Pub Date : 2024-11-21DOI: 10.1038/s41388-024-03227-6
Aditi Jain, Alan Barge, Christopher N. Parris
Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer’s intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.
{"title":"Combination strategies with PARP inhibitors in BRCA-mutated triple-negative breast cancer: overcoming resistance mechanisms","authors":"Aditi Jain, Alan Barge, Christopher N. Parris","doi":"10.1038/s41388-024-03227-6","DOIUrl":"10.1038/s41388-024-03227-6","url":null,"abstract":"Triple-negative breast cancer (TNBC) is a particularly aggressive breast cancer subtype, characterised by a higher incidence in younger women, rapid metastasis, and a generally poor prognosis. Patients with TNBC and BRCA mutations face additional therapeutic challenges due to the cancer’s intrinsic resistance to conventional therapies. Poly (ADP-ribose) polymerase inhibitors (PARPis) have emerged as a promising targeted treatment for BRCA-mutated TNBC, exploiting vulnerabilities in the homologous recombination repair (HRR) pathway. However, despite initial success, the efficacy of PARPis is often compromised by the development of resistance mechanisms, including HRR restoration, stabilisation of replication forks, reduced PARP1 trapping, and drug efflux. This review explores latest breakthroughs in overcoming PARPi resistance through combination therapies. These strategies include the integration of PARPis with chemotherapy, immunotherapy, antibody-drug conjugates, and PI3K/AKT pathway inhibitors. These combinations aim to enhance the therapeutic efficacy of PARPis by targeting multiple cancer progression pathways. The review also discusses the evolving role of PARPis within the broader treatment paradigm for BRCA-mutated TNBC, emphasising the need for ongoing research and clinical trials to optimise combination strategies. By tackling the challenges associated with PARPi resistance and exploring novel combination therapies, this review sheds light on the future possibilities for improving outcomes for patients with BRCA-mutated TNBC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 4","pages":"193-207"},"PeriodicalIF":6.9,"publicationDate":"2024-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03227-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142687737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1038/s41388-024-03219-6
Tianwei Chen, Lauren M. Ashwood, Olga Kondrashova, Andreas Strasser, Gemma Kelly, Kate D. Sutherland
The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.
{"title":"Breathing new insights into the role of mutant p53 in lung cancer","authors":"Tianwei Chen, Lauren M. Ashwood, Olga Kondrashova, Andreas Strasser, Gemma Kelly, Kate D. Sutherland","doi":"10.1038/s41388-024-03219-6","DOIUrl":"10.1038/s41388-024-03219-6","url":null,"abstract":"The tumour suppressor gene p53 is one of the most frequently mutated genes in lung cancer and these defects are associated with poor prognosis, albeit some debate exists in the lung cancer field. Despite extensive research, the exact mechanisms by which mutant p53 proteins promote the development and sustained expansion of cancer remain unclear. This review will discuss the cellular responses controlled by p53 that contribute to tumour suppression, p53 mutant lung cancer mouse models and characterisation of p53 mutant lung cancer. Furthermore, we discuss potential approaches of targeting mutant p53 for the treatment of lung cancer.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 3","pages":"115-129"},"PeriodicalIF":6.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03219-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682300","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-20DOI: 10.1038/s41388-024-03228-5
Kelby Kane, Deanna Edwards, Jin Chen
Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC’s role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.
