TET2-STAT3-CXCL5 nexus promotes neutrophil lipid transfer to fuel lung adeno-to-squamous transition.

Phenotypic plasticity is a rising cancer hallmark, and lung adeno-to-squamous transition (AST) triggered by LKB1 inactivation is significantly associated with drug resistance. Mechanistic insights into AST are urgently needed to identify therapeutic vulnerability in LKB1-deficient lung cancer. Here, we find that ten-eleven translocation (TET)-mediated DNA demethylation is elevated during AST in KrasLSL-G12D/+; Lkb1L/L (KL) mice, and knockout of individual Tet genes reveals that Tet2 is required for squamous transition. TET2 promotes neutrophil infiltration through STAT3-mediated CXCL5 expression. Targeting the STAT3-CXCL5 nexus effectively inhibits squamous transition through reducing neutrophil infiltration. Interestingly, tumor-infiltrating neutrophils are laden with triglycerides and can transfer the lipid to tumor cells to promote cell proliferation and squamous transition. Pharmacological inhibition of macropinocytosis dramatically inhibits neutrophil-to-cancer cell lipid transfer and blocks squamous transition. These data uncover an epigenetic mechanism orchestrating phenotypic plasticity through regulating immune microenvironment and metabolic communication, and identify therapeutic strategies to inhibit AST.

Facet-Dependent Fe2O3/BiVO4(110)/BiVO4(010)/Fe2O3 Dual S-Scheme Photocatalyst as an Efficient Visible-Light-Driven Peroxymonosulfate Activator for Norfloxacin Degradation.

A lack of eco-friendly, highly active photocatalyst for peroxymonosulfate (PMS) activation and unclear environmental risks are significant challenges. Herein, we developed a double S-scheme Fe2O3/BiVO4(110)/BiVO4(010)/Fe2O3 photocatalyst to activate PMS and investigated its impact on wheat seed germination. We observed an improvement in charge separation by depositing Fe2O3 on the (010) and (110) surfaces of BiVO4. This enhancement is attributed to the formation of a dual S-scheme charge transfer mechanism at the interfaces of Fe2O3/BiVO4(110) and BiVO4(010)/Fe2O3. By introducing PMS into the system, photogenerated electrons effectively activate PMS, generating reactive oxygen species (ROS) such as hydroxyl radicals (·OH) and sulfate radicals (SO4·-). Among the tested systems, the 20% Fe2O3/BiVO4/Vis/PMS system exhibits the highest catalytic efficiency for norfloxacin (NOR) removal, reaching 95% in 40 min. This is twice the catalytic efficiency of the Fe2O3/BiVO4/PMS system, 1.8 times that of the Fe2O3/BiVO4 system, and 5 times that of the BiVO4 system. Seed germination experiments revealed that Fe2O3/BiVO4 heterojunction was beneficial for wheat seed germination, while PMS had a significant negative effect. This study provides valuable insights into the development of efficient and sustainable photocatalytic systems for the removal of organic pollutants from wastewater.

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.

EML4-ALK fusions drive lung adeno-to-squamous transition through JAK-STAT activation.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, exhibits strong cancer plasticity. We find that ALK rearrangement is detectable in 5.1-7.5% of human LUAS, and transgenic expression of EML4-ALK drives lung adenocarcinoma (LUAD) formation initially and squamous transition at late stage. We identify club cells as the main cell-of-origin for squamous transition. Through recapitulating lineage transition in organoid system, we identify JAK-STAT signaling, activated by EML4-ALK phase separation, significantly promotes squamous transition. Integrative study with scRNA-seq and immunostaining identify a plastic cell subpopulation in ALK-rearranged human LUAD showing squamous biomarker expression. Moreover, those relapsed ALK-rearranged LUAD show notable upregulation of squamous biomarkers. Consistently, mouse squamous tumors or LUAD with squamous signature display certain resistance to ALK inhibitor, which can be overcome by combined JAK1/2 inhibitor treatment. This study uncovers strong plasticity of ALK-rearranged tumors in orchestrating phenotypic transition and drug resistance and proposes a potentially effective therapeutic strategy.

Correction to: Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis.

[This corrects the article DOI: 10.1093/nsr/nwab232.].

Counteracting lineage-specific transcription factor network finely tunes lung adeno-to-squamous transdifferentiation through remodeling tumor immune microenvironment.

