Prostate cancer (PCa) is one of the most common malignancies in men globally, with bone metastasis being a leading cause of death in advanced disease. Emerging evidence links methylcrotonyl-CoA carboxylase subunit 2 (MCC...Prostate cancer (PCa) is one of the most common malignancies in men globally, with bone metastasis being a leading cause of death in advanced disease. Emerging evidence links methylcrotonyl-CoA carboxylase subunit 2 (MCCC2) to the migratory and invasive capacities of PCa cells, but its regulatory mechanisms in bone metastasis and therapeutic potential remain unclear. Here, liquid chromatography-mass spectrometry identified LTBP1 as a direct interacting partner of MCCC2, validated by co-immunoprecipitation and GST pulldown assays. Functional studies demonstrated that MCCC2 promotes PCa cell migration, invasion in vitro, and bone metastasis in vivo. Mechanistically, MCCC2 competitively inhibits SMURF1-mediated ubiquitination and degradation of LTBP1, stabilizing LTBP1 to activate TGF-β signaling. Clinically, high MCCC2 expression correlates with elevated LTBP1 levels, increased bone metastasis incidence, and poor prognosis in PCa patients. These findings reveal that MCCC2 drives PCa bone metastasis via the LTBP1-TGF-β axis, highlighting MCCC2 as a promising therapeutic target for preventing or treating bone metastasis.
Immune checkpoint blockade (ICB) based therapy improved clinical outcomes in clear cell renal cell carcinoma (ccRCC), yet prognosis remains dismal in patients with advanced disease, especially those with sarcomatoid diff...Immune checkpoint blockade (ICB) based therapy improved clinical outcomes in clear cell renal cell carcinoma (ccRCC), yet prognosis remains dismal in patients with advanced disease, especially those with sarcomatoid differentiation. Tumor-associated macrophages (TAMs), abundantly infiltrating in the tumor immune microenvironment (TIME), emerge as regulators of tumor evolution and immune evasion. This study aims to characterize the clinical relevance, functional phenotypes, and therapeutic vulnerability of FN1 TAMs. We performed an integrated analysis across five cohorts to assess the clinical relevance of FN1 TAMs infiltration in ccRCC. Single-cell and spatial transcriptomics analyses characterized the transcriptomic profiles and spatial distribution of FN1 TAMs. Flow cytometry analysis further quantified the phenotype of FN1 TAMs and associated CD8 T cells features. Ex vivo functional assays using patient-derived tumors assessed the efficacy of FN1 blockade, as well as combination with PD-1 blockade. FN1 TAMs preferentially enriched in tumors with sarcomatoid differentiation and correlated with epithelial-mesenchymal transition (EMT) signatures. High infiltration of FN1 TAMs related to immunotherapy resistance and inferior survival outcomes in ccRCC. FN1 TAMs exhibited an M2-polarized immunosuppressive phenotype and were associated with CD8 T cells dysfunction. FN1 blockade reversed EMT-associated transcriptional programs, reduced immunosuppressive molecule expression in macrophages, and restored CD8 T cells effector function. Combination therapy targeting FN1 and PD-1 synergistically enhanced T cell cytotoxicity and tumor cell apoptosis. FN1 TAMs, enriched in sarcomatoid-differentiated ccRCC, mediate immune suppression and confer resistance to immunotherapy. FN1 blockade remodels the TIME, promotes tumor apoptosis, and represents a potential therapeutic strategy in ccRCC.
