Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers because it is typically detected at an advanced stage, progresses rapidly, and resists current therapies. Consequently, early diagnostic biomarkers a...Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers because it is typically detected at an advanced stage, progresses rapidly, and resists current therapies. Consequently, early diagnostic biomarkers and novel therapeutic targets are urgently needed. Epithelial Cell Transforming Sequence 2 (ECT2) is a Rho family guanine nucleotide exchange factor that was originally identified as an oncoprotein and later shown to regulate cytokinesis. Here, we evaluated ECT2 expression in human PDAC and its functional requirement for transformed growth and tumorigenicity. We found that ECT2 expression is elevated early in PDAC tumorigenesis, remains high throughout progression, and correlates with poor patient survival. Furthermore, a significant pool of ECT2 is mis-localized in the cytoplasm of PDAC cells. Knockdown of ECT2 inhibited 3D-transformed growth, invasion, and in vivo tumor formation while having little impact on PDAC cell cytokinesis. Mechanistically, we found that ECT2 is required for activation of Rac1 and RhoA and downstream MEK/ERK and ROCK signaling, respectively. Consistent with these findings, analyses of PDAC patient datasets revealed a strong association between ECT2 expression and Rho GTPase as well as MEK/ERK and ROCK pathway signatures. Finally, genetic or pharmacologic targeting of ECT2 signaling enhanced PDAC cell sensitivity to MEK inhibition. Taken together, our data identify ECT2 as an early driver of PDAC transformation and highlight it as a promising therapeutic target.
Liang Y, Guo Y, Huang X
… +18 more, Wang Q, Wu Y, Ye H, Long Q, Pang M, Lei X, Jiang Y, Yin M, Chen Y, Zheng Y, Xu X, Yang Q, Yang J, Chen J, Chen J, Li H, Xie Y, Su W
Resistance to osimertinib in lung adenocarcinoma presents a significant hurdle in contemporary lung cancer therapy, with splicing dysregulation being instrumental in tumorigenesis and progression. The mechanism via which...Resistance to osimertinib in lung adenocarcinoma presents a significant hurdle in contemporary lung cancer therapy, with splicing dysregulation being instrumental in tumorigenesis and progression. The mechanism via which alternate splicing facilitates osimertinib resistance in lung cancer is still ambiguous. We aimed to examine the pivotal function of the splicing factor hnRNPA1 in osimertinib resistance in lung cancer. The impact of hnRNPA1 on osimertinib resistance in lung cancer was confirmed by small interfering RNA and CDX models. RNA-seq, RIP, CLIP-qPCR, and COIP methodologies were utilized to examine the mechanistic role of hnRNPA1 in osimertinib resistance in lung cancer. Furthermore, virtual docking was employed to evaluate natural small-molecule drugs that target hnRNPA1.Elevated levels of the splicing factor hnRNPA1 were detected in lung adenocarcinoma cells exhibiting resistance to osimertinib, and the silencing of hnRNPA1 enhanced the sensitivity of these resistant cells to osimertinib. Mechanistically, hnRNPA1 governs multiple splicing events linked to cancer, notably the splicing of NEDD4L. Decreased hnRNPA1 enhances the generation of short NEDD4L splice variants, resulting in the ubiquitination and degradation of EGFR, which sensitizes resistant cells to osimertinib. Moreover, hnRNPA1 undergoes methylation modification by PRMT7, which facilitates splicing activities. The research elucidated the mechanism responsible for aberrant splicing in osimertinib resistance in lung cancer and identified hnRNPA1 as a prospective therapeutic target for counteracting this resistance.