血管中的内皮细胞（EC）是每个器官系统的看门人，决定着器官系统的代谢环境。在正常情况下，内皮细胞是相对静止的，具有器官特异性表达特征和代谢特征。在癌症中，血管内皮细胞会进行新陈代谢重编程，以促进新血管的形成，从而助长肿瘤的生长和转移。除了 EC 对肿瘤细胞的作用外，迂曲的肿瘤血管还限制了 T 淋巴细胞的浸润和活动，同时还促进了其他辅助性促血管生成免疫细胞的招募，从而形成了一种免疫抑制环境。这些因素有助于癌细胞的转移扩散，并导致抗药性。在癌症免疫疗法的配合下恢复更稳定的血管系统的概念正在成为克服癌症治疗障碍的一种潜在方法。这篇综述总结了内皮细胞的新陈代谢、它们对营养摄取和输送的调控，以及它们在塑造肿瘤微环境和抗肿瘤免疫方面的影响。我们重点介绍了针对肿瘤血管和利用免疫反应的新治疗方法。了解肿瘤微环境中代谢状态和营养水平的整合以及免疫细胞、肿瘤细胞和血管内皮细胞之间的相互影响可能会为治疗干预提供新的途径。
{"title":"The influence of endothelial metabolic reprogramming on the tumor microenvironment","authors":"Kelby Kane, Deanna Edwards, Jin Chen","doi":"10.1038/s41388-024-03228-5","DOIUrl":"10.1038/s41388-024-03228-5","url":null,"abstract":"Endothelial cells (ECs) that line blood vessels act as gatekeepers and shape the metabolic environment of every organ system. In normal conditions, endothelial cells are relatively quiescent with organ-specific expression signatures and metabolic profiles. In cancer, ECs are metabolically reprogrammed to promote the formation of new blood vessels to fuel tumor growth and metastasis. In addition to EC’s role on tumor cells, the tortuous tumor vasculature contributes to an immunosuppressive environment by limiting T lymphocyte infiltration and activity while also promoting the recruitment of other accessory pro-angiogenic immune cells. These elements aid in the metastatic spreading of cancer cells and contribute to therapeutic resistance. The concept of restoring a more stabilized vasculature in concert with cancer immunotherapy is emerging as a potential approach to overcoming barriers in cancer treatment. This review summarizes the metabolism of endothelial cells, their regulation of nutrient uptake and delivery, and their impact in shaping the tumor microenvironment and anti-tumor immunity. We highlight new therapeutic approaches that target the tumor vasculature and harness the immune response. Appreciating the integration of metabolic state and nutrient levels and the crosstalk among immune cells, tumor cells, and ECs in the TME may provide new avenues for therapeutic intervention.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 2","pages":"51-63"},"PeriodicalIF":6.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03228-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142682305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1038/s41388-024-03232-9
Jianzhong Yu, Jichang Han, Meng Yu, Huanwen Rui, An Sun, Hao Li
MYC-driven medulloblastomas (MB) are highly aggressive pediatric brain tumors with poor outcomes, and effective therapies remain limited despite intensive multimodal treatments. Targeting MYC directly is challenging, but exploiting MYC-mediated synthetic lethality holds promise. In this study, we investigated the combined effects of EZH2 and PARP inhibitors in MYC-high medulloblastoma and demonstrated that EZH2 inhibition significantly increased the sensitivity of MYC-high MB tumor cells to PARP inhibitors. This effect occurs through the upregulation of NUPR1, which promotes error-prone non-homologous end-joining (NHEJ) DNA repair by facilitating the recruitment of the XRCC4-LIG4 complex to DNA damage sites. This amplification of error-prone NHEJ DNA repair leads to genetic instability and eventual cell death in cells treated with the PARP inhibitor. The synergistic effect of EZH2 and PARP inhibitors was further validated in both in vitro and in vivo MB models without observed toxicity. These findings reveal a novel therapeutic strategy for MYC-high MB by co-targeting EZH2 and PARP, suggesting that this combination could potentially overcome the clinical challenges associated with this aggressive tumor subtype and warrants further investigation in clinical trials.
{"title":"EZH2 inhibition sensitizes MYC-high medulloblastoma cancers to PARP inhibition by regulating NUPR1-mediated DNA repair","authors":"Jianzhong Yu, Jichang Han, Meng Yu, Huanwen Rui, An Sun, Hao Li","doi":"10.1038/s41388-024-03232-9","DOIUrl":"10.1038/s41388-024-03232-9","url":null,"abstract":"MYC-driven medulloblastomas (MB) are highly aggressive pediatric brain tumors with poor outcomes, and effective therapies remain limited despite intensive multimodal treatments. Targeting MYC directly is challenging, but exploiting MYC-mediated synthetic lethality holds promise. In this study, we investigated the combined effects of EZH2 and PARP inhibitors in MYC-high medulloblastoma and demonstrated that EZH2 inhibition significantly increased the sensitivity of MYC-high MB tumor cells to PARP inhibitors. This effect occurs through the upregulation of NUPR1, which promotes error-prone non-homologous end-joining (NHEJ) DNA repair by facilitating the recruitment of the XRCC4-LIG4 complex to DNA damage sites. This amplification of error-prone NHEJ DNA repair leads to genetic instability and eventual cell death in cells treated with the PARP inhibitor. The synergistic effect of EZH2 and PARP inhibitors was further validated in both in vitro and in vivo MB models without observed toxicity. These findings reveal a novel therapeutic strategy for MYC-high MB by co-targeting EZH2 and PARP, suggesting that this combination could potentially overcome the clinical challenges associated with this aggressive tumor subtype and warrants further investigation in clinical trials.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 6","pages":"391-405"},"PeriodicalIF":6.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03232-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676080","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-19DOI: 10.1038/s41388-024-03205-y
Wenchao Zhang, Lin Qi, Haodong Xu, Chi Yin, Zhuowen Yu, Ruiling Xu, Chengyao Feng, Xiaolei Ren, Chao Tu, Zhihong Li
Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.