Ovarian clear cell carcinoma (OCCC) is a highly aggressive gynecological malignancy characterized by distinct clinicopathological features and resistance to chemotherapy. Despite advances in multi-omics characterization,...Ovarian clear cell carcinoma (OCCC) is a highly aggressive gynecological malignancy characterized by distinct clinicopathological features and resistance to chemotherapy. Despite advances in multi-omics characterization, the translational regulatory landscape of OCCC remains unexplored. Here, we performed ribosome profiling to systematically investigate translation control mechanisms in OCCC. We conducted an integrated analysis of transcriptomic and translatomic data from 22 clinical specimens. This study is the first to analyze translational dysregulation in OCCC at sub-codon resolution using translational group data resources. Integrated analysis identified novel unannotated open reading frames (ORFs) encoding functional micropeptides. Furthermore, we uncovered widespread translational dysregulation in OCCC, with experimental validation confirming the pro-tumorigenic role of translationally upregulated RBM4. This study bridges a critical gap between genomic, transcriptomic, and proteomic landscapes in OCCC, offering valuable mechanistic insights into its pathogenesis.
Oknin-Vaisman A, Panda D, Novak R
… +12 more, Kheshaiboun G, Bitman-Lotan E, Gandhesiri S, Kazi R, Pahor N, von Heyl Zu Herrnsheim V, Abu Ahmad Y, Kamnesky G, Mosler T, Diefenbacher ME, Brik A, Orian A
Aggressive and therapy-resistant cancers present a significant challenge to treatment and are associated with poor patients' survival. Identifying molecular pathways and compounds that target these pathways is critical f...Aggressive and therapy-resistant cancers present a significant challenge to treatment and are associated with poor patients' survival. Identifying molecular pathways and compounds that target these pathways is critical for improving patient outcomes. RNF4, an E3 Ubiquitin ligase, is pivotal for tumorigenesis in part by stabilizing oncoproteins and its role in DNA repair, thereby enhancing cancer cell survival and driving tumorigenesis. Elevated RNF4 levels are associated with poor prognosis in patients with carcinomas, melanoma, and sarcoma. Here, we describe the design and development of R4VPs, dual degrader compounds connecting two E3 ubiquitin ligases; Von Hippel-Lindau protein (VHL) with RNF4. R4VPs promote RNF4 degradation and thereby reduce the levels of its stabilized phosphorylated oncoproteins, while concomitantly eliminating VHL. R4VPs selectively induce ferroptotic cell death in cancer cells, sparing non-tumorigenic and primary cells in part by binding and modifying the anti-ferroptotic selanoproteins GPX4. R4VPs-induced ferroptosis preferentially targeting cells harboring tumor-driving mutations in the EGFR pathway, whereas it does not affect PI3K-transformed cells. As a consequence, R4VPs effectively induce cell death in Receptor Tyrosine Kinase inhibitor-resistant melanoma and primary patient sarcoma cells. Our findings highlight the potential of selective ferroptosis inducers, such as R4VPs, as a therapeutic strategy for hard-to-treat cancers.
AntiPD-1 immunotherapy improves survival in advanced hepatocellular carcinoma (HCC), but responses remain limited by the immunosuppressive, acidic tumor microenvironment (TME). We investigated whether intratumoral alkali...AntiPD-1 immunotherapy improves survival in advanced hepatocellular carcinoma (HCC), but responses remain limited by the immunosuppressive, acidic tumor microenvironment (TME). We investigated whether intratumoral alkalization with sodium bicarbonate could enhance PD-1 blockade. Bicarbonate-induced intracellular alkalization disrupted mitochondrial membrane potential, triggered rupture, and activated the cGAS-STING pathway via cytosolic mitochondrial DNA release, while simultaneously inducing immunogenic cell death (ICD). In murine models, intratumoral bicarbonate recruited and activated dendritic cells and T cells, suppressing tumor growth and synergizing with antiPD-1 therapy. In a prospective clinical study (ChiCTR2100053537), 28 patients with advanced-stage and 2 with intermediate-stage HCC received Tislelizumab plus intratumoral 5% sodium bicarbonate. The objective response rate was 93.3% (CR 53.3%, PR 40.0%); median progression-free survival was 31 months, and median overall survival was not reached. Treatment was well tolerated. Biopsies revealed significantly increased CD3⁺, CD4⁺, and CD8⁺ T-cell infiltration with combination therapy versus Tislelizumab alone. In line with our previous work, through this mitochondria-centered mechanism bicarbonate links metabolic reprogramming with innate and adaptive immune activation. Thus, intratumoral bicarbonate functions as a safe and accessible immunometabolic adjuvant that markedly enhances PD-1 blockade efficacy in HCC.
