Pub Date : 2024-07-26DOI: 10.1038/s41389-024-00530-5
Merel Elise van Luyk, Ana Krotenberg Garcia, Maria Lamprou, Saskia Jacoba Elisabeth Suijkerbuijk
Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker "loser" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.
{"title":"Cell competition in primary and metastatic colorectal cancer.","authors":"Merel Elise van Luyk, Ana Krotenberg Garcia, Maria Lamprou, Saskia Jacoba Elisabeth Suijkerbuijk","doi":"10.1038/s41389-024-00530-5","DOIUrl":"10.1038/s41389-024-00530-5","url":null,"abstract":"<p><p>Adult tissues set the scene for a continuous battle between cells, where a comparison of cellular fitness results in the elimination of weaker \"loser\" cells. This phenomenon, named cell competition, is beneficial for tissue integrity and homeostasis. In fact, cell competition plays a crucial role in tumor suppression, through elimination of early malignant cells, as part of Epithelial Defense Against Cancer. However, it is increasingly apparent that cell competition doubles as a tumor-promoting mechanism. The comparative nature of cell competition means that mutational background, proliferation rate and polarity all factor in to determine the outcome of these processes. In this review, we explore the intricate and context-dependent involvement of cell competition in homeostasis and regeneration, as well as during initiation and progression of primary and metastasized colorectal cancer. We provide a comprehensive overview of molecular and cellular mechanisms governing cell competition and its parallels with regeneration.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"28"},"PeriodicalIF":5.9,"publicationDate":"2024-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11282291/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141767003","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}
The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.
{"title":"USP32 facilitates non-small cell lung cancer progression via deubiquitinating BAG3 and activating RAF-MEK-ERK signaling pathway.","authors":"Shuang Li, Lina Yang, Xiaoyan Ding, Hongxiao Sun, Xiaolei Dong, Fanghao Yang, Mengjun Wang, Huhu Zhang, Ya Li, Bing Li, Chunyan Liu","doi":"10.1038/s41389-024-00528-z","DOIUrl":"10.1038/s41389-024-00528-z","url":null,"abstract":"<p><p>The regulatory significance of ubiquitin-specific peptidase 32 (USP32) in tumor is significant, nevertheless, the biological roles and regulatory mechanisms of USP32 in non-small cell lung cancer (NSCLC) remain unclear. According to our research, USP32 was strongly expressed in NSCLC cell lines and tissues and was linked to a bad prognosis for NSCLC patients. Interference with USP32 resulted in a significant inhibition of NSCLC cell proliferation, migration potential, and EMT development; on the other hand, USP32 overexpression had the opposite effect. To further elucidate the mechanism of action of USP32 in NSCLC, we screened H1299 cells for interacting proteins and found that USP32 interacts with BAG3 (Bcl2-associated athanogene 3) and deubiquitinates and stabilizes BAG3 in a deubiquitinating activity-dependent manner. Functionally, restoration of BAG3 expression abrogated the antitumor effects of USP32 silencing. Furthermore, USP32 increased the phosphorylation level of the RAF/MEK/ERK signaling pathway in NSCLC cells by stabilizing BAG3. In summary, these findings imply that USP32 is critical to the development of NSCLC and could offer a theoretical framework for the clinical diagnosis and management of NSCLC patients in the future.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"27"},"PeriodicalIF":5.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11271578/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727512","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}
The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction.