骨肉瘤是儿童和年轻人中常见的原发性恶性骨肿瘤，在提高转移或复发病例的存活率方面进展有限。由于激酶在调节细胞网络中发挥着关键作用，激酶抑制剂已成为治疗骨肉瘤的潜在药物。然而，由于代偿性致癌信号通路的激活会削弱治疗效果，单药激酶抑制剂往往面临挑战。在本研究中，我们在骨肉瘤细胞中进行了美国 FDA 批准的激酶抑制剂的联合筛选。我们发现ALK抑制剂和FLT3抑制剂的组合是一种有效的基于激酶的骨肉瘤治疗策略。我们的研究结果表明，组合疗法能协同抑制细胞系、患者衍生的器官组织和异种移植模型中的骨肉瘤。从机理上讲，抑制FLT3能显著促进ALK的活化，进而增强其下游的PI3K/Akt和MAPK信号通路。联合使用 ALK 抑制剂可以逆转这一过程。因此，我们的研究表明，协同阻断 FLT3 和 ALK 可协同抑制骨肉瘤，为其治疗提供了一种潜在的替代方案。
{"title":"Cooperative blockade of FLT3 and ALK synergistically suppresses growth of osteosarcoma","authors":"Wenchao Zhang, Lin Qi, Haodong Xu, Chi Yin, Zhuowen Yu, Ruiling Xu, Chengyao Feng, Xiaolei Ren, Chao Tu, Zhihong Li","doi":"10.1038/s41388-024-03205-y","DOIUrl":"10.1038/s41388-024-03205-y","url":null,"abstract":"Osteosarcoma is a common primary malignant bone tumor in children and young adults, with limited progress in improving survival rates for metastatic or recurrent cases. Kinase inhibitors have emerged as potential treatments for osteosarcoma due to the critical role kinases play in regulating cellular networks. However, single-agent kinase inhibitors often face challenges due to the activation of compensatory oncogenic signaling pathways, which can undermine treatment efficacy. In this study, a combination screening of FDA-approved kinase inhibitors was conducted in osteosarcoma cells. We identified the combination of ALK inhibitor and FLT3 inhibitor as a potent kinase-based therapeutic strategy for osteosarcoma. Our results showed that the combinatorial treatment synergistically suppressed osteosarcoma in cell lines, patient-derived organoids, and xenograft models. Mechanistically, the inhibition of FLT3 significantly promoted the activation of ALK, which subsequently enhanced its downstream PI3K/Akt and MAPK signaling pathways. The combinatorial use of an ALK inhibitor could reverse this process. Thus, our study demonstrates that the cooperative blockade of FLT3 and ALK synergistically suppresses osteosarcoma, providing a potential alternative for its treatment.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 7","pages":"427-438"},"PeriodicalIF":6.9,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03205-y.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142676075","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Tumor-infiltrating lymphocytes can influence tumorigenesis and progression. We found PD-L1 can inhibit the infiltration of memory T (Tm) cells in vivo and in vitro by reducing the secretion of CXCL9, CXCL10 in colorectal cancer. Patients with high PD-L1 expression have minimal Tm cell infiltration, accompanied with a higher incidence of tumor metastasis. Single-cell sequencing revealed that PD-L1 mainly inhibited the infiltration of a specific Tm cell subset characterized by the expression of FGFBP2 gene. To clarify the distribution of FGFBP2(+)Tm cells, peripheral blood, lymph nodes, colon polyps, primary tumor, and liver metastases samples were collected. As the tumor progressed, the infiltration of FGFBP2(+) memory T cells gradually increased and accumulated in liver metastases. By establishing a mouse metastasis model, we found in high PD-L1 expression group, the luciferin intensity of metastatic tumor was significantly higher, the number of metastatic nodules and the weight of metastases were also increased. The number of FGFBP2(+) Tm cells in peripheral blood and in liver/lung metastases were increased. Therefore, the expression of PD-L1 in primary tumor can promote the occurrence of metastases, and FGFBP2(+)Tm cells may be involved in the formation of metastases. Furthermore, the result showed that the number of FGFBP2(+) Tm cells in metastases was positively correlated with the number of vessels in liver/lung metastases. In conclusion, we confirmed that the expression of PD-L1 in primary tumor can increase the number of FGFBP2(+) Tm cells in peripheral blood and promote tumor metastasis, which is likely to be caused by the angiogenesis of FGFBP2(+) Tm cells in metastases.