Lymphangiogenesis is essential for tumor lymphatic metastasis, yet the molecular mechanisms governing the activation of its key cytokine, VEGF-C, remain unclear. Herein, we identified a circRNA, circFOCAD, through VEGF-C...Lymphangiogenesis is essential for tumor lymphatic metastasis, yet the molecular mechanisms governing the activation of its key cytokine, VEGF-C, remain unclear. Herein, we identified a circRNA, circFOCAD, through VEGF-C maturation-associated multiple transcription sequencing. CircFOCAD is overexpressed in lymph node (LN)-metastatic bladder cancer (BCa) and is associated with poor prognosis. In footpad popliteal LN metastasis and orthotopic BCa models, circFOCAD enhances VEGF-C-dependent lymphangiogenesis and LN metastasis in BCa. Mechanistically, circFOCAD potentiates pro-VEGF-C cleavage by facilitating the expression of CCBE1 and its newly identified partner, the metalloprotease ADAM10. Specifically, circFOCAD promotes ADAM10 promoter H3K9 acetylation by recruiting YBX1. ADAM10 requires CCBE1 as a scaffold, binding at residue R301/R302, to interact with N-terminal propeptide of pro-VEGF-C at residue E58, provoking VEGF-C maturation and sustaining lymphangiogenesis in BCa. Clinically, neutralizing antibodies against CCBE1 and ADAM10 diminished the LN metastatic of BCa in a patient-derived xenograft (PDX) model. Our findings indicate that circFOCAD acts as an initiator of VEGF-C maturation and may represent a promising therapeutic target in LN metastatic BCa.
Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to improve early diagnosis and identify new treatments for advanced disease. Despite huge progress in understanding changes to the ge...Prostate cancer is a common cancer in males and there is an urgent unmet clinical need to improve early diagnosis and identify new treatments for advanced disease. Despite huge progress in understanding changes to the genome and proteome in prostate cancer, there is a relative delay in revealing the full aspects of the prostate cancer glycome and glycoproteome. Glycobiology has been fundamental in recent discoveries in the medical field, including translational cancer research. Glycans functionally contribute to the cancer hallmarks and serve as important diagnostic biomarkers and targets for therapeutic intervention. Changes to glycans are common in prostate cancer and include increased branching of complex N-glycans, changes in sialylation, increased fucosylation, altered PSA glycosylation and the expression of truncated O-glycans. This review discusses the role of glycans in fundamental mechanisms controlling prostate cancer growth, metastasis and immune evasion. Emphasis is placed on discoveries made during the last decade, including new insights provided by N-glycan imaging mass spectrometry (IMS) profiling of prostate cancer tissues, new discoveries into the role of aberrant glycosylation in prostate tumour biology, as well as recent studies investigating glycans, glycosyltransferase enzymes and glycan binding proteins as therapeutic targets.
In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a h...In recent years, new cases of thyroid cancer (TC) in China have accounted for about 10% of all newly diagnosed malignant tumors, ranking as the third most common cancer. Familial papillary thyroid carcinoma (fPTC) is a hereditary subtype for which large-scale clinical cohort studies are lacking and definitive susceptibility genes remain elusive. A large fPTC clinical cohort (171 cases), 490 sporadic papillary thyroid carcinoma (sPTC) patients, and 500 healthy blood samples from physical examination were collected in the study. Whole-genome sequencing (WGS) and whole-exome sequencing (WES) were used to screen for susceptibility genes. Three MCM2 gene mutations (c.1092 C > G, p.N364K; c.1975A>G, p.I659V; and c. 2379 G > A, p.M793I) in 8 patients from 4 distinct families were identified as candidate susceptibility variants. These mutations disrupt the interaction of MCM2 with its partner proteins (MCM3-7), leading to ubiquitination of free MCM monomers. Levels of DNA damage, γ-H2AX foci, RPA foci, and micronucleus formation were significantly elevated in MCM2-deficient cells. Cell-derived xenograft (CDX) modeling, combined with WES and RNA-seq analyses, revealed that MCM2-deficient tumors exhibited significantly faster growth rates and increased chromosomal instability (CIN). MAPK signaling and the PI3K-AKT pathway were significantly over-activated in MCM2-deficient tumors. In our study, based on the fPTC cohort, germline variants of MCM2 predispose to fPTC. The variants disrupt the MCM complex, leading to ubiquitination of free monomeric MCM proteins. MCM2 deficiency induces cell cycle arrest, DNA damage, and CIN, ultimately accelerating tumorigenesis through oncogenic pathway activation. These findings identify MCM2 as a low-frequency, moderately penetrant susceptibility gene for fPTC and underscore the clinical value of MCM2 testing in informing early detection, preventive management, and precision treatment strategies for familial papillary thyroid carcinoma.