{"title":"YAP/TAZ interacts with RBM39 to confer resistance against indisulam.","authors":"Toshinori Ando, Kento Okamoto, Yume Ueda, Nanako Kataoka, Tomoaki Shintani, Souichi Yanamoto, Mutsumi Miyauchi, Mikihito Kajiya","doi":"10.1038/s41389-024-00527-0","DOIUrl":"10.1038/s41389-024-00527-0","url":null,"abstract":"<p><p>The Hippo pathway and its downstream effectors, Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ), are essential for cell growth and organ development. Emerging evidence revealed that the Hippo pathway and YAP/TAZ are frequently dysregulated by multiple genetic alterations in solid cancers including head and neck squamous cell carcinoma (HNSCC); however, the YAP/TAZ-nuclear interactome remains unclear. RNA-binding motif protein 39 (RBM39) enhances transcriptional activity of several transcription factors and also regulates mRNA splicing. Indisulam degrading RBM39 induces alternative splicing, leading to cell death. However, clinical trials of indisulam have failed to show effectiveness. Therefore, clarifying the resistance mechanism against splicing inhibitors is urgently required. In this study, we identified RBM39 as a novel YAP/TAZ-interacting molecule by proteome analysis. RBM39 promoted YAP/TAZ transcriptional activity. We further elucidated that indisulam reduces RBM39/YAP/TAZ-mediated integrin or collagen expression, thereby inactivating focal adhesion kinase (FAK) important for cell survival. Moreover, indisulam also induced alternative splicing of cell cycle- or DNA metabolism-related genes. YAP/TAZ hyperactivation delayed indisulam-induced RBM39 degradation, which restored the integrin/collagen expression to activate FAK, and alternative splicing, thereby conferring resistance against indisulam in vitro and in vivo. Our findings may aid to develop a novel cancer therapy focusing on YAP/TAZ/RBM39 interaction.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"25"},"PeriodicalIF":5.9,"publicationDate":"2024-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11247092/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141616903","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}
Pub Date : 2024-07-11DOI: 10.1038/s41389-024-00525-2
Anne M van Harten, Ronak Shah, D Vicky de Boer, Marijke Buijze, Maaike Kreft, Ji-Ying Song, Lisa M Zürcher, Heinz Jacobs, Ruud H Brakenhoff
Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of developing malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy is a mainstay of HNSCC treatment, cisplatin is contra-indicated for FA-HNSCC patients. This dilemma necessitates the identification of novel treatment modalities tolerated by FA-HNSCC patients. To identify druggable targets, an siRNA-based genetic screen was previously performed in HNSCC-derived cell lines from FA and non-FA tumor origin. Here, we report that the Ribonucleotide Reductase (RNR) complex, consisting of the RRM1 and RRM2 subunits, was identified as a therapeutic target for both, FA and non-FA HNSCC. While non-FA HNSCC cells responded differentially to RNR depletion, FA-HNSCC cells were consistently found hypersensitive. This insight was confirmed pharmacologically using 2', 2'-difluoro 2'deoxycytidine (dFdC), also known as gemcitabine, a clinically used nucleotide analog that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed severe, long-lasting toxicity on the hematopoietic stem and progenitor compartments in Fancg-/- mice, gemcitabine was well tolerated and had only a mild, transient impact. Taken together, our data implicate that gemcitabine-based chemoradiotherapy could serve as an alternative HNSCC treatment in Fanconi patients, and deserves clinical testing.
范可尼贫血症(Fanconi anemia,FA)是一种罕见的遗传性疾病,由FA/BRCA通路中的失活突变引起,该通路对DNA链间交联(ICL)的有效修复至关重要。该病的特点是先天性畸形、骨髓衰竭和早期罹患恶性肿瘤的风险增加,尤其是头颈部鳞状细胞癌(HNSCC)。虽然ICL诱导顺铂联合放疗是治疗HNSCC的主要方法,但顺铂却是FA-HNSCC患者的禁忌症。面对这一难题,有必要找出 FA-HNSCC 患者可以耐受的新型治疗方式。为了确定可用药的靶点,以前曾对来自 FA 和非 FA 肿瘤来源的 HNSCC 细胞系进行了基于 siRNA 的基因筛选。在此,我们报告了由 RRM1 和 RRM2 亚基组成的核糖核苷酸还原酶(RNR)复合物被确定为 FA 和非 FA HNSCC 的治疗靶点。虽然非 FA HNSCC 细胞对 RNR 缺失的反应不同,但 FA-HNSCC 细胞始终对其不敏感。这一观点通过使用 2'、2'-二氟 2'脱氧胞苷(dFdC)(也称为吉西他滨)得到了药理证实,这是一种临床常用的核苷酸类似物,是 RNR 复合物的强效抑制剂。重要的是,顺铂暴露对Fancg-/-小鼠的造血干细胞和祖细胞组具有严重、持久的毒性,而吉西他滨的耐受性良好,仅有轻微、短暂的影响。综上所述,我们的数据表明,以吉西他滨为基础的化放疗可作为范可尼患者HNSCC的替代治疗方法,值得进行临床试验。
