanistically, we reveal that HYL001 downregulates glutaminase (GLS) expression to block glutamine metabolism, blunt tricarboxylic acid cycle, and amplify mitochondrial oxidative stress, leading to apoptotic cell death. Therefore, HYL001 displays significant antitumor activity in vivo, both as a single agent and combined with paclitaxel. Furthermore, HYL001 represses CSCs of fresh tumor tissues derived from liver cancer patients. This study provides critical implications for CSCs biology and development of potent anti-CSCs drugs.

Understanding the versatile roles and applications of EpCAM in cancers: from bench to bedside.

Epithelial cell adhesion molecule (EpCAM) functions not only in physiological processes but also participates in the development and progression of cancer. In recent decades, extensive efforts have been made to decipher the role of EpCAM in cancers. Great advances have been achieved in elucidating its structure, molecular functions, pathophysiological mechanisms, and clinical applications. Beyond its well-recognized role as a biomarker of cancer stem cells (CSCs) or circulating tumor cells (CTCs), EpCAM exhibits novel and promising value in targeted therapy. At the same time, the roles of EpCAM in cancer progression are found to be highly context-dependent and even contradictory in some cases. The versatile functional modules of EpCAM and its communication with other signaling pathways complicate the study of this molecule. In this review, we start from the structure of EpCAM and focus on communication with other signaling pathways. The impacts on the biology of cancers and the up-to-date clinical applications of EpCAM are also introduced and summarized, aiming to shed light on the translational prospects of EpCAM.

A Novel hepatocellular carcinoma specific hypoxic related signature for predicting prognosis and therapeutic responses.

Hypoxia is an important feature of the tumor microenvironment(TME) and is closely associated with cancer metastasis, immune evasion, and drug resistance. However, the precise role of hypoxia in hepatocellular carcinoma(HCC), as well as its influence on the TME, and drug sensitivity remains unclear. We found the excellent survival prediction value of Hypoxia_DEGs_Score model. In hypoxic HCC, somatic mutation, copy number variation, and DNA methylation were closely related to hypoxic changes and affected tumorigenesis, progression, metastasis, and drug resistance. In HCC, aggravated hypoxic stress was found to be accompanied by an immune exclusion phenotype and increased infiltration of immunosuppressive cells. In the validation cohort, patients with high Hypoxia_DEGs_Score were found to have worse immunotherapeutic outcomes and prognoses, and may benefit from drugs against cell cycle signaling pathways rather than those inhibiting the PI3K/mTOR pathway. Hypoxia_DEGs_Score has an excellent predictive capability of changes in the TME, the efficacy of immunotherapy, and the response of drugs. Therefore, Hypoxia_DEGs_Score can help develop personalized immunotherapy regimens and improve the prognosis of HCC patients.

TRIM proteins in hepatocellular carcinoma.

The tripartite motif (TRIM) protein family is a highly conserved group of E3 ligases with 77 members known in the human, most of which consist of a RING-finger domain, one or two B-box domains, and a coiled-coil domain. Generally, TRIM proteins function as E3 ligases to facilitate specific proteasomal degradation of target proteins. In addition, E3 ligase independent functions of TRIM protein were also reported. In hepatocellular carcinoma, expressions of TRIM proteins are both regulated by genetic and epigenetic mechanisms. TRIM proteins regulate multiple biological activities and signaling cascades. And TRIM proteins influence hallmarks of HCC. This review systematically demonstrates the versatile roles of TRIM proteins in HCC and helps us better understand the molecular mechanism of the development and progression of HCC.

Morphology-dependent photoresponsive behaviors of a self-assembled system based on a single cyanostilbene derivative.

In recent years, photoresponsive supramolecular self-assemblies have shown great potential in various fields. However, it is still a great challenge to integrate and control multiple photoresponsive behaviors in a self-assembled system. Herein, we design a novel cyanostilbene-based molecule VOE. In the aggregated state, it has different photoresponsive behaviors under different morphologies. When VOE molecules are dispersed in a 70% H2O/THF mixture, two different assembly morphologies are obtained as the aging time changes. One is weakly emissive nanoparticles with amorphous packing arrangements, and the other is highly emissive microbelts with well-ordered stacking modes. When they are irradiated with blue light (420 nm), the disordered assembly structure of nanoparticles leads to a [2+2] cycloaddition reaction, while a Z/E isomerization reaction occurs in ordered packed microbelts. Therefore, we can use a self-assembled system to generate two different morphologies, enabling completely different emissions and photoresponsive behaviors.

Confined-domain crosslink-enhanced emission effect in carbonized polymer dots.

Revealing the photoluminescence (PL) origin and mechanism is a most vital but challenging topic of carbon dots. Herein, confined-domain crosslink-enhanced emission (CEE) effect was first studied by a well-designed model system of carbonized polymer dots (CPDs), serving as an important supplement to CEE in the aspect of spatial interactions. The "addition-condensation polymerization" strategy was adopted to construct CPDs with substituents exerting different degrees of steric hindrance. The effect of confined-domain CEE on the structure and luminescence properties of CPDs have been systematically investigated by combining characterizations and theoretical calculations. Such tunable spatial interactions dominated the coupling strength of the luminophores in one particle, and eventually resulted in the modulated PL properties of CPDs. These findings provide insights into the structural advantages and the PL mechanism of CPDs, which are of general significance to the further development of CPDs with tailored properties.

DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6.

Discoidin domain receptor 1 (DDR1) is a member of the receptor tyrosine kinase family, and its ligand is collagen. Previous studies demonstrated that DDR1 is highly expressed in many tumors. However, its role in hepatocellular carcinoma (HCC) remains obscure. In this study, we found that DDR1 was upregulated in HCC tissues, and the expression of DDR1 in TNM stage II-IV was higher than that in TNM stage I in HCC tissues, and high DDR1 expression was associated with poor prognosis. Gene expression analysis showed that DDR1 target genes were functionally involved in HCC metastasis. DDR1 positively regulated the migration and invasion of HCC cells and promoted lung metastasis. Human Phospho-Kinase Array showed that DDR1 activated ERK/MAPK signaling pathway. Mechanically, DDR1 interacted with ARF6 and activated ARF6 through recruiting PSD4. The kinase activity of DDR1 was required for ARF6 activation and its role in metastasis. High expression of PSD4 was associated with poor prognosis in HCC. In summary, our findings indicate that DDR1 promotes HCC metastasis through collagen induced DDR1 signaling mediated PSD4/ARF6 signaling, suggesting that DDR1 and ARF6 may serve as novel prognostic biomarkers and therapeutic targets for metastatic HCC.