Patients with advanced breast cancer (BC) often experience bone metastasis, leading to severe skeletal complications and a significant decline in prognosis. However, the molecular mechanisms underlying BC bone metastasis...Patients with advanced breast cancer (BC) often experience bone metastasis, leading to severe skeletal complications and a significant decline in prognosis. However, the molecular mechanisms underlying BC bone metastasis remain largely unexplored. This study identified the long non-coding RNA LCAL4 as specifically upregulated in bone-metastatic BC, where it serves as an independent predictor of poor survival. Gain- and loss-of-function experiments in intracardiac and intratibial mouse models demonstrate that ectopic LCAL4 expression markedly enhances BC cell-mediated osteolytic bone metastasis. Mechanistically, LCAL4 acts as a molecular scaffold, directly binding the RNA/DNA-binding protein FUS, promoting its nuclear accumulation, and recruiting it to the MMP13 promoter. The LCAL4-FUS ribonucleoprotein complex then recruits RNA polymerase II and induces H3K4me3 deposition, thereby activating MMP13 transcription. Secreted MMP13 stimulates osteoclast differentiation and enhances bone-resorptive activity. The release of TGF-β from resorbed bone further accelerates tumor proliferation, establishing a self-reinforcing cycle that drives osteolytic metastasis. Notably, genetic disruption of the LCAL4-FUS-MMP13 pathway significantly suppresses BC bone metastasis. These findings highlight the pivotal role of the LCAL4-FUS-MMP13 axis in BC skeletal colonization and osteolytic progression, highlighting its potential as a therapeutic target for managing BC bone metastasis.
Identification and characterization of novel mechanisms driving melanoma metastases and ways to target them are paramount for the development of effective treatment modalities. Here, we employed in vivo CRISPR knockout s...Identification and characterization of novel mechanisms driving melanoma metastases and ways to target them are paramount for the development of effective treatment modalities. Here, we employed in vivo CRISPR knockout screening targeting the genes associated with poor prognosis to identify Polr1a as a potent driver of melanoma metastasis. High Polr1a levels correlate with increased metastasis and reduced survival in patients. Polr1a inhibition suppressed migration, invasion, and the ability of melanoma cells to colonize lungs. Ribo-seq analysis revealed that Polr1a is involved in regulating the non-canonical NF-κB pathway. Indeed, targeting Polr1a decreased levels of RelB and p52 and suppressed non-canonical NF-κB transcriptional activity; this suppression was responsible for the effects of Polr1a on melanoma cell migration. Accordingly, pharmacological inhibition of Polr1/Polr1a suppressed cell migration, tumor growth, and metastases. We discuss the potential utilization of Polr1 inhibitors for neoadjuvant treatment of melanoma.
The low oxygen tension frequently found in tumors drives the expression of hypoxia-inducible factors (HIFs), thereby supporting rapid cancer cell proliferation and metastasis. Therefore, the prolonged expression of HIF-1...The low oxygen tension frequently found in tumors drives the expression of hypoxia-inducible factors (HIFs), thereby supporting rapid cancer cell proliferation and metastasis. Therefore, the prolonged expression of HIF-1α, the master regulator of the adaptation to hypoxia, is a crucial protective mechanism for solid tumor progression. Here we report that RNF122, the novel E3 ligase of HIF-1α, is a hypoxia responsive gene. Importantly, loss of RNF122 dramatically promoted breast cancer cell migration, invasion, and metastasis. In the presence of hypoxia, HIF-1α transcriptionally activates the expression of RNF122, which in turn directly interacts with HIF-1α in the cytoplasm, promoting its degradation through K27-linked polyubiquitination. Consequently, RNF122 suppresses the transcriptional activity of HIF-1α and its target gene expression, thereby inhibiting the glucose metabolism and angiogenesis of breast cancer cells under hypoxic condition. Clinically, copy number loss of RNF122 occurs in 39% of breast cancer patients, and the level of RNF122 is positively correlated with increased overall survival. Taken together, our findings discovered a negative feedback loop between RNF122 and HIF-1α that inhibits hypoxia-mediated tumorigenic activity, revealing a novel mechanism by which neoplastic cells sustain HIF-1α-dependent malignancy under hypoxic condition in RNF122-negative breast cancers.