{"title":"Gemcitabine as chemotherapy of head and neck cancer in Fanconi anemia patients.","authors":"Anne M van Harten, Ronak Shah, D Vicky de Boer, Marijke Buijze, Maaike Kreft, Ji-Ying Song, Lisa M Zürcher, Heinz Jacobs, Ruud H Brakenhoff","doi":"10.1038/s41389-024-00525-2","DOIUrl":"10.1038/s41389-024-00525-2","url":null,"abstract":"<p><p>Fanconi anemia (FA) is a rare hereditary disease resulting from an inactivating mutation in the FA/BRCA pathway, critical for the effective repair of DNA interstrand crosslinks (ICLs). The disease is characterized by congenital abnormalities, progressing bone marrow failure, and an increased risk of developing malignancies early in life, in particular head and neck squamous cell carcinoma (HNSCC). While ICL-inducing cisplatin combined with radiotherapy is a mainstay of HNSCC treatment, cisplatin is contra-indicated for FA-HNSCC patients. This dilemma necessitates the identification of novel treatment modalities tolerated by FA-HNSCC patients. To identify druggable targets, an siRNA-based genetic screen was previously performed in HNSCC-derived cell lines from FA and non-FA tumor origin. Here, we report that the Ribonucleotide Reductase (RNR) complex, consisting of the RRM1 and RRM2 subunits, was identified as a therapeutic target for both, FA and non-FA HNSCC. While non-FA HNSCC cells responded differentially to RNR depletion, FA-HNSCC cells were consistently found hypersensitive. This insight was confirmed pharmacologically using 2', 2'-difluoro 2'deoxycytidine (dFdC), also known as gemcitabine, a clinically used nucleotide analog that is a potent inhibitor of the RNR complex. Importantly, while cisplatin exposure displayed severe, long-lasting toxicity on the hematopoietic stem and progenitor compartments in Fancg-/- mice, gemcitabine was well tolerated and had only a mild, transient impact. Taken together, our data implicate that gemcitabine-based chemoradiotherapy could serve as an alternative HNSCC treatment in Fanconi patients, and deserves clinical testing.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"26"},"PeriodicalIF":5.9,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11239817/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590964","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}
Pub Date : 2024-07-09DOI: 10.1038/s41389-024-00526-1
Giovana Carrasco, Ifigeneia Stavrou, Mairi Treanor-Taylor, Henry Beetham, Martin Lee, Roza Masalmeh, Artur Carreras-Soldevila, David Hardman, Miguel O Bernabeu, Alex von Kriegsheim, Gareth J Inman, Adam Byron, Valerie G Brunton
Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.
{"title":"Involvement of Kindlin-1 in cutaneous squamous cell carcinoma.","authors":"Giovana Carrasco, Ifigeneia Stavrou, Mairi Treanor-Taylor, Henry Beetham, Martin Lee, Roza Masalmeh, Artur Carreras-Soldevila, David Hardman, Miguel O Bernabeu, Alex von Kriegsheim, Gareth J Inman, Adam Byron, Valerie G Brunton","doi":"10.1038/s41389-024-00526-1","DOIUrl":"10.1038/s41389-024-00526-1","url":null,"abstract":"<p><p>Kindler syndrome (KS) is a rare genodermatosis resulting from loss-of-function mutations in FERMT1, the gene that encodes Kindlin-1. KS patients have a high propensity to develop aggressive and metastatic cutaneous squamous cell carcinoma (cSCC). Here we show in non-KS-associated patients that elevation of FERMT1 expression is increased in actinic keratoses compared to normal skin, with a further increase in cSCC supporting a pro-tumorigenic role in this population. In contrast, we show that loss of Kindlin-1 leads to increased SCC tumor growth in vivo and in 3D spheroids, which was associated with the development of a hypoxic tumor environment and increased glycolysis. The metalloproteinase Mmp13 was upregulated in Kindlin-1-depleted tumors, and increased expression of MMP13 was responsible for driving increased invasion of the Kindlin-1-depleted SCC cells. These results provide evidence that Kindlin-1 loss in SCC can promote invasion through the upregulation of MMP13, and offer novel insights into how Kindlin-1 loss leads to the development of a hypoxic environment that is permissive for tumor growth.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"24"},"PeriodicalIF":5.9,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11233684/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141563991","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}
Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/β-Catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.
