Oncogenesis最新文献

{"title":"Retraction Note: MEK inhibitors induce apoptosis via FoxO3a-dependent PUMA induction in colorectal cancer cells.","authors":"Lin Lin, Dapeng Ding, Yanmei Jiang, Yan Li, Shijun Li","doi":"10.1038/s41389-024-00543-0","DOIUrl":"10.1038/s41389-024-00543-0","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"41"},"PeriodicalIF":5.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of pancreatic cancer-specific protease substrates for protease-dependent targeted delivery.","authors":"Etienne J Slapak, Danny A Zwijnenburg, Jan Koster, Maarten F Bijlsma, C Arnold Spek","doi":"10.1038/s41389-024-00542-1","DOIUrl":"10.1038/s41389-024-00542-1","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) presents significant challenges due to the inadequacy of existing chemotherapeutics, which often result in toxicity-dependent dose limitations and premature cessation of therapy. Targeted delivery of therapeutic molecules offers a promising solution. Given that PDAC is marked by a desmoplastic reaction with extensive aberrant protease activity, protease-dependent targeted delivery could minimize off-target toxicities and is of increasing interest. The efficacy of targeted delivery hinges on the specificity of the substrates used; insufficient specificity can lead to off-target effects, reducing the advantage over non-targeted methods. Here, we employ an unbiased library approach to screen over 7 million peptide substrates for proteolytic cleavage by PDAC cell lysates, identifying 37 substrates enriched by at least 500-fold after three rounds of selection. As systemically administered targeted delivery depends on the absence of substrate cleavage in circulation, the peptide library was also screened against whole blood lysates, and enriched substrates were removed from the PDAC-enriched dataset to obtain PDAC-specific substrates. In vitro validation using FRET-peptides showed that 13 of the selected 15 substrates are cleaved by a panel of PDAC cell line lysates. Moreover, evaluation against healthy murine organ and human blood lysates to assess off-target cleavage revealed that the identified substrates are indeed PDAC-specific and that several substrates may be superior with respect to PDAC specificity over the CAPN2-responsive substrate, which has recently shown preclinical potential in targeted therapy, but future animal models should address the potential superiority. Overall, we thus identified substrates with high selectivity and sensitivity for PDAC that could be employed in protease-dependent targeted therapies.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"40"},"PeriodicalIF":5.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682267","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sertraline/chloroquine combination therapy to target hypoxic and immunosuppressive serine/glycine synthesis-dependent glioblastomas.","authors":"Anaís Sánchez-Castillo, Kim G Savelkouls, Alessandra Baldini, Judith Hounjet, Pierre Sonveaux, Paulien Verstraete, Kim De Keersmaecker, Barbara Dewaele, Benny Björkblom, Beatrice Melin, Wendy Y Wu, Rickard L Sjöberg, Kasper M A Rouschop, Martijn P G Broen, Marc Vooijs, Kim R Kampen","doi":"10.1038/s41389-024-00540-3","DOIUrl":"10.1038/s41389-024-00540-3","url":null,"abstract":"<p><p>The serine/glycine (ser/gly) synthesis pathway branches from glycolysis and is hyperactivated in approximately 30% of cancers. In ~13% of glioblastoma cases, we observed frequent amplifications and rare mutations in the gene encoding the enzyme PSPH, which catalyzes the last step in the synthesis of serine. This urged us to unveil the relevance of PSPH genetic alterations and subsequent ser/gly metabolism deregulation in the pathogenesis of glioblastoma. Primary glioblastoma cells overexpressing PSPH and PSPH^V116I showed an increased clonogenic capacity, cell proliferation, and migration, supported by elevated nucleotide synthesis and utilization of reductive NAD(P). We previously identified sertraline as an inhibitor of ser/gly synthesis and explored its efficacy at suboptimal dosages in combination with the clinically pretested chloroquine to target ser/gly^high glioblastoma models. Interestingly, ser/gly^high glioblastomas, including PSPH^amp and PSPH^V116I, displayed selective synergistic inhibition of proliferation in response to combination therapy. PSPH knockdown severely affected ser/gly^high glioblastoma clonogenicity and proliferation, while simultaneously increasing its sensitivity to chloroquine treatment. Metabolite landscaping revealed that sertraline/chloroquine combination treatment blocks NADH and