Human lung adenosquamous cell carcinoma (LUAS), containing both adenomatous and squamous pathologies, harbors strong plasticity and is significantly associated with poor prognosis. We established an up-to-date comprehensive genomic and transcriptomic landscape of LUAS in 109 Chinese specimens and demonstrated LUAS development via adeno-to-squamous transdifferentiation. Unsupervised transcriptomic clustering and dynamic network biomarker analysis identified an inflammatory subtype as the critical transition stage during LUAS development. Dynamic dysregulation of the counteracting lineage-specific transcription factors (TFs), containing adenomatous TFs NKX2-1 and FOXA2, and squamous TFs TP63 and SOX2, finely tuned the lineage transition via promoting CXCL3/5-mediated neutrophil infiltration. Genomic clustering identified the most malignant subtype featured with STK11-inactivation, and targeting LSD1 through genetic deletion or pharmacological inhibition almost eradicated STK11-deficient lung tumors. These data collectively uncover the comprehensive molecular landscape, oncogenic driver spectrum and therapeutic vulnerability of Chinese LUAS.

Oxidative stress-triggered Wnt signaling perturbation characterizes the tipping point of lung adeno-to-squamous transdifferentiation.

Lkb1 deficiency confers the Kras-mutant lung cancer with strong plasticity and the potential for adeno-to-squamous transdifferentiation (AST). However, it remains largely unknown how Lkb1 deficiency dynamically regulates AST. Using the classical AST mouse model (Kras LSL-G12D/+;Lkb1flox/flox, KL), we here comprehensively analyze the temporal transcriptomic dynamics of lung tumors at different stages by dynamic network biomarker (DNB) and identify the tipping point at which the Wnt signaling is abruptly suppressed by the excessive accumulation of reactive oxygen species (ROS) through its downstream effector FOXO3A. Bidirectional genetic perturbation of the Wnt pathway using two different Ctnnb1 conditional knockout mouse strains confirms its essential role in the negative regulation of AST. Importantly, pharmacological activation of the Wnt pathway before but not after the tipping point inhibits squamous transdifferentiation, highlighting the irreversibility of AST after crossing the tipping point. Through comparative transcriptomic analyses of mouse and human tumors, we find that the lineage-specific transcription factors (TFs) of adenocarcinoma and squamous cell carcinoma form a "Yin-Yang" counteracting network. Interestingly, inactivation of the Wnt pathway preferentially suppresses the adenomatous lineage TF network and thus disrupts the "Yin-Yang" homeostasis to lean towards the squamous lineage, whereas ectopic expression of NKX2-1, an adenomatous lineage TF, significantly dampens such phenotypic transition accelerated by the Wnt pathway inactivation. The negative correlation between the Wnt pathway and AST is further observed in a large cohort of human lung adenosquamous carcinoma. Collectively, our study identifies the tipping point of AST and highlights an essential role of the ROS-Wnt axis in dynamically orchestrating the homeostasis between adeno- and squamous-specific TF networks at the AST tipping point.

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Efficacy of compound aluminum sulfate injection as a monotherapeutic regimen in non-muscle invasive bladder cancer patients: a retrospective single-arm cohort study.

Background: Compound aluminum sulfate injection (CASI) originated from a Chinese traditional medicine, "Kuzhiye", and has been used in treating non-muscle invasive bladder cancer (NMIBC). Previous studies suggested that CASI was a potential monotherapeutic drug for NMIBC. However, the efficacy and safety of CASI in the treatment of NMIBC, as well as the long-term recurrence after treatment, need to be further evaluated. Methods: A multicenter retrospective single-arm cohort study was conducted. From 2006 to 2009, 101 patients (74 men and 27 women, aged 58.9±11.9 years) with T1 or benign NMIBC were enrolled. Each patient was directly injected with CASI through catheter needle into the root of NMIBC. Vital signs, electrocardiography, blood count, blood biochemistry, and urine analysis were re-examined on day 2 and day 14 after CASI injection, together with a cystoscopic examination 4 weeks after CASI treatment was performed for all patients to assess the clinical activity and safety of CASI. To study long-term efficacy, patients in center 2 were followed up for recurrence with a median follow-up time of 13.8 years. Results: For the 101 patients enrolled in this study, demographic characteristics in the 3 centers showed no significant differences. After CASI, 2 patients showed administration site-dependent, but not dose-dependent, increase in their aluminum concentration in 24 hours without obvious abnormality in blood biochemistry. The overall effective rate was 97.03%, including complete tumor necrosis in 94 patients. Treatment-related adverse events occurred in 20 patients (19.80%), including 9 drug-related and 11 cystoscopy-related adverse events (AEs). All AEs were endurable and disappeared within 2 weeks without any treatment. The maximum tolerated single dose of CASI was 21 mL. Among the 43 patients at center 2, 3 patients were excluded because they changed to other treatment regimen. As of April 2022, of the 40 patients enrolled, 22 had no recurrence and 7 relapsed. The follow-up time was 2-16.2 years. The other 11 patients were lost to follow up. Conclusions: CASI may be an effective and safe option for the treatment of NMIBC and is expected to be a potential monotherapy regimen for NMIBC.

