Cell Death & Disease最新文献

{"title":"The cytoplasmic-nuclear transport of DDX3X promotes immune-mediated liver injury in mice regulated by endoplasmic reticulum stress.","authors":"Zihao Fan, Ling Xu, Yao Gao, Yaling Cao, Yuan Tian, Zhenzhen Pan, Linlin Wei, Sisi Chen, Xiangying Zhang, Mei Liu, Feng Ren","doi":"10.1038/s41419-024-07076-9","DOIUrl":"10.1038/s41419-024-07076-9","url":null,"abstract":"<p><p>Immune-mediated liver injury is a common characteristic of various liver diseases, including autoimmune and viral hepatitis. Here, we investigated the role of DEAD-box helicase 3, X-linked (DDX3X) in immune-mediated liver injury. Liver injury was induced in C57BL/6J mice via concanavalin A (Con A). DDX3X hepatocyte-specific knockout (DDX3X^ΔHep) mice and control (DDX3X^fl/fl) mice were utilized to investigate the role of DDX3X in liver injury. Primary hepatocytes were treated with tunicamycin (TM) to induce ER stress in vitro. The expression of DDX3X in patients with various liver diseases was evaluated. Hepatic DDX3X expression increased, and DDX3X translocated from the cytoplasm to the nucleus during Con A-induced liver injury. DDX3X deficiency ameliorated mouse liver injury and reduced ER stress in liver tissue. The inhibition of ER stress with 4-PBA significantly attenuated liver injury while decreasing DDX3X levels in liver tissue. However, the upregulation of hepatic DDX3X expression reversed Con A-induced liver injury and negated the protective effect of 4-PBA. Mechanistically, the nuclear translocation of DDX3X promoted ER stress-induced apoptosis through the transcriptional induction of CHOP. Moreover, DDX3X was elevated and translocated into the nucleus in patients with HBV-LF and AIH. Additionally, serum DDX3X levels markedly increased in patients with HBV-LF, and a consistent decrease in DDX3X was associated with a good prognosis. The cytoplasmic-to-nuclear translocation of DDX3X promotes ER stress-induced apoptosis, which is an obligatory step that drives hepatic necrosis and tissue damage. Notably, DDX3X is a potential therapeutic target for immune-mediated liver injury.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442484/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342379","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC00887 promotes GCN5-dependent H3K27cr level and CRC metastasis via recruitment of YEATS2 and enhancing ETS1 expression.","authors":"Meijian Liao, Wendan Zheng, Yifan Wang, Mengting Li, Xiaolin Sun, Nan Liu, Jia Yao, Fuxing Dong, Qingling Wang, Yu Ma, Jie Mou","doi":"10.1038/s41419-024-07091-w","DOIUrl":"10.1038/s41419-024-07091-w","url":null,"abstract":"<p><p>Recent observations have revealed upregulation of H3K27cr in colorectal cancer (CRC) tissues; however, the underlying cause remains elusive. This study aimed to investigate the mechanism of H3K27cr upregulation and its roles in CRC metastasis. Clinically, our findings showed that H3K27cr served as a highly accurate diagnostic marker to distinguish CRC tissues from healthy controls. Elevated levels of LINC00887 and H3K27cr were associated with a poorer prognosis in CRC patients. Functionally, LINC00887 and H3K27cr facilitated the migration and invasion of CRC cells. Mechanistically, LINC00887 interacted with SIRT3 protein. Overexpressed of LINC00887 obstructed the enrichment of SIRT3 within GCN5 promoter, thereby elevating H3K27ac but not H3K27cr level within this region, subsequently activating GCN5 expression. This activation increased the global level of H3K27cr, promoting the enrichment of GCN5, H3K27cr, and YEATS2 within ETS1 promoter, activating ETS1 transcription and ultimately promoting the metastasis of CRC. The in vivo study demonstrated that inhibition of LINC00887 suppressed CRC metastasis, but this inhibitory effect was nullified when mice were treated with NaCr. In conclusion, our results confirmed the diagnostic biomarker potential of H3K27cr in individuals with CRC, and proposed a functional model to elucidate the involvement of LINC00887 in promoting CRC metastasis by elevating H3K27cr level.