Colorectal cancer (CRC) represents the third most prevalent malignancy and the second leading cause of cancer mortality worldwide. Metabolic dysregulation is critically involved in CRC pathogenesis. Functional metabolomi...Colorectal cancer (CRC) represents the third most prevalent malignancy and the second leading cause of cancer mortality worldwide. Metabolic dysregulation is critically involved in CRC pathogenesis. Functional metabolomics aims to translate metabolite biomarkers into mechanistic insights. In this study, comprehensive metabolomic profiling of 1257 participants across discovery and validation cohorts identified β-hydroxybutyrate, carnitine, and acetylcarnitine as potential early diagnostic biomarkers for CRC. This panel demonstrated robust diagnostic performance, achieving 88.79% sensitivity and 95% specificity in an independent validation set of 400 samples. Utilizing an AOM/DSS-induced mouse model under control or high-fat diet conditions, elevated carnitine and acetylcarnitine levels were shown to originate primarily from dietary intake. In vivo and in vitro analyses revealed that these metabolites drive oncogenic metabolic reprogramming via upregulated CPT1A expression, thereby accelerating CRC progression. Immunoprecipitation assays indicated carnitine and acetylcarnitine treatment increased PPARγ while decreasing FXR expression. Conversely, the FXR agonist GW4064 or β-hydroxybutyrate elevated FXR and suppressed PPARγ. Furthermore, β-hydroxybutyrate counteracted the proliferative effects of carnitine and acetylcarnitine by activating FXR and modulating the PPARγ/PGC1α/CPT1A axis. Genetic silencing of CPT1A or β-hydroxybutyrate administration inhibited the PI3K/AKT pathway, restored intestinal barrier function, attenuated inflammation, and significantly suppressed CRC advancement. These findings elucidate a novel mechanism whereby β-hydroxybutyrate attenuates high-fat diet-associated CRC through FXR signaling modulation, revealing promising metabolic strategies for CRC prevention.
Colorectal carcinoma (CRC) remains a leading cause of cancer mortality, largely due to metastasis. Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that co...Colorectal carcinoma (CRC) remains a leading cause of cancer mortality, largely due to metastasis. Solid tumors, including CRC, must adapt to intratumoral hypoxia and oxidative stress, but the tumor-cell programs that couple these pressures to metastatic competence remain unclear. Across human CRC cohorts and cell lines, HIF-1α was coordinately upregulated and co-expressed with the metabolic effectors GLUT3 and fatty-acid synthase (FASN), most prominently in metastatic lesions. Using HIF-1α (HRE), SREBP1 (SRE), and NRF2 (ARE) transcriptional reporters, we identified HRE-high and SRE-high CRC subpopulations with enhanced clonogenicity and invasion that drove accelerated tumor growth and increased lung metastatic burden across multiple CRC models. Mechanistically, IGF1 and insulin signaling through IGF1R and AKT-mTOR increased HIF-1α and induced FASN and GLUT3, enabling lipogenic, glycolytic, and antioxidant programs to withstand hypoxic and oxidative stress. HIF-1α engaged an HRE-containing proximal region of the human FASN promoter independently of SREBP1. Stress assays revealed functional specialization: FASN promoted NRF2-associated antioxidant capacity and resistance to oxidative injury, whereas GLUT3 preferentially supported hypoxia tolerance. In vivo, lipid nanoparticle-encapsulated echinomycin rapidly suppressed HRE, SRE, and ARE activity, reduced peri-hypoxic induction of FASN and GLUT3, inhibited tumor growth, and eliminated lung metastasis. These findings define a growth factor-responsive, HIF-1α-centered stress-adaptive state and highlight HIF-1α transcriptional activity as a therapeutic target in metastatic CRC.