Glioma is a highly aggressive central nervous system malignancy characterized by profound immune evasion, the underlying mechanisms of which remain incompletely defined. This study investigated how the transcription fact...Glioma is a highly aggressive central nervous system malignancy characterized by profound immune evasion, the underlying mechanisms of which remain incompletely defined. This study investigated how the transcription factor RBP-J drives immune suppression through activation of NNMT in cancer-associated fibroblasts (CAFs). By integrating single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST), we identified a CAF-specific NNMT-high subpopulation enriched at the tumor margin and closely associated with M2 macrophages. Bioinformatic analyses using Seurat and Monocle3 delineated a stromal-immune regulatory network and highlighted RBP-J as a potential upstream regulator of NNMT. Mechanistic experiments demonstrated that RBP-J directly binds to the NNMT promoter and activates its transcription, leading to intracellular SAM depletion, reduced H3K27me3 levels, and epigenetic upregulation of SAA3. Elevated SAA3 promoted M2 macrophage recruitment and polarization, resulting in CD8 T cell exhaustion and immune suppression. In vivo experiments using an orthotopic glioma model confirmed that NNMT-high CAFs accelerated tumor growth, increased M2 macrophage infiltration, and diminished CD8 T cell activity. Importantly, combined treatment with an NNMT inhibitor and αPD-1 partially reversed the immunosuppressive microenvironment and significantly enhanced therapeutic efficacy. Collectively, this study identifies the RBP-J/NNMT/SAA3 axis as a critical stromal-driven mechanism of immune evasion in glioma and provides a rationale for targeting metabolic-epigenetic pathways to improve immunotherapy outcomes. Schematic Diagram Illustrating the Molecular Mechanism by Which RBP-J Promotes Immune Evasion in Glioma via Activation of NNMT in CAFs, Leading to H3K27 Demethylation-Mediated Upregulation of SAA3 and Subsequent Reprogramming of M2 Macrophages.
Conventional immune checkpoint inhibitors (ICIs) remain largely ineffective in microsatellite-stable metastatic colorectal cancer (MSS mCRC), where low tumor immunogenicity and molecular heterogeneity across metastatic s...Conventional immune checkpoint inhibitors (ICIs) remain largely ineffective in microsatellite-stable metastatic colorectal cancer (MSS mCRC), where low tumor immunogenicity and molecular heterogeneity across metastatic sites underpin therapeutic resistance. We present a comprehensive transcriptomics analysis of metastatic and primary tumor biopsies from MSS mCRC patients treated with botensilimab (BOT; Fc-enhanced anti-CTLA-4) ± balstilimab (BAL; anti-PD-1). Self-organizing map (SOM) machine learning stratified tumors into four molecular types, including a liver-like (LIV) subtype characterized by metabolic reprogramming and immunosuppressive signatures, and proliferative (PRO), inflammatory (INF), and mesenchymal (MES) types concordant with pan-cancer classifications. PRO, INF, and MES types were enriched for epithelial tumor cells, immune cells, and fibroblasts, respectively, defining immune-depleted, immune-enriched, and fibrotic states along a plasticity gradient. We observed treatment-related transcriptomic shifts toward immune-enriched states via upregulation of antigen presentation, T cell recruitment, and cytotoxicity pathways. INF and MES tumor types exhibited improved clinical responses and survival vs PRO and LIV types. This study identified distinct tumor microenvironment states that align along an immunophenotype axis marked by CD74, interferon-γ, and APOBEC3 expression identified previously for primary CRC. Our findings provide novel insights into molecular correlates of immunotherapy response in MSS mCRC, potentially informing future therapeutic strategies to expand ICI efficacy to historically unresponsive tumors.
Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistoche...Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistochemistry and western blot revealed high expression of AREG in CRC tumors compared to other CRCs. Our findings indicate that AREG translocates into the nucleus, a process potentially facilitated by the inhibition of endocytosis. Transcriptomic analyses suggest an association between AREG expression and genes regulating EGFR signaling, replication fork dynamics, and homologous recombination. Depletion of AREG via siRNA or CRISPR-Cas9 led to S/G₂ arrest, replication tract shortening, and increased RAD51, RPA, and γH2AX foci, resulting in a 40-60% reduction in proliferation effects that were not fully recapitulated by small-molecule EGFR inhibitors. In xenograft models, AREG knockout reduced tumor growth and suppressed the phosphorylation of EGFR, ERK, STAT3, and BRAF. Furthermore, combining AREG loss with EGFR inhibition appeared to enhance antitumor effects. These findings suggest that AREG may function as a mediator of EGFR signaling and genome maintenance in CRC.