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11443008/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Treating ICB-resistant cancer by inhibiting PD-L1 via DHHC3 degradation induced by cell penetrating peptide-induced chimera conjugates.","authors":"Yu-Ying Shi, Gang Fan, Ruirong Tan, Shan Li, Hua-Bing Sun, Rui Li, Mengni Yang, Shanshan Gao, Miao Liu, Meng-Yuan Dai","doi":"10.1038/s41419-024-07073-y","DOIUrl":"10.1038/s41419-024-07073-y","url":null,"abstract":"<p><p>The current selection of ligands for both proteins of interest (POI) and E3 ubiquitin ligase significantly restricts the scope of targeted protein degradation (TPD) technologies. This study introduces cell-penetrating peptide-induced chimera conjugates (cp-PCCs) targeting the DHHC3 enzyme involved in PD-L1 palmitoylation. This approach disrupts PD-L1's immunosuppressive function, enhancing anti-tumor immunity. We developed cp-PCCs to degrade DHHC3, directly linking DHHC3-mediated PD-L1 palmitoylation to PD-L1 stability on tumor cells. Our research utilized both in vitro assays and in vivo experiments in immune checkpoint blockade-resistant mouse models. We focused on a CRBN-based cp-PCC named PCC16, which demonstrated a DC50 of 102 nmol for DHHC3 degradation and significantly reduced PD-L1 levels. In resistant models, PCC16 not only robustly downregulated PD-L1 but also exhibited substantial anti-tumor activity in vivo without significant toxicity. This outperformed traditional inhibitors, showcasing the potential of cp-PCC technology to bypass current PROTAC limitations. Our findings suggest that cp-PCCs offer a promising method for targeting PD-L1 through DHHC3 inhibition and support their continued exploration as a versatile tool in cancer immunotherapy, especially for tumors resistant to standard treatments.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442653/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342392","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted therapy of cancer stem cells: inhibition of mTOR in pre-clinical and clinical research.","authors":"Boram Son, Wonhwa Lee, Hyeonjeong Kim, Heungsoo Shin, Hee Ho Park","doi":"10.1038/s41419-024-07077-8","DOIUrl":"10.1038/s41419-024-07077-8","url":null,"abstract":"<p><p>Cancer stem cells (CSCs) are a type of stem cell that possesses not only the intrinsic abilities of stem cells but also the properties of cancer cells. Therefore, CSCs are known to have self-renewal and outstanding proliferation capacity, along with the potential to differentiate into specific types of tumor cells. Cancers typically originate from CSCs, making them a significant target for tumor treatment. Among the related cascades of the CSCs, mammalian target of rapamycin (mTOR) pathway is regarded as one of the most important signaling pathways because of its association with significant upstream signaling: phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) pathway and mitogen‑activated protein kinase (MAPK) cascade, which influence various activities of stem cells, including CSCs. Recent studies have shown that the mTOR pathway not only affects generation of CSCs but also the maintenance of their pluripotency. Furthermore, the maintenance of pluripotency or differentiation into specific types of cancer cells depends on the regulation of the mTOR signal in CSCs. Consequently, the clinical potential and importance of mTOR in effective cancer therapy are increasing. In this review, we demonstrate the association between the mTOR pathway and cancer, including CSCs. Additionally, we discuss a new concept for anti-cancer drug development aimed at overcoming existing drawbacks, such as drug resistance, by targeting CSCs through mTOR inhibition.