Genome-wide association studies (GWASs) have revealed the lung cancer susceptibility-associated non-coding SNP rs17728461 C/G. In this study, we demonstrated that rs17728461 is also associated with lung cancer outcome. T...Genome-wide association studies (GWASs) have revealed the lung cancer susceptibility-associated non-coding SNP rs17728461 C/G. In this study, we demonstrated that rs17728461 is also associated with lung cancer outcome. The risk G allele increases the proliferative index and motility of cancer cells and promotes cancer metastasis in vivo in a xenograft mouse model. Mechanistically, rs17728461-G establishes a physical interchromosomal interaction between the rs17728461-bearing DNA fragment and the RAB27A gene locus and thereby increases RAB27A expression and promotes subsequent exosome secretion. eQTL analysis and immunostaining revealed an association between rs17728461-G and increased RAB27A expression in human lung cancers. These findings reveal a noncoding SNP-mediated interchromosomal regulatory mechanism underlying lung cancer progression.
Alternative RNA splicing is a fundamental mechanism for enhancing proteomic diversity, and its dysregulation is a hallmark of cancer progression. However, the dynamic regulatory networks controlling oncogenic splicing ev...Alternative RNA splicing is a fundamental mechanism for enhancing proteomic diversity, and its dysregulation is a hallmark of cancer progression. However, the dynamic regulatory networks controlling oncogenic splicing events remain poorly understood. Our previous work identified the inclusion of CLSTN1 exon 11 as critical for the epithelial-to-mesenchymal transition (EMT). Here, we demonstrate that this splicing event promotes breast cancer metastasis by enhancing cell migration, invasion, and the generation of circulating tumor cells (CTCs) in vivo. To translate this finding into a therapeutic strategy, we developed splice-switching antisense oligonucleotides (ASOs) that effectively reverse exon 11 inclusion and suppress cancer cell migration. Furthermore, through systematic screening, we identified the RNA-binding protein TIA1 as a key suppressor of exon 11 inclusion. TIA1 inhibits EMT and metastasis, but its function is antagonized during EMT by phosphorylation mediated by the kinase DAPK3, which is upregulated in this process. This work defines a novel DAPK3-TIA1-CLSTN1 splicing axis that drives breast cancer metastasis, revealing new layers of post-transcriptional regulation and presenting promising therapeutic avenues for targeting pro-metastatic splicing.
Determining effective treatment strategies for prostate cancer patients with bone metastasis remains a difficult issue. Targeted engineered exosomes have the potential to deliver anticancer drugs to tumor sites in a high...Determining effective treatment strategies for prostate cancer patients with bone metastasis remains a difficult issue. Targeted engineered exosomes have the potential to deliver anticancer drugs to tumor sites in a highly efficient and precise manner while minimizing treatment-related side effects. Here, we assessed the function and value of targeted engineered exosomes loaded with circAKR1A1 (OE-circAKR1A1-exosomes) in bone metastatic prostate cancer cells. The function and underlying mechanism of OE-circAKR1A1-exosomes were investigated via in vivo and in vitro experiments. We observed a positive correlation between circAKR1A1 expression and prostate cancer metastasis and progression. Both in vivo and in vitro experiments confirmed that OE-circAKR1A1-exosomes specifically targeted prostate cancer cells in the bone microenvironment. This targeting mechanism activated the PI3K/Akt signalling pathway, thereby facilitating tumor invasion and metastasis. Collectively, our findings suggest that circAKR1A1 is a driver and treatment target for metastatic prostate cancer. Targeted delivery of therapeutic circRNAs via engineered exosomes represents a highly promising clinical therapeutic approach. The schematic diagram of this study E3 aptamer-modified engineered exosomes loaded with circAKR1A1 specifically target bone metastases in PCa, thereby activating the PI3K/Akt signalling pathway to facilitate tumor invasion and metastasis.