{"title":"USP21-mediated G3BP1 stabilization accelerates proliferation and metastasis of esophageal squamous cell carcinoma via activating Wnt/β-Catenin signaling.","authors":"Jiazhong Guo, Yunpeng Zhao, Huacong Sui, Lei Liu, Fanrong Liu, Lingxiao Yang, Fengyuan Gao, Jinfu Wang, Yilin Zhu, Lingbing Li, Xiangqing Song, Peng Li, Zhongxian Tian, Peichao Li, Xiaogang Zhao","doi":"10.1038/s41389-024-00524-3","DOIUrl":"10.1038/s41389-024-00524-3","url":null,"abstract":"<p><p>Lacking effective therapeutic targets heavily restricts the improvement of clinical prognosis for patients diagnosed with esophageal squamous cell carcinoma (ESCC). Ubiquitin Specific Peptidase 21 (USP21) is dysregulated in plenty of human cancers, however, its potential function and relevant molecular mechanisms in ESCC malignant progression as well as its value in clinical translation remain largely unknown. Here, in vitro and in vivo experiments revealed that aberrant upregulation of USP21 accelerated the proliferation and metastasis of ESCC in a deubiquitinase-dependent manner. Mechanistically, we found that USP21 binds to, deubiquitinates, and stabilizes the G3BP Stress Granule Assembly Factor 1 (G3BP1) protein, which is required for USP21-mediated ESCC progression. Further molecular studies demonstrated that the USP21/G3BP1 axis played a tumor-promoting role in ESCC progression by activating the Wnt/β-Catenin signaling pathway. Additionally, disulfiram (DSF), an inhibitor against USP21 deubiquitylation activity, markedly abolished the USP21-mediated stability of G3BP1 protein and significantly displayed an anti-tumor effect on USP21-driving ESCC progression. Finally, the regulatory axis of USP21/G3BP1 was demonstrated to be aberrantly activated in ESCC tumor tissues and closely associated with advanced clinical stages and unfavorable prognoses, which provides a promising therapeutic strategy targeting USP21/G3BP1 axis for ESCC patients.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"23"},"PeriodicalIF":5.9,"publicationDate":"2024-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11192907/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141437268","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}
Pub Date : 2024-06-13DOI: 10.1038/s41389-024-00522-5
Meng Gao, Hang Dong, Siyi Jiang, Fangping Chen, Yunfeng Fu, Yanwei Luo
The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.
高凝状态是多发性骨髓瘤(MM)患者的标志,并与疾病进展有关。活化的血小板会分泌外泌体,促进实体瘤的生长。然而,血小板衍生的外泌体在 MM 中的作用尚不完全清楚。我们旨在研究血小板衍生的外泌体如何促进 MM 细胞生长的内在机制。我们通过流式细胞术、Western印迹、蛋白质组分析、共免疫沉淀、免疫荧光染色和NOD/SCID小鼠皮下移植模型来研究外泌体LRG1对多发性骨髓瘤细胞生长的作用。MM患者的外周血血小板处于高度活化状态,来自MM患者的富血小板血浆能显著促进U266细胞和RPMI8226细胞的增殖并减少细胞凋亡。在 MM 血小板衍生的外泌体中,富亮氨酸-α-2-糖蛋白 1(LRG1)明显富集。使用LRG1抗体阻断受体细胞中的LRG1,可明显消除血小板衍生外泌体对MM细胞的增殖促进作用。外泌体LRG1含量高与MM患者预后不良有关。机理研究发现,LRG1与Olfactomedin 4(OLFM4)相互作用,通过激活上皮细胞向间质转化(EMT)信号通路和促进血管生成来加速MM的进展。我们的研究结果表明,阻断LRG1是治疗MM的一种很有前景的治疗策略。
{"title":"Activated platelet-derived exosomal LRG1 promotes multiple myeloma cell growth.","authors":"Meng Gao, Hang Dong, Siyi Jiang, Fangping Chen, Yunfeng Fu, Yanwei Luo","doi":"10.1038/s41389-024-00522-5","DOIUrl":"10.1038/s41389-024-00522-5","url":null,"abstract":"<p><p>The hypercoagulable state is a hallmark for patients with multiple myeloma (MM) and is associated with disease progression. Activated platelets secrete exosomes and promote solid tumor growth. However, the role of platelet-derived exosomes in MM is not fully clear. We aim to study the underlying mechanism of how platelet-derived exosomes promote MM cell growth. Flow cytometry, Western blot, proteome analysis, co-immunoprecipitation, immunofluorescence staining, and NOD/SCID mouse subcutaneous transplantation model were performed to investigate the role of exosomal LRG1 on multiple myeloma cell growth. Peripheral blood platelets in MM patients were in a highly activated state, and platelet-rich plasma from MM patients significantly promoted cell proliferation and decreased apoptotic cells in U266 and RPMI8226 cells. Leucine-rich-alpha-2-glycoprotein 1 (LRG1) was significantly enriched in MM platelet-derived exosomes. Blocking LRG1 in recipient cells using LRG1 antibody could significantly eliminate the proliferation-promoting effect of platelet-derived exosomes on MM cells. And high exosomal LRG1 was associated with poor prognosis of patients with MM. Mechanistic studies revealed that LRG1 interacted with Olfactomedin 4 (OLFM4) to accelerate MM progression by activating the epithelial-to-mesenchymal transition (EMT) signaling pathway and promoting angiogenesis. Our results revealed that blocking LRG1 is a promising therapeutic strategy for the treatment of MM.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"21"},"PeriodicalIF":6.2,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176168/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317934","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}
Pub Date : 2024-06-13DOI: 10.1038/s41389-024-00521-6
Abhibhav Sharma, Julia Debik, Bjørn Naume, Hege Oma Ohnstad, Tone F Bathen, Guro F Giskeødegård
Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.