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11442590/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ACSL4-mediated lipid rafts prevent membrane rupture and inhibit immunogenic cell death in melanoma.","authors":"Xi Zhao, Zenglu Zhao, Bingru Li, Shuyu Huan, Zixi Li, Jianlan Xie, Guoquan Liu","doi":"10.1038/s41419-024-07098-3","DOIUrl":"10.1038/s41419-024-07098-3","url":null,"abstract":"<p><p>Chemotherapy including platinum-based drugs are a possible strategy to enhance the immune response in advanced melanoma patients who are resistant to immune checkpoint blockade (ICB) therapy. However, the immune-boosting effects of these drugs are a subject of controversy, and their impact on the tumor microenvironment are poorly understood. In this study, we discovered that lipid peroxidation (LPO) promotes the formation of lipid rafts in the membrane, which mediated by Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4) impairs the sensitivity of melanoma cells to platinum-based drugs. This reduction primarily occurs through the inhibition of immunogenic ferroptosis and pyroptosis by reducing cell membrane pore formation. By disrupting ACSL4-mediaged lipid rafts via the removal of membrane cholesterol, we promoted immunogenic cell death, transformed the immunosuppressive environment, and improved the antitumor effectiveness of platinum-based drugs and immune response. This disruption also helped reverse the decrease in CD8⁺ T cells while maintaining their ability to secrete cytokines. Our results reveal that ACSL4-dependent LPO is a key regulator of lipid rafts formation and antitumor immunity, and that disrupting lipid rafts has the potential to enhance platinum-based drug-induced immunogenic ferroptosis and pyroptosis in melanoma. This novel strategy may augment the antitumor immunity of platinum-based therapy and further complement ICB therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11439949/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SETD8 inhibition targets cancer cells with increased rates of ribosome biogenesis.","authors":"Matilde Murga, Gema Lopez-Pernas, Robert Soliva, Elena Fueyo-Marcos, Corina Amor, Ignacio Faustino, Marina Serna, Alicia G Serrano, Lucía Díaz, Sonia Martínez, Carmen Blanco-Aparicio, Marta Elena Antón, Brinton Seashore-Ludlow, Joaquín Pastor, Rozbeh Jafari, Miguel Lafarga, Oscar Llorca, Modesto Orozco, Oscar Fernández-Capetillo","doi":"10.1038/s41419-024-07106-6","DOIUrl":"10.1038/s41419-024-07106-6","url":null,"abstract":"<p><p>SETD8 is a methyltransferase that is overexpressed in several cancers, which monomethylates H4K20 as well as other non-histone targets such as PCNA or p53. We here report novel SETD8 inhibitors, which were discovered while trying to identify chemicals that prevent 53BP1 foci formation, an event mediated by H4K20 methylation. Consistent with previous reports, SETD8 inhibitors induce p53 expression, although they are equally toxic for p53 proficient or deficient cells. Thermal stability proteomics revealed that the compounds had a particular impact on nucleoli, which was confirmed by fluorescent and electron microscopy. Similarly, Setd8 deletion generated nucleolar stress and impaired ribosome biogenesis, supporting that this was an on-target effect of SETD8 inhibitors. Furthermore, a genome-wide CRISPR screen identified an enrichment of nucleolar factors among those modulating the toxicity of SETD8 inhibitors. Accordingly, the toxicity of SETD8 inhibition correlated with MYC or mTOR activity, key regulators of ribosome biogenesis. Together, our study provides a new class of SETD8 inhibitors and a novel biomarker to identify tumors most likely to respond to this therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11438997/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342376","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered molecular and cellular mechanisms in KIF5A-associated neurodegenerative or neurodevelopmental disorders.","authors":"Marta Cozzi, Stefania Magri, Barbara Tedesco, Guglielmo Patelli, Veronica Ferrari, Elena Casarotto, Marta Chierichetti, Paola Pramaggiore, Laura Cornaggia, Margherita Piccolella, Mariarita Galbiati, Paola Rusmini, Valeria Crippa, Jessica Mandrioli, Davide Pareyson, Chiara Pisciotta, Stefano D'Arrigo, Antonia Ratti, Lorenzo Nanetti, Caterina Mariotti, Elisa Sarto, Viviana Pensato, Cinzia Gellera, Daniela Di Bella, Riccardo M Cristofani, Franco Taroni, Angelo