Prostate cancer (PCa) progression, particularly to castration-resistant prostate cancer (CRPC), is driven by androgen receptor (AR) reactivation and epigenetic alterations. Here, we identify lysine methyltransferase 2D (...Prostate cancer (PCa) progression, particularly to castration-resistant prostate cancer (CRPC), is driven by androgen receptor (AR) reactivation and epigenetic alterations. Here, we identify lysine methyltransferase 2D (KMT2D) as a critical epigenetic oncogene in PCa. KMT2D expression is elevated in PCa and correlates with poor prognosis. Mechanistically, KMT2D facilitates AR signaling by recruiting the pioneer factor FOXA1 to AR-specific enhancers, promoting chromatin accessibility and activating AR target genes. FOXA1 mutations impair this regulation, demonstrating their functional interplay. Furthermore, KMT2D-FOXA1-AR axis modulates ketone body metabolism via transcriptional control of HMGCS2, supporting tumor growth. Pharmacological inhibition of UTX, a COMPASS complex demethylase essential for KMT2D function, disrupts H3K4me1 deposition and suppresses AR signaling and tumor proliferation. Altogether, we characterize KMT2D as a key driver of AR-dependent PCa progression and propose UTX inhibition as a promising therapeutic strategy.
Lymphangiogenesis drives gastric cancer lymph node (GC LN) metastasis via neuro-immune-cancer interactions in the tumor microenvironment. However, the underlying mechanisms remain incompletely understood. Here, we demons...Lymphangiogenesis drives gastric cancer lymph node (GC LN) metastasis via neuro-immune-cancer interactions in the tumor microenvironment. However, the underlying mechanisms remain incompletely understood. Here, we demonstrate that chronic stress (CS) in GC patients correlates with poorer short-term prognosis, perineural/lymphovascular invasion, and advanced LN staging. Mechanistically, CS-induced neutrophil extracellular traps (NETs) are key mediators of LN metastasis. Inhibiting NETs suppressed popliteal LN metastasis and lymphangiogenesis. In vitro and in vivo experiments revealed that CS upregulated acetylcholine (ACh) and choline acetyltransferase (ChAT) levels, with ACh directly inducing NETs formation in a dose-dependently. Exogenous ACh increased LN metastasis (volume), whereas gastric vagotomy attenuated CS-mediated orthotopic tumor growth. Functional assays confirmed that ACh-driven NETs enhanced GC cell malignant behaviors, accelerated adhesive suspension state transformation via extracellular matrix remodeling, and activated a feedforward ACh-NGF axis. This triggered PKC-γ/STAT3-S100A8/A9-ROS cascade, mediating NETs formation and upregulating VEGFA/C. Protein analysis showed CD300ld overexpression in CSGC tissues, independent of ACh signaling. Notably, combined targeting of the NGF/TrkA and CD300ld exerted synergistic anti-LN metastatic and lymphangiogenic effects. Collectively, this study elucidates a CS-driven mechanism regulating NETs to promote GC LN metastasis and identifies NGF/TrkA and CD300ld as therapeutic targets for GC LN metastasis.