ATP generation and restricts nucleotide synthesis, thereby inhibiting glioblastoma proliferation. Our previous studies highlight ser/gly^high cancer cell modulation of its microenvironment at the level of immune suppression. To this end, high PSPH expression predicts poor immune checkpoint therapy responses in glioblastoma patients. Interestingly, we show that PSPH amplifications in glioblastoma facilitate the expression of immune suppressor galectin-1, which can be inhibited by sertraline treatment. Collectively, we revealed that ser/gly^high glioblastomas are characterized by enhanced clonogenicity, migration, and suppression of the immune system, which could be tackled using combined sertraline/chloroquine treatment, revealing novel therapeutic opportunities for this subgroup of GBM patients.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"39"},"PeriodicalIF":5.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561346/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625213","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Condensate remodeling reorganizes innate SS18 in synovial sarcomagenesis.","authors":"Pengli Li, Ziwei Zhai, Yixin Fan, Wei Li, Minjing Ke, Xiaoxi Li, Huiru Gao, Yu Fu, Zhaoyi Ma, Wenhui Zhang, Hongyan Yi, Jin Ming, Yue Qin, Bo Wang, Junqi Kuang, Duanqing Pei","doi":"10.1038/s41389-024-00539-w","DOIUrl":"10.1038/s41389-024-00539-w","url":null,"abstract":"<p><p>SS18-SSX onco-fusion protein formed through aberrant chromosomal translocation t (X, 18; p11, q11), is the hallmark and plays a critical role in synovial sarcomagenesis. The recent works indicated that both the pathological SS18-SSX tumorigenic fusion and the corresponding intrinsic physiological SS18 protein can form condensates but appear to have disparate properties. The underlying regulatory mechanism and the consequent biological significance remain largely unknown. We show that the physical properties of oncogenic fusion protein SS18-SSX condensates within cells undergo alterations compared to the proto-oncogene protein SS18. By small-molecule screening and mutant assay, we identified the recognition of H2AK119ub histone modification could account for the distinctive properties of SS18-SSX1 condensates. Notably, we show that SS18-SSX1 condensates have impact on SS18 condensates and hijack that in a phase separation manner, resulting in the relocation of protein SS18 to the H2AK119ub modification targeted by SS18-SSX1. Consequently, this leads to the downregulation of tumor suppressor genes occupied by SS18 physiologically, like CAV1 and DAB2. These results reveal the underlying mechanism of genomic disorder and tumorigenesis caused by the remodeling of oncoprotein SS18-SSX1 condensates at the macroscopic level.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"38"},"PeriodicalIF":5.9,"publicationDate":"2024-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11519567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142522592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ubiquitin-specific protease 10 determines colorectal cancer outcome by modulating epidermal growth factor signaling via inositol polyphosphate-4-phosphatase type IIB.","authors":"Kateryna Kubaichuk, Timo Seitz, Ulrich Bergmann, Virpi Glumoff, Daniela Mennerich, Thomas Kietzmann","doi":"10.1038/s41389-024-00538-x","DOIUrl":"10.1038/s41389-024-00538-x","url":null,"abstract":"<p><p>Although there have been advances in understanding colorectal cancer (CRC) pathogenesis, significant gaps still exist, highlighting the need for deeper insights. Dysregulated protein homeostasis, including perturbations in the epidermal growth factor receptor (EGFR) pathway, remains a focal point in CRC pathogenesis. Within this context, the roles of ubiquitin ligases and deubiquitinases have attracted attention, but exploration of their precise contributions is still in its early stages. To address this gap, we investigated the involvement of the deubiquitinase USP10 in CRC. Our in vitro and in vivo study reveals a new paradigm in CRC biology and unravels a novel mechanistic axis, demonstrating for the first time the involvement of inositol polyphosphate 4-phosphatase type II B (INPP4B) in USP10-mediated CRC modulation. Specifically, our study demonstrates that the loss of USP10 results in reduced sensitivity to the EGFR tyrosine kinase inhibitors gefitinib and osimertinib. This is accompanied by a decrease in the activation of the AKT1/PKB pathway upon EGF stimulation, which is mediated by INPP4B. Importantly, in vivo xenograft experiments validate these findings and highlight the crucial role of