Poletti","doi":"10.1038/s41419-024-07096-5","DOIUrl":"10.1038/s41419-024-07096-5","url":null,"abstract":"<p><p>Mutations targeting distinct domains of the neuron-specific kinesin KIF5A associate with different neurodegenerative/neurodevelopmental disorders, but the molecular bases of this clinical heterogeneity are unknown. We characterised five key mutants covering the whole spectrum of KIF5A-related phenotypes: spastic paraplegia (SPG, R17Q and R280C), Charcot-Marie-Tooth disease (CMT, R864*), amyotrophic lateral sclerosis (ALS, N999Vfs*40), and neonatal intractable myoclonus (NEIMY, C975Vfs*73) KIF5A mutants. CMT-R864*-KIF5A and ALS-N999Vfs*40-KIF5A showed impaired autoinhibition and peripheral localisation accompanied by altered mitochondrial distribution, suggesting transport competence disruption. ALS-N999Vfs*40-KIF5A formed SQSTM1/p62-positive inclusions sequestering WT-KIF5A, indicating a gain of toxic function. SPG-R17Q-KIF5A and ALS-N999Vfs*40-KIF5A evidenced a shorter half-life compared to WT-KIF5A, and proteasomal blockage determined their accumulation into detergent-insoluble inclusions. Interestingly, SPG-R280C-KIF5A and ALS-N999Vfs*40-KIF5A both competed for degradation with proteasomal substrates. Finally, NEIMY-C975Vfs*73-KIF5A displayed a similar, but more severe aberrant behaviour compared to ALS-N999Vfs*40-KIF5A; these two mutants share an abnormal tail but cause disorders on the opposite end of KIF5A-linked phenotypic spectrum. Thus, our observations support the pathogenicity of novel KIF5A mutants, highlight abnormalities of recurrent variants, and demonstrate that both unique and shared mechanisms underpin KIF5A-related diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11437142/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircSEC24B activates autophagy and induces chemoresistance of colorectal cancer via OTUB1-mediated deubiquitination of SRPX2.","authors":"Di Wang, Yongge Li, Weilong Chang, Meina Feng, Yiming Yang, Xiuxiang Zhu, Zhibo Liu, Yang Fu","doi":"10.1038/s41419-024-07057-y","DOIUrl":"https://doi.org/10.1038/s41419-024-07057-y","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are a type of regulatory RNA that feature covalently closed single-stranded loops. Evidence suggested that circRNAs play important roles in the progression and development of various cancers. However, the impact of circRNA on autophagy-mediated progression of colorectal cancer (CRC) remains unclear. The objective of this project was to investigate the influence of circSEC24B on autophagy and its underlying mechanisms in CRC. To validate the presence and circular structure of circSEC24B in CRC cells and tissues, PCR and Sanger sequencing techniques were employed. Drug resistance and invasive phenotype of CRC cells were evaluated using CCK8, transwell, and Edu assays. Gain- and loss-of-function experiments were conducted to assess the effects of circSEC24B and its protein partner on the growth, invasion, and metastasis of CRC cells in vitro and in vivo. Interactions between circSEC24B, OTUB1, and SRPX2 were analyzed through immunofluorescence, RNA-pulldown, and RIP assays. Mass spectrometry analysis was used to identify potential binding proteins of circRNA in CRC cells. Vectors were constructed to investigate the specific structural domain of the deubiquitinating enzyme OTUB1 that binds to circSEC24B. Results showed that circSEC24B expression was increased in CRC tissues and cell lines, and it enhanced CRC cell proliferation and autophagy levels. Mechanistically, circSEC24B promoted CRC cell proliferation by regulating the protein stability of SRPX2. Specifically, circSEC24B acted as a scaffold, facilitating the binding of OTUB1 to SRPX2 and thereby enhancing its protein stability. Additionally, evidence suggested that OTUB1 regulated SRPX2 expression through an acetylation-dependent mechanism. In conclusion, this study demonstrated that circSEC24B activated autophagy and induced chemoresistance in CRC by promoting the deubiquitination of SRPX2, mediated by the deubiquitinating enzyme OTUB1.