{"title":"PD-L1 promotes tumor metastasis by regulating the infiltration of FGFBP2(+)Tm cells in colorectal cancer","authors":"Meng Zhuang, Jialiang Liu, Yuegang Li, Jinzhu Zhang, Zheng Jiang, Xishan Wang, Jianqiang Tang","doi":"10.1038/s41388-024-03223-w","DOIUrl":"10.1038/s41388-024-03223-w","url":null,"abstract":"Tumor-infiltrating lymphocytes can influence tumorigenesis and progression. We found PD-L1 can inhibit the infiltration of memory T (Tm) cells in vivo and in vitro by reducing the secretion of CXCL9, CXCL10 in colorectal cancer. Patients with high PD-L1 expression have minimal Tm cell infiltration, accompanied with a higher incidence of tumor metastasis. Single-cell sequencing revealed that PD-L1 mainly inhibited the infiltration of a specific Tm cell subset characterized by the expression of FGFBP2 gene. To clarify the distribution of FGFBP2(+)Tm cells, peripheral blood, lymph nodes, colon polyps, primary tumor, and liver metastases samples were collected. As the tumor progressed, the infiltration of FGFBP2(+) memory T cells gradually increased and accumulated in liver metastases. By establishing a mouse metastasis model, we found in high PD-L1 expression group, the luciferin intensity of metastatic tumor was significantly higher, the number of metastatic nodules and the weight of metastases were also increased. The number of FGFBP2(+) Tm cells in peripheral blood and in liver/lung metastases were increased. Therefore, the expression of PD-L1 in primary tumor can promote the occurrence of metastases, and FGFBP2(+)Tm cells may be involved in the formation of metastases. Furthermore, the result showed that the number of FGFBP2(+) Tm cells in metastases was positively correlated with the number of vessels in liver/lung metastases. In conclusion, we confirmed that the expression of PD-L1 in primary tumor can increase the number of FGFBP2(+) Tm cells in peripheral blood and promote tumor metastasis, which is likely to be caused by the angiogenesis of FGFBP2(+) Tm cells in metastases.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 6","pages":"378-390"},"PeriodicalIF":6.9,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668557","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-17DOI: 10.1038/s41388-024-03225-8
Zhao-Xin Gao, Chun-Lan Li, Han Zhang, Guo-Hao Zhang, Yu Zhang, Xiang-Yu Guo, Zhi-Yuan Tang, Peng Gao, Hai-Ting Liu
Breast cancer (BC) is the most common malignant tumor in women, and the majority of BC-related deaths are due to tumor metastasis. There is emerging evidence for the role of long noncoding RNAs (lncRNAs) in tumor progression. Nevertheless, lncRNAs that drive metastasis in patients with BC and the underlying mechanisms of lncRNAs are still largely elusive. In this study, we showed that LINC00882 was highly expressed in metastatic BC tissues, and a receiver operating characteristic (ROC) curve was able to distinguish well between BC cases with lymph node metastasis (LNM) and those without LNM. Functionally, LINC00882 promoted BC invasion and metastasis in vitro and in vivo. Mechanistically, at the transcriptional level, CEBP-β could bind directly to the LINC00882 promoter region and activate its transcription. Moreover, at the posttranscriptional level, m6A modification of LINC00882 mediated by methyltransferase-like 14 (METTL14) promoted its expression via an IGF2BP2-dependent pathway. Furthermore, 514–615 nucleotides of LINC00882 could directly interact with poly (A) binding protein cytoplasmic 1 (PABPC1) and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA and enhancing the ELK3 protein level. E-cadherin expression was suppressed via ELK3-mediated transcription inhibition, subsequently activating epithelial–mesenchymal transition to promote BC metastasis. These results highlight the role of LINC00882 in BC, and LINC00882 may be a diagnostic and therapeutic target for BC.
