Despite therapeutic advances, esophageal squamous cell carcinoma (ESCC) remains lethal due to metabolic adaptation via aerobic glycolysis. Here we report that VAV2 functions as an oncoprotein promoting this metabolic switch in ESCC. VAV2 overexpression enhances glycolytic flux—evidenced by increased glucose uptake, lactate production, and ECAR—while reducing oxygen consumption. Mechanistically, VAV2 upregulates EIF3F expression, enabling EIF3F to deubiquitinate and stabilize MTA1, which subsequently activates HIF-1α and its downstream targets GLUT1 and LDHA. EIF3F knockdown attenuates VAV2-driven oncogenic phenotypes and tumor progression in xenograft models, validating this axis as a functional dependency. This study uncovers a “signaling-deubiquitination-metabolism” regulatory nexus in ESCC and provides rationale for targeting VAV2-EIF3F interaction to overcome glycolysis-dependent therapy resistance.
BACKGROUND:Metabolic dysfunctions are associated with increased cancer morbidity and rapid tumor progression. The alpha1-oleate complex has been used successfully to treat bladder cancer in a placebo-controlled Phase II study. Studies of the related BAMLET complexes recently identified effects on metabolism, suggesting additional functions of the "HAMLET family" of tumoricidal complexes. AIMS:To investigate if intravesical alpha1-oleate treatment affects metabolism in bladder cancer tissue. MATERIALS AND METHODS:Samples were obtained from patients with NMIBC, enrolled in a placebo-controlled study of intravesical alpha1-oleate treatment [1]. Cells shed into the urine were harvested at each instillation and biopsies obtained at TURBT after six instillations of alpha1-oleate. The shed cells and biopsies were subjected to RNA sequencing and genome-wide transcriptomic analysis, and urine samples were analyzed using adipokine arrays. RESULTS:RNA sequencing detected significant inhibition of metabolic genes and networks in shed cells and tissue biopsies from alpha1-oleate treated patients, compared to the placebo group. Genes and gene networks regulating glucose and lipid synthesis were inhibited in alpha1-oleate treated patients, including ADIPOQ, which encodes the lipid- and glucose-regulating protein adiponectin and LEP, which encodes the metabolism and fat storage regulator Leptin. Leptin was further identified as an upstream regulator of the adiponectin response to alpha1-oleate and LEP and ADIPOQ networks showed strong interconnection in treated tissues. Analysis of shed tumor cells, suggested rapid kinetics of the metabolic response and urine levels of adiponectin and leptin were increased post-treatment, compared to pre-treatment samples and the shed tumor cells in urine contained adiponectin and leptin, as shown by immunohistochemistry. CONCLUSIONS:The findings identify potent local effects of alpha1-oleate treatment on tumor metabolism, after intravesical instillation. The metabolic regulators adiponectin and leptin were affected in tumor tissue and cells containing adiponectin and leptin were shed into the urine, potentially depleting the tumor of cells with high adipokine levels. These potent effects suggest a new molecular approach for targeting and inhibiting key regulators of cancer metabolism in superficial tumors. TRIAL REGISTRATION:Doubleblinded Phase I/II clinical trial (EudraCT 201600426914 NCT03560479, Registration Date 20180521).
BACKGROUND:Small cell lung cancer (SCLC) is a deadly cancer with few treatment options and poor prognosis, creating a dire need for improving therapies. Poly (ADP-ribose) polymerase inhibitors (PARPi) have been tested as a treatment strategy, but patient response varies. We aimed to identify novel approaches to sensitize SCLC to PARPi through a genome-wide CRISPR dropout screen. METHODS:Genome-wide CRISPR dropout screening was conducted in two SCLC cell lines using the PARPi, olaparib, as the selection pressure. Stable shRNA-mediated knockdown cell lines were validated by Western blotting and tested for olaparib sensitivity by assaying for cell viability. Synergy between PARPi and autophagy inhibition was tested by treating SCLC cell lines and analyzing cell viability using SynergyFinder+. The therapeutic strategy combining AZD5305 (PARPi) and GNS561 (novel autophagy inhibitor) was tested in cell line-derived xenograft mouse models. RESULTS:CRISPR screening identified the loss of mTOR negative regulators as a mechanism of PARPi sensitivity in SCLC, and knockdown of TSC1 and TSC2 sensitized SCLC cell lines to olaparib. Therapeutic strategies combining PARPi and autophagy inhibition demonstrated synergy in SCLC cell lines, and combination therapy with AZD5305 and GNS561 was effective in cell line-derived xenograft mouse models. CONCLUSIONS:Autophagy inhibition downstream of the mTOR pathway is a mechanism of PARPi sensitivity in SCLC. This suggests that a therapeutic combination of autophagy inhibition and PARPi is a promising treatment strategy in SCLC, paving the way for the adoption of novel treatments in this disease context.