乳腺癌(BC)是全球癌症相关死亡的主要原因。乳腺癌的多样性和异质性给生存预测带来了挑战,因为诊断相似的患者对治疗的反应往往不同。通过基因表达谱分析已经建立了与临床相关的 BC 固有亚型,并已在临床中应用。虽然这些固有亚型与临床结果有显著关联,但其5年以上的长期生存预测往往偏离预期的临床结果。本研究旨在基于综合多组学分析,确定BC自然发生的长期预后亚组。本研究纳入了奥斯陆2研究中335名未经治疗的BC患者的临床队列,并进行了长期随访(>12年)。研究采用了多组学因子分析(MOFA+)来整合从肿瘤组织中获得的转录组学、蛋白质组学和代谢组学数据。我们的分析揭示了三个显著的多组学群组,这些群组的 BC 患者的长期预后存在显著差异(p = 0.005)。这些多组学集群在两个独立的大型队列(METABRIC 和 TCGA)中得到了验证。重要的是,在这些队列中,以前建立的内在亚型在超过 12 年的长期随访中缺乏预后关联。通过系统生物学方法,我们在预后群组中发现了细胞周期和免疫相关通路的不同富集水平。对 BC 进行多组学综合分析后,发现了三个具有独特临床和生物学特征的不同群组。值得注意的是,这些多组学集群与长期存活率有着密切的联系,优于已确定的固有亚型。
{"title":"Comprehensive multi-omics analysis of breast cancer reveals distinct long-term prognostic subtypes.","authors":"Abhibhav Sharma, Julia Debik, Bjørn Naume, Hege Oma Ohnstad, Tone F Bathen, Guro F Giskeødegård","doi":"10.1038/s41389-024-00521-6","DOIUrl":"10.1038/s41389-024-00521-6","url":null,"abstract":"<p><p>Breast cancer (BC) is a leading cause of cancer-related death worldwide. The diverse nature and heterogeneous biology of BC pose challenges for survival prediction, as patients with similar diagnoses often respond differently to treatment. Clinically relevant BC intrinsic subtypes have been established through gene expression profiling and are implemented in the clinic. While these intrinsic subtypes show a significant association with clinical outcomes, their long-term survival prediction beyond 5 years often deviates from expected clinical outcomes. This study aimed to identify naturally occurring long-term prognostic subgroups of BC based on an integrated multi-omics analysis. This study incorporates a clinical cohort of 335 untreated BC patients from the Oslo2 study with long-term follow-up (>12 years). Multi-Omics Factor Analysis (MOFA+) was employed to integrate transcriptomic, proteomic, and metabolomic data obtained from the tumor tissues. Our analysis revealed three prominent multi-omics clusters of BC patients with significantly different long-term prognoses (p = 0.005). The multi-omics clusters were validated in two independent large cohorts, METABRIC and TCGA. Importantly, a lack of prognostic association to long-term follow-up above 12 years in the previously established intrinsic subtypes was shown for these cohorts. Through a systems-biology approach, we identified varying enrichment levels of cell-cycle and immune-related pathways among the prognostic clusters. Integrated multi-omics analysis of BC revealed three distinct clusters with unique clinical and biological characteristics. Notably, these multi-omics clusters displayed robust associations with long-term survival, outperforming the established intrinsic subtypes.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"22"},"PeriodicalIF":6.2,"publicationDate":"2024-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176181/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141317935","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}
Metabolic reprogramming has become increasingly important in tumor biology research. The glucose metabolic pathway is a major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor that acts as a scaffold protein to suppress tumor malignancy in breast cancer. Interestingly, DAB2IP has also been found to be a potential regulator of glucose uptake; however, the exact mechanism remains unclear. In this study, we found that DAB2IP inhibited glucose uptake under hypoxia conditions in breast cancer cells by suppressing HIF-1α signals. Mechanically, DAB2IP interacted with the E3 ubiquitin ligase STUB1 via its PER domain, thus triggering STUB1 mediated HIF-1α ubiquitylation and degradation, and inhibit glucose metabolism and tumor progression. Deleting the PER domain abrogated the DAB2IP-related inhibitory effects on glucose uptake, intracellular ATP production, and lactic acid production in breast cancer cells. These findings elucidate the biological roles of DAB2IP in cancer-related glucose metabolism as well as a novel mechanism by which STUB1-driven HIF-1α ubiquitylated degradation is regulated in breast cancer.