Identification of TAZ as the essential molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Small-cell lung cancer (SCLC) is a recalcitrant cancer characterized by high metastasis. However, the exact cell type contributing to metastasis remains elusive. Using a Rb1 L/L /Trp53 L/L mouse model, we identify the NCAMhiCD44lo/- subpopulation as the SCLC metastasizing cell (SMC), which is progressively transitioned from the non-metastasizing NCAMloCD44hi cell (non-SMC). Integrative chromatin accessibility and gene expression profiling studies reveal the important role of the SWI/SNF complex, and knockout of its central component, Brg1, significantly inhibits such phenotypic transition and metastasis. Mechanistically, TAZ is silenced by the SWI/SNF complex during SCLC malignant progression, and its knockdown promotes SMC transition and metastasis. Importantly, ectopic TAZ expression reversely drives SMC-to-non-SMC transition and alleviates metastasis. Single-cell RNA-sequencing analyses identify SMC as the dominant subpopulation in human SCLC metastasis, and immunostaining data show a positive correlation between TAZ and patient prognosis. These data uncover high SCLC plasticity and identify TAZ as the key molecular switch in orchestrating SCLC phenotypic transition and metastasis.

Removal behavior and mechanisms of cadmium and lead by coupled ethylenediaminetetraacetic acid washing and electrochemical reduction: influence of current conditions.

Ethylenediaminetetraacetic acid (EDTA) washing has been used extensively to remediate heavy metal-contaminated soils. Electrochemical reduction treatment of spent washing solution is an effective method of EDTA regeneration. However, at present, these two technologies are usually regarded as two independent treatment processes. This research raised a new heavy metal-contaminated soil treatment strategy-a combination technique of coupled EDTA washing and electrochemical reduction. We speculated that the combination of EDTA washing and electroreduction treatment could improve the efficiency of Cd and Pb removal from contaminated soil. In this study, the removal performance and mechanisms of Cd and Pb under different current conditions were investigated based on a coupling of EDTA washing and electrochemical reduction. The combination technique can increase Cd and Pb removal efficiencies by 13.37-15.24% and 14.91-27.05%, respectively, compared with EDTA washing alone. Sequential extraction analysis showed that the reducible fraction improved metal removal efficiency. The percentage of metal removed increased with an increased current value and EDTA concentration. In addition, pulse current mode removed more Cd and Pb than continuous current, although the difference was not significant (p > 0.05). However, pulse current could effectively eliminate the cathodic hydrogen evolution reaction, resulting in a further heavy metal deposition at the cathode. The combination technique exhibited enhanced removal efficiency due to EDTA regeneration in the suspension and the cathodic reduction reaction. The most cost-effective treatment in 48 h was a pulse current mode of 32 min on/16 min off-32 mA-EDTA-10 mM, where 47.56% of Cd and 77.00% of Pb were removed from the soil with an electric energy consumption of 8.24 Wh.

Stem Cell Factor SOX2 Confers Ferroptosis Resistance in Lung Cancer via Upregulation of SLC7A11.

Ferroptosis is a lipid peroxidation-dependent cell death caused by metabolic dysfunction. Ferroptosis-associated enzymes are promising therapeutic targets for cancer treatment. However, such therapeutic strategies show limited efficacy due to drug resistance and other largely unknown underlying mechanisms. Here we report that cystine transporter SLC7A11 is upregulated in lung cancer stem-like cells (CSLC) and can be activated by stem cell transcriptional factor SOX2. Mutation of SOX2 binding site in SLC7A11 promoter reduced SLC7A11 expression and increased sensitivity to ferroptosis in cancer cells. Oxidation at Cys265 of SOX2 inhibited its activity and decreased the self-renewal capacity of CSLCs. Moreover, tumors with high SOX2 expression were more resistant to ferroptosis, and SLC7A11 expression was positively correlated with SOX2 in both mouse and human lung cancer tissue. Together, our study provides a mechanism by which cancer cells evade ferroptosis and suggests that oxidation of SOX2 can be a potential therapeutic target for cancer treatment. SIGNIFICANCE: This study uncovers a SOX2-SLC7A11 regulatory axis that confers resistance to ferroptosis in lung cancer stem-like cells.

Efficient catalytic ozonation of bisphenol A by three-dimensional mesoporous CeOx-loaded SBA-16.