Mutations are highly prevalent in the TP53 tumor suppressor gene, which encodes p53, in lung adenocarcinoma (LUAD). However, targeted therapies centered on p53 mutations remain challenging. Here, we found MST4 highly exp...Mutations are highly prevalent in the TP53 tumor suppressor gene, which encodes p53, in lung adenocarcinoma (LUAD). However, targeted therapies centered on p53 mutations remain challenging. Here, we found MST4 highly expressed in LUAD and linked to patient survival. Functional assays using CRISPR-generated MST4-knockout LUAD cell lines revealed context-dependent dual roles of MST4: tumor-suppressive in wild-type p53 (wtp53) cells (inhibiting proliferation, colony formation, migration) and oncogenic in gain-of-function (GOF) p53 cells. Mechanistically, MST4 directly interacts with p53, competing with MDM2 to prevent K48-linked ubiquitination and degradation of both wtp53 and GOF-mutant p53, which explains cell-context-dependent phenotypes of MST4 suppression. Preclinically, targeting MST4 significantly repressed tumor formation of xenograft model with GOF-mutant p53. Collectively, our findings identify MST4 as a context-dependent regulator of LUAD, whose function is dictated by p53 mutation status. MST4 stabilizes p53 via a novel MDM2-competitive, kinase-independent mechanism, and targeting MST4 represents a promising therapeutic strategy for GOF-mutant p53-driven LUAD.
Schoeps B, Estermann S, Berchtold S
… +20 more, Beil J, Yurttas C, Mayr M, Volland A, Tort AG, Glatz MC, Martin F, Smirnow I, Klammsteiner N, Kloker LD, Smolle M, Nolden T, Rettenmaier R, Kleemann R, Schwaiger T, Petersson M, Elbers K, Knobbe-Thomsen C, Lauer UM, Das K
The sparking interest in oncolytic viruses (OV) faces challenges in clinical translation due to limitations of pre-clinical models and the lack of predictive biomarkers for OV activity. Furthermore, functional assays whi...The sparking interest in oncolytic viruses (OV) faces challenges in clinical translation due to limitations of pre-clinical models and the lack of predictive biomarkers for OV activity. Furthermore, functional assays which could determine permissivity of human tumors to OVs in a straightforward way are still lacking. Here, we present a novel ex vivo permissivity assay to precisely quantify replication of OVs in viable patient-derived tumors. As example, replication of reporter protein-expressing oncolytic VSV-GP variants was tracked via fluorescence, luminescence or qPCR across 133 patient-derived tumor samples (resection fragments/slices, biopsies) spanning more than 20 tumor entities. Based on the results of our comprehensive testing and by employing VSV-GP-NanoLuc-Katushka, we were able to establish a semi-automated permissivity assay with minimal hands-on time, allowing robust and real-time tracking of viral replication in patient-derived tumor samples. Given the urgent demand for innovative cancer treatments, this novel permissivity assay could be applied to select patients with tumors permissive to OV replication and might thus also show an enhanced clinical response.
Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been...Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been clarified. From our previous research, liver-specific SIRT1 knockout (LKO) mice developed hyperglycemia within two months and developed fatty liver with whole-body insulin resistance around nine months of age. When the mice's age extended to one year, they presented surprisingly higher lung tumor vulnerabilities in contrast to wild type as determined by macroscopic observation and histological examination. Interestingly, all lung tumors in these mice were classified as lung adenocarcinomas. Microarray analysis revealed elevated levels of MDM2, an oncoprotein, leading to the downregulation of its target genes such as p21 and GADD45. In vitro, the disruption of MDM2 leads to impaired cell cycle checkpoints and increased cell proliferation, which is accompanied by genomic instability, eventually causing full transformation in normal lung epithelia. In addition, the heat shock factor 1 (HSF1) transcription factor was found to regulate MDM2 directly and would decrease in the nucleus under high glucose conditions. Knockdown of HSF1 in the bronchial epithelial cell line (NL20) can increase MDM2 expression and cell proliferation. Human lung adenocarcinomas also displayed elevated MDM2 levels, with a correlation between MDM2 expression and lung cancer survival rates. Collectively, our findings suggest that liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through the HSF1-MDM2 pathway. Hyperglycemia may represent an underexplored cause of lung adenocarcinomas through impairment of cell cycle checkpoints, providing valuable insights for lung cancer prevention and future precision medicine.