Venetoclax-based therapies have revolutionized acute myeloid leukemia (AML) treatment, yet disease progression remains a challenge due to limited response and acquired drug resistance. Identifying molecular drivers of AM...Venetoclax-based therapies have revolutionized acute myeloid leukemia (AML) treatment, yet disease progression remains a challenge due to limited response and acquired drug resistance. Identifying molecular drivers of AML progression and resistance is essential for improving therapeutic outcomes. Genes normally silenced in normal tissues but aberrantly activated in cancers, such as Cancer-Testis (CT) genes, are promising targets for cancer diagnostics and therapy. Through a CRISPR screen focused on CT genes and cancer-associated genes exhibiting a CT-like expression profile (CT-like gene), we identified the ATPase TRIP13 as critical for AML progression while dispensable for normal hematopoiesis in genetic mouse models. Mechanistically, we discovered that TRIP13 localizes to mitochondria, where it interacts with apoptosis-inducing factor (AIF), a component of respiratory complex I. This interaction promotes leukemia progression and confers drug resistance by preventing AIF translocation to the nucleus, thereby reducing apoptotic priming and shifting energy metabolism from glycolysis to oxidative phosphorylation (OXPHOS) coupled with increased fatty acid oxidation (FAO). Genetic or pharmacological disruption of the TRIP13-AIF interaction suppressed OXPHOS, reduced leukemia cell viability, and overcame venetoclax resistance in vitro and in vivo. These findings uncover a novel mechanism by which AML cells exploit germline programs to sustain progression and resist therapy, positioning the TRIP13-AIF interaction as a promising therapeutic target for AML.
'Liver injury-liver fibrosis/cirrhosis-liver cancer' is the key evolution pathway of hepatocellular carcinoma (HCC), chronic inflammation serving as a major driving force in this process. However, the regulatory mechanis...'Liver injury-liver fibrosis/cirrhosis-liver cancer' is the key evolution pathway of hepatocellular carcinoma (HCC), chronic inflammation serving as a major driving force in this process. However, the regulatory mechanisms underlying this process require further clarification. Here, the carcinogen-induced liver injury, liver fibrosis, and HCC models were investigated in the wild-type and STK39-knockout mice. Mass spectrometry analysis and immunoprecipitation assays were used to identify the interaction factors of STK39. QPCR, ELISA, and immunofluorescence were applied for the expression of inflammatory factors. In this study, we report that STK39 is gradually upregulated during the evolution of HCC (liver injury-liver fibrosis-liver cancer). Consequently, overexpression of STK39 further encouraged the evolution of HCC by facilitating a macrophage inflammatory response, as demonstrated in carcinogen-induced liver injury, liver fibrosis, and HCC models. Pharmacological inhibition of STK39 significantly slows the progression of HCC; however, this effect was considerably diminished after macrophage clearance. Mechanistically, mass spectrometry analysis and immunoprecipitation assays identified that STK39 interacted with PKR and promoted the activation of the PKR/NF-κB axis. Which, in turn, enhanced the macrophage inflammatory response and accelerated the evolution of HCC. The inflammatory factor TNF-α further induces the expression of STK39, suggesting a positive feedback regulation process exists. More notably, STK39 inhibition improves the efficacy of sorafenib and anti-PD1 therapy. In conclusions, our study reveals that STK39 holds significant potential for the early diagnosis and treatment of HCC.
Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in cancer, but how APA functions in tumorigenesis remains elusive. We analyzed APA events in osteosarcoma...Alternative polyadenylation (APA), an important post-transcriptional regulatory mechanism, is aberrantly activated in cancer, but how APA functions in tumorigenesis remains elusive. We analyzed APA events in osteosarcoma (OS) tissues and identified 3' UTR alterations associated with both OS patient prognosis and gene expression changes involving loss of tumor-suppressive miRNA binding sites. In OS tumors, MTERF3 3' UTRs were recurrently shortened and MTERF3 mRNA levels were upregulated, and indicated poor prognosis. OS cells with shorter MTERF3 3' UTRs displayed elevated proliferation, migration, and invasion ability compared to the cells with control or longer MTERF3 3' UTR. Moreover, system correlation analysis revealed that CPSF2 is a candidate upstream regulator of MTERF3 3' UTR length. Mechanistically, CPSF2 favored use of the proximal poly (A) site in the 3' UTR of MTERF3, resulting in a short-3' UTR MTERF3 isoform that produced more MTERF3 protein due to loss of miR-182-5p binding sites. The shortened MTERF3 3' UTR disrupted competing endogenous RNA (ceRNA) cross-talk, resulting in downregulation of the tumor suppressor gene ADCY6. Collectively, these findings demonstrate that CPSF2-mediates MTERF3 3' UTR shortening through APA to promote OS tumor progression.
High-grade serous ovarian cancer (HGSOC) remains one of the most common and lethal gynecological malignancies. Distinct gene expression molecular subtypes (GEMS) of HGSOC, with associated differences in outcome, have pre...High-grade serous ovarian cancer (HGSOC) remains one of the most common and lethal gynecological malignancies. Distinct gene expression molecular subtypes (GEMS) of HGSOC, with associated differences in outcome, have previously been described: Epithelial-A (Epi-A)/C3/Differentiated, Epithelial-B (Epi-B)/C2/Immunoreactive, Stem-like B (Stem-B)/C6, Mesenchymal (Mes)/C1, and Stem-like A (Stem-A)/C5/Proliferative. Notably, the Mes and Stem-A OC subtypes are associated with more advanced-stage tumors and poorer clinical outcomes, representing a molecular subtype of unmet clinical need. Hallmarks of HGSOC also include a high prevalence of genomic instability and increased replication stress. In this study, we demonstrate that HGSOC Mes/Stem-A (MSA) cell lines exhibit elevated levels of replication stress and increased sensitivity to ATR inhibitors. Additionally, through DNA fiber analysis, we observed significantly higher replication fork rates and ssDNA accumulation in MSA subtype cells. Consistent with the high levels of replication stress identified in these subtypes, MSA patient-derived xenograft models further validated the therapeutic vulnerability to ATR inhibition. The characteristic replication stress profile of the MSA subtype suggests its utility as a candidate biomarker for identifying patients most likely to benefit from ATR inhibition.
Despite aggressive multimodal therapy, including cytotoxic chemotherapy, surgery, and radiation, the prognosis for patients with Ewing sarcoma remains poor, particularly for those with metastatic or relapsed disease. Com...Despite aggressive multimodal therapy, including cytotoxic chemotherapy, surgery, and radiation, the prognosis for patients with Ewing sarcoma remains poor, particularly for those with metastatic or relapsed disease. Combining agents that increase DNA replication stress with ATR-CHK1-WEE1 pathway inhibitors, which disrupt the DNA damage response and cell cycle checkpoints, is a promising strategy under clinical investigation in Ewing sarcoma and other cancers. However, the mechanisms by which these drug combinations selectively kill cancer cells under replication stress remain incompletely understood and are often attributed, without strong supporting evidence in many tumor types, to forced mitotic entry. In this study, we show that inhibition of the ATR-CHK1-WEE1 pathway in S-phase-arrested Ewing sarcoma cells triggers rapid apoptosis within 2-4 h, without widespread mitotic entry. This apoptotic response is driven by the activation of cyclin-dependent kinase 1 (CDK1) and is caspase-dependent. We further show that dual targeting of DNA replication and ATR-CHK1-WEE1 signaling in Ewing sarcoma tumors suppresses protein synthesis, and inhibition of protein synthesis prevents cell cycle progression and premature mitotic entry-providing a mechanistic explanation for why aberrant CDK1 activation does not drive mitosis in this context. Moreover, while apoptosis is induced rapidly following drug treatment, the suppression of protein synthesis is prolonged and persists beyond drug removal, suggesting distinct early and late mechanisms of drug-induced toxicity. Collectively, these findings define a unique CDK1- and caspase-dependent apoptotic pathway in response to replication stress and offer new insights into the molecular basis of this therapeutic vulnerability in Ewing sarcoma.