Herein, we demonstrated the construction of three-dimensional (3D) cerium oxide (CeOx)/SBA-16 nanocomposites for efficient removal of bisphenol A (BPA) via a catalytic ozonation, with a high BPA mineralization up to 60.9% in 90 min. On one hand, the CeOx/SBA-16 mesoporous structured materials presented large surface area and uniform pore distribution, which was conducive to the adsorption of transformation by-products (TBPs) and then, the mass transfer. On the other hand, CeOx/SBA-16 could enhance the ozone utilization efficiency and meanwhile facilitate the formation of OH, the main reactive oxygen species. Through the exploration of dissoluble organic matters and the identification of the reaction intermediates, two BPA degradation pathways were proposed. This approach reported here will benefit the design and construction of mesoporous structured materials for catalytic elimination of hazards to remediate the environment.

Distinct mechanisms for TMPRSS2 expression explain organ-specific inhibition of SARS-CoV-2 infection by enzalutamide.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly become a global public health threat. The efficacy of several repurposed drugs has been evaluated in clinical trials. Among these drugs, a second-generation antiandrogen agent, enzalutamide, was proposed because it reduces the expression of transmembrane serine protease 2 (TMPRSS2), a key component mediating SARS-CoV-2-driven entry, in prostate cancer cells. However, definitive evidence for the therapeutic efficacy of enzalutamide in COVID-19 is lacking. Here, we evaluated the antiviral efficacy of enzalutamide in prostate cancer cells, lung cancer cells, human lung organoids and Ad-ACE2-transduced mice. Tmprss2 knockout significantly inhibited SARS-CoV-2 infection in vivo. Enzalutamide effectively inhibited SARS-CoV-2 infection in human prostate cells, however, such antiviral efficacy was lacking in human lung cells and organoids. Accordingly, enzalutamide showed no antiviral activity due to the AR-independent TMPRSS2 expression in mouse and human lung epithelial cells. Moreover, we observed distinct AR binding patterns between prostate cells and lung cells and a lack of direct binding of AR to TMPRSS2 regulatory locus in human lung cells. Thus, our findings do not support the postulated protective role of enzalutamide in treating COVID-19 through reducing TMPRSS2 expression in lung cells.

Nanog maintains stemness of Lkb1-deficient lung adenocarcinoma and prevents gastric differentiation.

Growing evidence supports that LKB1-deficient KRAS-driven lung tumors represent a unique therapeutic challenge, displaying strong cancer plasticity that promotes lineage conversion and drug resistance. Here we find that murine lung tumors from the KrasLSL-G12D/+ ; Lkb1flox/flox (KL) model show strong plasticity, which associates with up-regulation of stem cell pluripotency genes such as Nanog. Deletion of Nanog in KL model initiates a gastric differentiation program and promotes mucinous lung tumor growth. We find that NANOG is not expressed at a meaningful level in human lung adenocarcinoma (ADC), as well as in human lung invasive mucinous adenocarcinoma (IMA). Gastric differentiation involves activation of Notch signaling, and perturbation of Notch pathway by the γ-secretase inhibitor LY-411575 remarkably impairs mucinous tumor formation. In contrast to non-mucinous tumors, mucinous tumors are resistant to phenformin treatment. Such therapeutic resistance could be overcome through combined treatments with LY-411575 and phenformin. Overall, we uncover a previously unappreciated plasticity of LKB1-deficient tumors and identify the Nanog-Notch axis in regulating gastric differentiation, which holds important therapeutic implication for the treatment of mucinous lung cancer.

ERG orchestrates chromatin interactions to drive prostate cell fate reprogramming.

Although cancer is commonly perceived as a disease of dedifferentiation, the hallmark of early-stage prostate cancer is paradoxically the loss of more plastic basal cells and the abnormal proliferation of more differentiated secretory luminal cells. However, the mechanism of prostate cancer proluminal differentiation is largely unknown. Through integrating analysis of the transcription factors (TFs) from 806 human prostate cancers, we found that ERG was highly correlated with prostate cancer luminal subtyping. ERG overexpression in luminal epithelial cells inhibited those cells' normal plasticity to transdifferentiate into a basal lineage, and ERG superseded PTEN loss, which favored basal differentiation. ERG KO disrupted prostate cell luminal differentiation, whereas AR KO had no such effects. Trp63 is a known master regulator of the prostate basal lineage. Through analysis of 3D chromatin architecture, we found that ERG bound and inhibited the enhancer activity and chromatin looping of a Trp63 distal enhancer, thereby silencing its gene expression. Specific deletion of the distal ERG binding site resulted in the loss of ERG-mediated inhibition of basal differentiation. Thus, ERG, in its fundamental role in lineage differentiation in prostate cancer initiation, orchestrated chromatin interactions and regulated prostate cell lineage toward a proluminal program.