The bone marrow (BM) microenvironment plays a key role in supporting B cell development. In acute lymphoblastic leukemia (B-ALL), the acquisition of oncogenic driver mutations blocks B cell differentiation at specific st...The bone marrow (BM) microenvironment plays a key role in supporting B cell development. In acute lymphoblastic leukemia (B-ALL), the acquisition of oncogenic driver mutations blocks B cell differentiation at specific stages. When these pre-leukemic cells acquire secondary mutations, B-ALL develops. However, the role of the BM microenvironment in pre-leukemic cell fate remains unknown. Here, using a murine model of spontaneous B-ALL development, we show that disrupted pre-BCR signaling in pre-leukemic cells modifies their fate. Blocking expression of the pre-BCR ligand Galectin-1 by the microenvironment impaired pre-leukemic cell proliferation and leukemia-initiating capacity. Consequently, B-ALL development was delayed, and B-ALL had a more mature phenotype, with cells expressing a BCR. Secondary mutations were also altered by changes to Galectin-1 expression. In its absence, mutations almost exclusively affected IL-7R signaling rather than both pre-BCR and IL-7R signaling. These results demonstrate that signals from bone marrow (BM) niches trigger leukemogenesis in cooperation with driver mutations and determine the fate of pre-leukemic B cells.
Elevated metabolites in the tumor microenvironment (TME), particularly lactic acid, create an immunosuppressive milieu that promotes immune escape and tumor progression. Dendritic cells (DCs) are pivotal in initiating an...Elevated metabolites in the tumor microenvironment (TME), particularly lactic acid, create an immunosuppressive milieu that promotes immune escape and tumor progression. Dendritic cells (DCs) are pivotal in initiating and regulating immune responses against tumors. However, the impact of lactic acid on DC death in the TME remains unclear. Our study reveals that lactic acid induces dose-dependent pyroptosis of bone marrow-derived DCs (BMDCs) through GSDMD cleavage. Mechanistically, this process involves monocarboxylate transporter 1(MCT1)-mediated signaling via the K/NLRP3/GSDMD axis, facilitating immune evasion and cancer progression. Furthermore, inhibiting MCT1 attenuated lactic acid-induced DC pyroptosis both in vitro and in vivo. These findings offer mechanistic insights into how lactic acid-mediated DC pyroptosis contributes to tumor immune evasion, suggesting potential targets for enhancing cancer therapies.
Cancer-associated fibroblasts (CAFs) are necessary constituents of the tumor microenvironment, significantly promoting cancer cell proliferation, invasion, and therapeutic resistance through the secretion of various fact...Cancer-associated fibroblasts (CAFs) are necessary constituents of the tumor microenvironment, significantly promoting cancer cell proliferation, invasion, and therapeutic resistance through the secretion of various factors. This study elucidates a novel metabolic-epigenetic mechanism by which glutathione peroxidase 8-positive (GPX8⁺) CAFs confer lenvatinib resistance in hepatocellular carcinoma (HCC). We demonstrate that GPX8 overexpression in CAFs activates the PI3K/AKT/mTOR signaling pathway by suppressing endoplasmic reticulum stress, driving glycolytic reprogramming and lactate production. HCC cells import this CAF-derived lactate via monocarboxylate transporter 1 (MCT1), elevating histone H3 lysine 18 lactylation (H3K18la) levels. Increased H3K18la enrichment at the promoter of bromodomain and PHD finger-containing protein 1 (BRPF1) transcriptionally upregulates BRPF1 expression. Furthermore, we found that BRPF1 mediates lenvatinib resistance in HCC by promoting H3K14ac and inducing activation of the EGFR pathway. Pharmacological inhibition of MCT1 (AZD3965) or BRPF1 (GSK5959), effectively reversed lenvatinib resistance in vitro and in vivo. These findings establish the GPX8⁺ CAF/lactate/MCT1/H3K18la/BRPF1/EGFR axis as a pivotal driver of lenvatinib resistance and identify MCT1 and BRPF1 as actionable therapeutic targets for overcoming resistance in HCC.