USP10, particularly in conjunction with INPP4B, in driving CRC progression. The findings enhance our understanding of CRC pathobiology and reveal a new regulatory axis involving USP10 and INPP4B in CRC progression. This unique insight identifies USP10 and INPP4B as potential therapeutic targets in CRC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"37"},"PeriodicalIF":5.9,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11479595/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142406672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The branched N-glycan of PD-L1 predicts immunotherapy responses in patients with recurrent/metastatic HNSCC.","authors":"Huai-Cheng Huang, Yen-Lin Huang, Yi-Ju Chen, Hsin-Yi Wu, Chia-Lang Hsu, Hsiang-Fong Kao, Bin-Chi Liao, Min-Shu Hsieh, Neng-Yu Lin, Yu-Hao Liao, Hsin-Lin Chen, Chun-Nan Chen, Tseng-Cheng Chen, Cheng-Ping Wang, Tsung-Lin Yang, Min-Chuan Huang, Mei-Chun Lin, Pei-Jen Lou","doi":"10.1038/s41389-024-00532-3","DOIUrl":"10.1038/s41389-024-00532-3","url":null,"abstract":"<p><p>Immunotherapy has revolutionized cancer treatment, but the lack of a reliable predictive biomarker for treatment response remains a challenge. Alpha-1,6-Mannosylglycoprotein 6-β-N-Acetylglucosaminyltransferase 5 (MGAT5) is a key regulator of complex N-glycan synthesis, and its dysregulation is associated with cancer progression. The lectin Phaseolus vulgaris leukoagglutinin (PHA-L) specifically binds to mature MGAT5 products. Previous studies have indicated elevated PHA-L staining in head and neck squamous cell carcinoma (HNSCC), which implies increased activity of MGAT5. However, the specific role of MGAT5 in HNSCC remains unclear. In this study, we found significantly higher PHA-L staining and MGAT5 expression in HNSCC tumors compared to adjacent non-tumor tissues. Using a mass spectrometry (MS)-based glycoproteomic approach, we identified 163 potential protein substrates of MGAT5. Functional analysis revealed that protein substrates of MGAT5 regulated pathways related to T cell proliferation and activation. We further discovered that PD-L1 was among the protein substrates of MGAT5, and the expression of MGAT5 protected tumor cells from cytotoxic T lymphocyte (CTL) killing. Treatment of nivolumab alleviated the protective effects of MGAT5 on CTL activity. Consistently, patients with MGAT5-positive tumors showed improved responses to immunotherapy compared to those with MGAT5-negative tumors. Using purified PD-L1 from HNSCC cells and a glycoproteomic approach, we further deciphered that the N35 and N200 sites carry the majority of complex N-glycans on PD-L1. Our findings highlight the critical role of MGAT5-mediated branched N-glycans on PD-L1 in modulating the interaction with the immune checkpoint receptor PD-1. Consequently, we propose that MGAT5 could serve as a biomarker to predict patients' responses to anti-PD-1 therapy. Furthermore, targeting the branched N-glycans at N35 and N200 of PD-L1 may lead to the development of novel diagnostic and therapeutic approaches.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"36"},"PeriodicalIF":5.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11445275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361802","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NRF2 signaling plays an essential role in cancer progression through the NRF2-GPX2-NOTCH3 axis in head and neck squamous cell carcinoma.","authors":"Xiaoye Jin, Xiayuan Lou, Haoxiang Qi, Chao Zheng, Bo Li, Xuerong Siwu, Ren Liu, Qiaoli Lv, An Zhao, Jian Ruan, Ming Jiang","doi":"10.1038/s41389-024-00536-z","DOIUrl":"https://doi.org/10.1038/s41389-024-00536-z","url":null,"abstract":"<p><p>The activation of nuclear factor erythroid 2-related factor 2 (NRF2) has been observed in various cancers. Yet its exact contribution to the development of head and neck squamous cell carcinoma (HNSCC) remains undetermined. We previously found that NRF2 signaling is critical for the differentiation of squamous basal progenitor cells, while disruption of NRF2 causes basal cell hyperplasia. In this study, we revealed a correlation between elevated NRF2 activity and poor outcomes in HNSCC patients. We demonstrated that NRF2 facilitates tumor proliferation, migration, and invasion, as evidenced by both in vitro and in vivo studies. Significantly, NRF2 augments the expression of the antioxidant enzyme GPX2, thereby enhancing the proliferative, migratory, and invasive properties of HNSCC cells. Activation of GPX2 is critical for sustaining cancer stem cells (CSCs) by up-regulating NOTCH3, a key driver of cancer progression. These results elucidate that NRF2 regulates HNSCC progression through the NRF2-GPX2-NOTCH3 axis. Our findings proposed that pharmacological targeting of the NRF2-GPX2-NOTCH3 axis could be a potential therapeutic approach against HNSCC.