{"title":"LINC00882, transcriptionally activated by CEBP-β and post-transcriptionally stabilized by METTL14-mediated m6A modification, exerts tumorigenesis by promoting PABPC1-mediated stabilization of ELK3 mRNA","authors":"Zhao-Xin Gao, Chun-Lan Li, Han Zhang, Guo-Hao Zhang, Yu Zhang, Xiang-Yu Guo, Zhi-Yuan Tang, Peng Gao, Hai-Ting Liu","doi":"10.1038/s41388-024-03225-8","DOIUrl":"10.1038/s41388-024-03225-8","url":null,"abstract":"Breast cancer (BC) is the most common malignant tumor in women, and the majority of BC-related deaths are due to tumor metastasis. There is emerging evidence for the role of long noncoding RNAs (lncRNAs) in tumor progression. Nevertheless, lncRNAs that drive metastasis in patients with BC and the underlying mechanisms of lncRNAs are still largely elusive. In this study, we showed that LINC00882 was highly expressed in metastatic BC tissues, and a receiver operating characteristic (ROC) curve was able to distinguish well between BC cases with lymph node metastasis (LNM) and those without LNM. Functionally, LINC00882 promoted BC invasion and metastasis in vitro and in vivo. Mechanistically, at the transcriptional level, CEBP-β could bind directly to the LINC00882 promoter region and activate its transcription. Moreover, at the posttranscriptional level, m6A modification of LINC00882 mediated by methyltransferase-like 14 (METTL14) promoted its expression via an IGF2BP2-dependent pathway. Furthermore, 514–615 nucleotides of LINC00882 could directly interact with poly (A) binding protein cytoplasmic 1 (PABPC1) and promote the interaction between PABPC1 and ELK3 mRNA, thereby stabilizing ELK3 mRNA and enhancing the ELK3 protein level. E-cadherin expression was suppressed via ELK3-mediated transcription inhibition, subsequently activating epithelial–mesenchymal transition to promote BC metastasis. These results highlight the role of LINC00882 in BC, and LINC00882 may be a diagnostic and therapeutic target for BC.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 6","pages":"363-377"},"PeriodicalIF":6.9,"publicationDate":"2024-11-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648521","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-11-15DOI: 10.1038/s41388-024-03226-7
Wen-Cheng Chung, Shubing Zhang, Azeddine Atfi, Keli Xu
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited understanding of etiology. Studies in mice showed that both acinar and ductal cells of the pancreas can be targeted by combination of oncogenic Kras and p53 mutations to form PDAC. How the transforming capacities of pancreatic cells are constrained, and whether a subset of cells could serve as a prime target for oncogenic transformation, remain obscure. Here we report that expression of a Notch modulator, Lunatic Fringe (Lfng), is restricted to a limited number of cells with centroacinar location and morphology in the adult pancreas. Lfng-expressing cells are preferentially targeted by oncogenic Kras along with p53 deletion to form PDAC, and deletion of Lfng blocks tumor initiation from these cells. Notch3 is a functional Notch receptor for PDAC initiation and progression in this context. Lfng is upregulated in acinar- and ductal-derived PDAC and its deletion suppresses these tumors. Finally, high LFNG expression is associated with high grade and poor survival in human patients. Taken together, Lfng marks a centroacinar subpopulation that is uniquely susceptible to oncogenic transformation when p53 is lost, and Lfng functions as an oncogene in all three lineages of the exocrine pancreas.