BACKGROUND:Ovarian cancer (OV) is a leading cause of cancer-related mortality, with cisplatin resistance being a major clinical challenge. This study investigates the role of the Notch ligand DLL1 in mediating ferroptosis resistance and its impact on cisplatin sensitivity in OV. METHODS:Multi-omics data, clinical samples, and OV cell lines were used to assess DLL1 expression, its link to prognosis, and its effect on the Nrf2/GPX4 axis. CCK-8, clone formation, and ferroptosis assays evaluated the impact of DLL1 on cell behavior and cisplatin sensitivity. RESULTS:DLL1 was upregulated in OV tissues and correlated with poor prognosis. Its knockdown inhibited cell proliferation, migration, and EMT, while inducing ferroptosis, evidenced by increased lipid peroxidation and mitochondrial dysfunction. Mechanistically, DLL1 activated the Nrf2/GPX4 antioxidant axis. DLL1 depletion sensitized OV cells to cisplatin. In vivo, combining DLL1-targeted therapy with a ferroptosis inducer significantly reduced tumor growth in cisplatin-resistant models. CONCLUSION:DLL1 drives cisplatin resistance in OV by enhancing ferroptosis resistance via the Notch-Nrf2/GPX4 axis. Targeting DLL1 alongside ferroptosis induction represents a promising therapeutic strategy, positioning DLL1 as a potential biomarker and target in drug-resistant OV.
BACKGROUND:The incidence of colorectal cancer (CRC) is closely associated with prolonged exposure to fine particulate matter (PM 2.5) and tobacco carcinogens, 4-methylnitrosamino-l-3-pyridyl-butanone (NNK). However, due to a lack of understanding of its intricate pathological processes, there is currently no approved clinical medication or successful treatment plan. Also, tobacco carcinogens and PM 2.5 are implicated in the progression of CRC by the onset of a metabolic disorder. Nonetheless, direct evidence connecting the metabolic disorder to NNK/PM 2.5-mediated CRC development has yet to be developed. METHODS:We investigated CRC cells treated with NNK/PM 2.5 to investigate the function of metabolic alterations in CRC (NNK/PM 2.5)-induced tumor growth. The results were verified using human CRC cancer samples, cell-derived xenografts, and online survival analysis. To clarify the mechanism of regulation of changes in metabolism, metabolic tracking, western blotting, massarray assay, real-time PCR, and reporter assays were conducted. SPSS version 20.0 or GraphPad Prism version 10.0 were used for all statistical analyses. RESULTS:Our research indicates that NNK/PM 2.5, elicit characteristics of metabolic syndrome, notably hyperglycemia, decrease in reactive oxygen species (ROS) contents, and a substantial upregulation of anti-oxidative stress-related gene expression, thereby facilitating the progression of colon cancer in a murine model. By increasing the expression of glucose transporter 3 (GLUT3) and glucose transporter 1 (GLUT1), NNK/PM 2.5 increases the uptake of glucose in tumor-associated macrophages. This leads to the increased expression of insulin-like growth factor 2 (IGF2), which in turn paracrinely hyper-activates the insulin receptor (IR) in colorectal cancer cells, facilitating its nuclear import. Through IR/NPM1 mediation, nuclear IR and nucleophosmin (NPM1) interact to activate the CD274 promoter and produce programmed death ligand-1 (PD-L1). Inhibiting glycolysis, diminishing macrophages, or obstructing PD-L1 impedes NNK/PM 2.5-induced colorectal cancer growth. Analysis of patient samples and public databases reveals elevated expression of tumoral PD-L1 and phosphorylated insulin-like growth factor 1 receptor/insulin receptor (pIGF-1R/IR), as well as elevated levels of IGF2 and GLUT1 in tumor-associated macrophages, suggesting possible negative prognostic biomarkers for patients with colorectal cancer. CONCLUSIONS:Our results provided new insights into the mechanisms of intestinal cancer progresses by paracrine IR-PD-L1 signaling, which is aided by the deregulation of oxidative stress and macrophage communication brought on by smoking carcinogen-induced the metabolic syndrome.