Despite substantial advances in targeting KRAS, tumor acquired resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergenc...Despite substantial advances in targeting KRAS, tumor acquired resistance to KRAS inhibitors (KRASi) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRASi resistance. Multi-omics profiling of resistant models revealed a chronic activation of the integrated stress response (ISR) and a concomitant upregulation of asparagine synthesis. We found that the ISR-inducible transcription factor ATF3 was upregulated and directly transactivated asparagine synthetase (ASNS), driving asparagine production. Genetic ablation of ATF3 or ASNS restored KRASi sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRASi resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRASi to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRAS inhibitor resistance.
Gaspar Lopes J, Markovic A, Champy CM
… +13 more, Aubourg N, Mathieu JR, Alberti F, Soyeux-Porte P, Drame K, Louarn M, Jamet T, Huc R, de la Taille A, Dutertre CA, Destouches D, Vacherot F, Firlej V
Worldwide, prostate cancer (PCa) ranks second in terms of incidence and eighth in terms of mortality. While most cancers remain silent after initial treatment, some tumors recur. At present, we are unable to predict whic...Worldwide, prostate cancer (PCa) ranks second in terms of incidence and eighth in terms of mortality. While most cancers remain silent after initial treatment, some tumors recur. At present, we are unable to predict which patients are at risk of recurrence. In order to determine this risk of recurrence as early as at the biopsy stage, and to enable better therapeutic management of patients, it is essential to identify new biomarkers. In this study, we have demonstrated that Cysteine Dioxygenase CDO1 could be a predictive marker in PCa progression. Transcriptomic analysis showed that CDO1 expression is significantly reduced in patients who have relapsed and lower CDO1 expression is associated with poorer survival outcomes. In PCa, CDO1 expression could be regulated by methylation and androgen signaling pathway. Furthermore, inhibition of CDO1 expression in VCaP prostate cancer cells led to increased cell migration and non-adherent growth. Finally, transcriptomic analysis of these cells with inhibited CDO1 expression demonstrates the complex role of CDO1 and its possible involvement in the mechanisms regulating endoplasmic reticulum stress and protein unfolding. Altogether, these results describe the loss of CDO1 as a marker of aggressiveness in PCa. Furthermore, the loss of CDO1 is thought to be responsible for tumor progression in vitro by acting on multiple signaling pathways.
Colorectal cancer (CRC) remains the third most common malignancy and a leading cause of cancer-related mortality worldwide. Despite immunotherapy advances, most CRCs respond poorly to immune checkpoint inhibitors due to...Colorectal cancer (CRC) remains the third most common malignancy and a leading cause of cancer-related mortality worldwide. Despite immunotherapy advances, most CRCs respond poorly to immune checkpoint inhibitors due to their immunologically "cold" phenotype characterized by low immunogenicity and a suppressive tumor microenvironment. Oxidative stress has emerged as a critical determinant of antitumor immunity, with excessive reactive oxygen species (ROS) triggering immunogenic cell death, releasing tumor-associated antigens and damage-associated molecular patterns. However, endogenous mechanisms linking ROS regulation to innate immune activation remain incompletely understood. Here, we identify a previously unreported mitochondria-associated long non-coding RNA, lncRNA 606938, whose expression is inversely correlated with CRC progression. Mechanistically, lncRNA 606938 is exported from the nucleus via the HuR-IGF2BP2 complex and translocated to mitochondria through the mitochondrial targeting sequence and HMG2 domains of mitochondrial transcription factor A (TFAM). Within mitochondria, lncRNA 606938 enhances oxidative phosphorylation (OXPHOS) by upregulating mitochondrial DNA-encoded OXPHOS subunits, leading to excessive ROS production. In addition, lncRNA 606938 facilitates the recognition of N6-methyladenosine (mA) sites on TFAM mRNA by IGF2BP2, thereby enhancing its stability and expression, further reinforcing mitochondrial oxidative stress. The elevated ROS induces mitochondrial damage and cytosolic release of mitochondrial DNA, which activates the cGAS-STING pathway and stimulates innate immune responses, ultimately suppressing tumor growth. Collectively, our findings highlight lncRNA 606938 as a novel upstream regulator of mitochondrial metabolism and innate immune activation, providing new insights into lncRNA-mediated reprogramming of the tumor immune microenvironment and uncovering a potential therapeutic strategy to sensitize CRC to immunotherapy.