代谢重编程在肿瘤生物学研究中变得越来越重要。葡萄糖代谢途径是一种主要的能量来源,在乳腺癌中经常出现失调。据广泛报道,DAB2IP 是一种肿瘤抑制因子,可作为支架蛋白抑制乳腺癌中肿瘤的恶性程度。有趣的是,DAB2IP 还被发现是葡萄糖摄取的潜在调节因子,但其确切机制仍不清楚。本研究发现,在缺氧条件下,DAB2IP 通过抑制 HIF-1α 信号来抑制乳腺癌细胞的葡萄糖摄取。在机制上,DAB2IP通过其PER结构域与E3泛素连接酶STUB1相互作用,从而引发STUB1介导的HIF-1α泛素化和降解,抑制葡萄糖代谢和肿瘤进展。删除 PER 结构域可减弱 DAB2IP 对乳腺癌细胞葡萄糖摄取、细胞内 ATP 生成和乳酸生成的抑制作用。这些发现阐明了 DAB2IP 在与癌症相关的葡萄糖代谢中的生物学作用,以及 STUB1 驱动的 HIF-1α 泛素化降解在乳腺癌中的新调控机制。
{"title":"DAB2IP inhibits glucose uptake by modulating HIF-1α ubiquitination under hypoxia in breast cancer.","authors":"Hongliang Dong, Weiyi Jia, Weijian Meng, Rui Zhang, Zhihong Qi, Zhuo Chen, Sophia Xie, Jiang Min, Liang Liu, Jie Shen","doi":"10.1038/s41389-024-00523-4","DOIUrl":"10.1038/s41389-024-00523-4","url":null,"abstract":"<p><p>Metabolic reprogramming has become increasingly important in tumor biology research. The glucose metabolic pathway is a major energy source and is often dysregulated in breast cancer. DAB2IP is widely reported to be a tumor suppressor that acts as a scaffold protein to suppress tumor malignancy in breast cancer. Interestingly, DAB2IP has also been found to be a potential regulator of glucose uptake; however, the exact mechanism remains unclear. In this study, we found that DAB2IP inhibited glucose uptake under hypoxia conditions in breast cancer cells by suppressing HIF-1α signals. Mechanically, DAB2IP interacted with the E3 ubiquitin ligase STUB1 via its PER domain, thus triggering STUB1 mediated HIF-1α ubiquitylation and degradation, and inhibit glucose metabolism and tumor progression. Deleting the PER domain abrogated the DAB2IP-related inhibitory effects on glucose uptake, intracellular ATP production, and lactic acid production in breast cancer cells. These findings elucidate the biological roles of DAB2IP in cancer-related glucose metabolism as well as a novel mechanism by which STUB1-driven HIF-1α ubiquitylated degradation is regulated in breast cancer.</p>","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"20"},"PeriodicalIF":6.2,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11166643/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141306489","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}
Pub Date : 2024-05-29DOI: 10.1038/s41389-024-00519-0
Changhwan Yoon, Jun Lu, Brendan C Yi, Kevin K Chang, M Celeste Simon, Sandra Ryeom, Sam S Yoon
{"title":"Retraction Note: PI3K/Akt pathway and Nanog maintain cancer stem cells in sarcomas.","authors":"Changhwan Yoon, Jun Lu, Brendan C Yi, Kevin K Chang, M Celeste Simon, Sandra Ryeom, Sam S Yoon","doi":"10.1038/s41389-024-00519-0","DOIUrl":"10.1038/s41389-024-00519-0","url":null,"abstract":"","PeriodicalId":19489,"journal":{"name":"Oncogenesis","volume":"13 1","pages":"18"},"PeriodicalIF":6.2,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11137036/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175952","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}