The identification of novel therapeutic targets and agents to overcome chemoresistance remains a central challenge in triple-negative breast cancer (TNBC). Here, we report three key innovations: the discovery of a novel...The identification of novel therapeutic targets and agents to overcome chemoresistance remains a central challenge in triple-negative breast cancer (TNBC). Here, we report three key innovations: the discovery of a novel oncogenic circRNA, circPARPBP, as a driver of chemoresistance; the elucidation of its mechanism through the recruitment of the SRCAP complex to activate CCL20 transcription and cancer stemness; and the demonstration that the natural compound isoliquiritigenin (ISL) effectively suppresses this axis to overcome chemoresistance. TNBC is the most aggressive subtype of breast cancer with poor prognosis and limited treatment options. In this study, we identified circPARPBP, a circRNA (hsa_circ_0000432) derived from PARPBP gene, which was aberrantly upregulated in TNBC tissues and cells. Clinically, the upregulation of circPARPBP was notably associated with TNBC chemoresistance. In vitro and in vivo experiments demonstrated that circPARPBP promoted TNBC progression and chemoresistance. Mechanistically, circPARPBP recruited the SNF2-related CBP activator protein (SRCAP) complex to activate C-C motif chemokine ligand 20 (CCL20) transcription and thus contributed to cancer stemness and chemoresistance. ISL, a key bioactive substance extracted from licorice root, effectively suppressed the circPARPBP-SRCAP-CCL20 signaling pathway. Notably, patient-derived xenograft models demonstrated that ISL treatment effectively overcame TNBC chemoresistance, with a superior benefit when in combination with conventional chemotherapy. Collectively, our study identifies circPARPBP as a novel regulator of TNBC progression and chemoresistance via SRCAP-mediated CCL20 activation, and provides a preclinical rationale for the clinical development of ISL as a potential therapy targeting this axis.
Li R, Ding R, Dan H
… +20 more, Du K, Zheng G, Wang S, Duan L, Wang P, Shen L, Feng L, Zhao P, Wang J, Feng D, Wu F, Yang Y, Zhou Z, Niu L, Wang W, Qiao X, Yang J, Feng F, Zheng J, Zhang J
Circadian disruption is linked to colorectal cancer (CRC) progression. We investigated the role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) in this context. Intestinal-specific Ndrg2 knockout exacer...Circadian disruption is linked to colorectal cancer (CRC) progression. We investigated the role of the tumor suppressor N-myc downstream-regulated gene 2 (NDRG2) in this context. Intestinal-specific Ndrg2 knockout exacerbated colorectal tumorigenesis in mice under circadian disruption. We identified NDRG2 as a novel stabilizer of the core clock protein Circadian Locomotor Output Cycles Kaput (CLOCK). Mechanistically, NDRG2 bidirectionally regulates CLOCK ubiquitination, inhibiting its degradation by the E3 ligase STIP1 Homology and U-Box Containing Protein 1 (STUB1) while promoting stabilization by the deubiquitinase Ubiquitin Specific Peptidase 8 (USP8). This NDRG2-CLOCK axis was crucial for oxaliplatin sensitivity. Integrated RNA sequencing and functional studies revealed that CLOCK transcriptionally represses Fibroblast Growth Factor 2 (FGF2), a chemoresistance driver. Thus, NDRG2 enhances CLOCK activity to suppress FGF2 and promote oxaliplatin efficacy. Clinically, oxaliplatin-sensitive CRC tissues showed higher NDRG2/CLOCK co-expression and lower FGF2 levels. Our work defines a pathway wherein NDRG2 inhibits tumorigenesis and chemoresistance by stabilizing CLOCK to transcriptionally represses FGF2, linking circadian regulation to therapy response, and nominating the NDRG2-STUB1/USP8-CLOCK-FGF2 axis as a therapeutic target.