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"35"},"PeriodicalIF":5.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437035/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351319","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"DKK1 as a chemoresistant protein modulates oxaliplatin responses in colorectal cancer.","authors":"Chi-Che Hsieh, Ting-Wei Li, Chun-Chun Li, Shang-Hung Chen, You-Lin Wei, Nai-Jung Chiang, Che-Hung Shen","doi":"10.1038/s41389-024-00537-y","DOIUrl":"https://doi.org/10.1038/s41389-024-00537-y","url":null,"abstract":"<p><p>Oxaliplatin is effective against colorectal cancer (CRC), but resistance hampers treatment. We found upregulated Dickkopf-1 (DKK1, a secreted protein) in oxaliplatin-resistant (OR) CRC cell lines and DKK1 levels increased by more than 2-fold in approximately 50% of oxaliplatin-resistant CRC tumors. DKK1 activates AKT via cytoskeleton-associated protein 4 (CKAP4, a DKK1 receptor), modulating oxaliplatin responses in vitro and in vivo. The leucine zipper (LZ) domain of CKAP4 and cysteine-rich domain 1 (CRD1) of secreted DKK1 are crucial for their interaction and AKT signaling. By utilizing the LZ protein, we disrupted DKK1 signaling, enhancing oxaliplatin sensitivity in OR CRC cells and xenograft tumors. This suggests that DKK1 as a chemoresistant factor in CRC via AKT activation. Targeting DKK1 with the LZ protein offers a promising therapeutic strategy for oxaliplatin-resistant CRC with high DKK1 levels. This study sheds light on oxaliplatin resistance mechanisms and proposes an innovative intervention for managing this challenge.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"34"},"PeriodicalIF":5.9,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142351318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TFCP2L1 drives stemness and enhances their resistance to Sorafenib treatment by modulating the NANOG/STAT3 pathway in hepatocellular carcinoma","authors":"Dongbo Qiu, Tiantian Wang, Yi Xiong, Kun Li, Xiusheng Qiu, Yuan Feng, Qinghai Lian, Yunfei Qin, Kunpeng Liu, Qi Zhang, Changchang Jia","doi":"10.1038/s41389-024-00534-1","DOIUrl":"https://doi.org/10.1038/s41389-024-00534-1","url":null,"abstract":"<p>Hepatocellular carcinoma (HCC) is a prevalent and aggressive malignancy associated with high risks of recurrence and metastasis. Liver cancer stem cells (CSCs) are increasingly recognized as pivotal drivers of these processes. In our previous research, we demonstrated the involvement of TFCP2L1 in maintaining the pluripotency of embryonic stem cells. However, its relevance to liver CSCs remains unexplored. In this study, we report an inverse correlation between TFCP2L1 protein levels in HCC tissue and patient outcomes. The knockdown of TFCP2L1 significantly reduced HCC cell proliferation, invasion, metastasis, clonal formation, and sphere-forming capacity, while its overexpression enhanced these functions. In addition, experiments using a nude mouse model confirmed TFCP2L1’s essential role in liver CSCs’ function and tumorigenic potential. Mechanistically, we showed that TFCP2L1 promotes the stemness of CSCs by upregulating NANOG, which subsequently activates the JAK/STAT3 pathway, thereby contributing to HCC pathogenesis. Importantly, we identified a specific small molecule targeting TFCP2L1’s active domain, which, in combination with Sorafenib, sensitizes hepatoma cells to treatment. Together, these findings underscore TFCP2L1’s pathological significance in HCC progression, supporting its potential as a prognostic biomarker and therapeutic target in this disease.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":""},"PeriodicalIF":6.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142189058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Dihydroartemisinin inhibits prostate cancer via JARID2/miR-7/miR-34a-dependent downregulation of Axl.","authors":"Juliano D Paccez, Kristal Duncan, Durairaj Sekar, Ricardo G Correa, Yihong Wang, Xuesong Gu, Manoj Bashin, Kelly Chibale, Towia A Libermann, Luiz F Zerbini","doi":"10.1038/s41389-024-00533-2","DOIUrl":"https://doi.org/10.1038/s41389-024-00533-2","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"32"},"PeriodicalIF":5.9,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11393321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142292657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}