{"title":"Lfng-expressing centroacinar cell is a unique cell-of-origin for p53 deficient pancreatic cancer","authors":"Wen-Cheng Chung, Shubing Zhang, Azeddine Atfi, Keli Xu","doi":"10.1038/s41388-024-03226-7","DOIUrl":"10.1038/s41388-024-03226-7","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies with limited understanding of etiology. Studies in mice showed that both acinar and ductal cells of the pancreas can be targeted by combination of oncogenic Kras and p53 mutations to form PDAC. How the transforming capacities of pancreatic cells are constrained, and whether a subset of cells could serve as a prime target for oncogenic transformation, remain obscure. Here we report that expression of a Notch modulator, Lunatic Fringe (Lfng), is restricted to a limited number of cells with centroacinar location and morphology in the adult pancreas. Lfng-expressing cells are preferentially targeted by oncogenic Kras along with p53 deletion to form PDAC, and deletion of Lfng blocks tumor initiation from these cells. Notch3 is a functional Notch receptor for PDAC initiation and progression in this context. Lfng is upregulated in acinar- and ductal-derived PDAC and its deletion suppresses these tumors. Finally, high LFNG expression is associated with high grade and poor survival in human patients. Taken together, Lfng marks a centroacinar subpopulation that is uniquely susceptible to oncogenic transformation when p53 is lost, and Lfng functions as an oncogene in all three lineages of the exocrine pancreas.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 6","pages":"348-362"},"PeriodicalIF":6.9,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41388-024-03226-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142639462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The dysregulated PI3K/AKT pathway is pivotal in the onset and progression of various cancers, including prostate cancer. However, targeting this pathway directly poses challenges due to compensatory upregulation of alternative oncogenic pathways. This study focuses on the novel regulatory activity of the Receptor for Activated Protein Kinase (RACK1), a scaffolding/adaptor protein, in governing the PI3K/AKT pathway within prostate cancer. Through a genetic mouse model, our research unveils RACK1’s pivotal role in orchestrating AKT activation and the genesis of prostate cancer. RACK1 deficiency hampers AKT activation, effectively impeding prostate tumor formation induced by PTEN and p53 deficiency. Mechanistically, RACK1 facilitates AKT membrane translocation and fosters its interaction with mTORC2, thereby promoting AKT activation and subsequent tumor cell proliferation and tumor formation. Notably, inhibiting AKT activation via RACK1 deficiency does not trigger feedback upregulation of HER3 and androgen receptor (AR) expression and activation, distinguishing it from direct PI3K or AKT targeting. These findings position RACK1 as a critical regulator of the PI3K/AKT pathway and a promising target for curtailing prostate cancer development arising from pathway aberrations.
{"title":"Unveiling RACK1: a key regulator of the PI3K/AKT pathway in prostate cancer development","authors":"Cancan Lyu, Prasanna Kuma Vaddi, Said Elshafae, Anirudh Pradeep, Deqin Ma, Songhai Chen","doi":"10.1038/s41388-024-03224-9","DOIUrl":"10.1038/s41388-024-03224-9","url":null,"abstract":"The dysregulated PI3K/AKT pathway is pivotal in the onset and progression of various cancers, including prostate cancer. However, targeting this pathway directly poses challenges due to compensatory upregulation of alternative oncogenic pathways. This study focuses on the novel regulatory activity of the Receptor for Activated Protein Kinase (RACK1), a scaffolding/adaptor protein, in governing the PI3K/AKT pathway within prostate cancer. Through a genetic mouse model, our research unveils RACK1’s pivotal role in orchestrating AKT activation and the genesis of prostate cancer. RACK1 deficiency hampers AKT activation, effectively impeding prostate tumor formation induced by PTEN and p53 deficiency. Mechanistically, RACK1 facilitates AKT membrane translocation and fosters its interaction with mTORC2, thereby promoting AKT activation and subsequent tumor cell proliferation and tumor formation. Notably, inhibiting AKT activation via RACK1 deficiency does not trigger feedback upregulation of HER3 and androgen receptor (AR) expression and activation, distinguishing it from direct PI3K or AKT targeting. These findings position RACK1 as a critical regulator of the PI3K/AKT pathway and a promising target for curtailing prostate cancer development arising from pathway aberrations.","PeriodicalId":19524,"journal":{"name":"Oncogene","volume":"44 5","pages":"322-335"},"PeriodicalIF":6.9,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142624849","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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