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11436887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing cell death in B-cell malignancies through targeted inhibition of Bcl-3.","authors":"Renée Daams, Thi Thu Phuong Tran, Mohamed Jemaà, Wondossen Sime, Ruta Mickeviciute, Sara Ek, Lars Rönnstrand, Julhash U Kazi, Ramin Massoumi","doi":"10.1038/s41419-024-07067-w","DOIUrl":"10.1038/s41419-024-07067-w","url":null,"abstract":"<p><p>The t(14;19)(q32;q13) is a rare recurring translocation found in B-cell lymphoproliferative malignancies, involving the Bcl-3 gene. This chromosomal translocation is often found in patients under the age of 50 and causes a more progressive disease. The Bcl-3 gene encodes a protein belonging to the IκB family of proteins, which tightly regulates NFκB signaling by acting as an activator or repressor of transcription. Previously, we developed a second-generation Bcl-3 inhibitor that could directly interfere with Bcl-3 signaling pathway, resulting in reduced melanoma cell proliferation, invasion, and migration. The present study aimed to investigate the effect of a Bcl-3 inhibitor on B-cell lymphoma and leukemia cells. It was found that treatment of cells with this inhibitor caused a decrease in cell proliferation and cell survival. Furthermore, Bcl-3 inhibition in B-cell malignant cells resulted in the loss of mitochondrial membrane potential and functionality, as well as the increased expression of cleaved caspase 3, indicating that cell death occurs through the intrinsic apoptotic pathway. This observation is further supported by reduced expression of cIAP1 protein 1 (cIAP1) upon treatment of cancer cells. Given the current lack of clinical advancements targeting Bcl-3 in oncology, this opens a novel avenue for the development and investigation of highly specific therapeutic interventions against B-cell malignancies.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427694/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumor specimen cold ischemia time impacts molecular cancer drug target discovery.","authors":"Silvia von der Heyde, Nithya Raman, Nina Gabelia, Xavier Matias-Guiu, Takayuki Yoshino, Yuichiro Tsukada, Gerry Melino, John L Marshall, Anton Wellstein, Hartmut Juhl, Jobst Landgrebe","doi":"10.1038/s41419-024-07090-x","DOIUrl":"https://doi.org/10.1038/s41419-024-07090-x","url":null,"abstract":"<p><p>Tumor tissue collections are used to uncover pathways associated with disease outcomes that can also serve as targets for cancer treatment, ideally by comparing the molecular properties of cancer tissues to matching normal tissues. The quality of such collections determines the value of the data and information generated from their analyses including expression and modifications of nucleic acids and proteins. These biomolecules are dysregulated upon ischemia and decompose once the living cells start to decay into inanimate matter. Therefore, ischemia time before final tissue preservation is the most important determinant of the quality of a tissue collection. Here we show the impact of ischemia time on tumor and matching adjacent normal tissue samples for mRNAs in 1664, proteins in 1818, and phosphosites in 1800 cases (tumor and matching normal samples) of four solid tumor types (CRC, HCC, LUAD, and LUSC NSCLC subtypes). In CRC, ischemia times exceeding 15 min impacted 12.5% (mRNA), 25% (protein), and 50% (phosphosites) of differentially expressed molecules in tumor versus normal tissues. This hypoxia- and decay-induced dysregulation increased with longer ischemia times and was observed across tumor types. Interestingly, the proteomics analysis revealed that specimen ischemia time above 15 min is mostly associated with a dysregulation of proteins in the immune-response pathway and less so with metabolic processes. We conclude that ischemia time is a crucial quality parameter for tissue collections used for target discovery and validation in cancer research.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":null,"pages":null},"PeriodicalIF":8.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11427669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}