Cancer research最新文献

A Paradigm Shift in Tumor Immunology: Th17 Cells and TGF-β in Intestinal Cancer Initiation

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-18 DOI: 10.1158/0008-5472.can-24-3361

Megan M. Wyatt, Chrystal M. Paulos

{"title":"A Paradigm Shift in Tumor Immunology: Th17 Cells and TGF-β in Intestinal Cancer Initiation","authors":"Megan M. Wyatt, Chrystal M. Paulos","doi":"10.1158/0008-5472.can-24-3361","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-3361","url":null,"abstract":"Cancer remains one of the most complex challenges in modern medicine, with intricate relationships between immune responses and tumor development. This article examines a groundbreaking study by Fesneau, Thevin and colleagues, published in Nature Immunology. This elegant body of work explores the link between chronic inflammation and cancer, particularly focusing on Th17 cells involved in intestinal cancer initiation. Th17 cells, known for their dual roles in immunity, can promote or inhibit tumor growth depending on their environment. This study reveals that a specific subset of Th17 cells, derived from IL-17-producing cells, can transition to a tumorigenic state when TGF-β signaling is impaired. Surprisingly, TGF-β acts as a crucial regulatory factor, maintaining the balance between immune tolerance and tumorigenesis by preventing Th17 cells from becoming tumorigenic. This research highlights the potential for therapeutic interventions targeting TGF-β signaling to prevent cancer initiation in chronic inflammatory conditions. The findings have clinical implications for improving cancer immunotherapies, including immune checkpoint inhibitors and adoptive T cell therapies, by enhancing the efficacy of treatments and mitigating the risk of tumorigenic transformations. Overall, this study provides insights into the mechanisms linking inflammation and cancer, paving the way for innovative strategies to harness the immunity in cancer treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245348","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}

引用次数: 0

Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-18 DOI: 10.1158/0008-5472.can-24-0940

Chengying Cui, Haojie Zhang, Congcong Yang, Mingwei Yin, Xinkun Teng, Miaomiao Yang, Dejie Kong, Jinzhi Zhang, Weidong Peng, Zhimin Chu, Jingjing Wang, Yating Sun, Liping Kang, Bin Lyu, Qian Gao, Mingqing Wu, Yongqiang Wang, Yang Li

{"title":"Inhibition of JNK Signaling Overcomes Cancer-Associated Fibroblast-Mediated Immunosuppression and Enhances the Efficacy of Immunotherapy in Bladder Cancer","authors":"Chengying Cui, Haojie Zhang, Congcong Yang, Mingwei Yin, Xinkun Teng, Miaomiao Yang, Dejie Kong, Jinzhi Zhang, Weidong Peng, Zhimin Chu, Jingjing Wang, Yating Sun, Liping Kang, Bin Lyu, Qian Gao, Mingqing Wu, Yongqiang Wang, Yang Li","doi":"10.1158/0008-5472.can-24-0940","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0940","url":null,"abstract":"Currently, only 20-40% of cancer patients benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunological landscape during treatment are critical for improving responsiveness to immunotherapy. Here, we identified JNK signaling in cancer-associated fibroblasts (CAFs) as a regulator of the immunosuppressive tumor microenvironment. Single-cell RNA sequencing of bladder cancer treated with a JNK inhibitor revealed enhanced cytotoxicity and effector functions of CD8+ T cells. In untreated tumors, CAFs interacted frequently with CD8+ T cells and mediated their exhaustion. JNK inhibition abrogated the immunosuppression function of CAFs by downregulating the expression of TSLP, thereby restoring CD8+ T cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the tumor microenvironment by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for cancer treatment.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142245350","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}

引用次数: 0

Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer 自噬抑制与树突状细胞招募相结合可诱导抗肿瘤免疫并提高胰腺癌免疫检查点阻断剂的敏感性

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-17 DOI: 10.1158/0008-5472.can-24-0830

Koki Oyama, Kohei Nakata, Chikanori Tsutsumi, Masataka Hayashi, Bo Zhang, Yuki Mochida, Tomohiko Shinkawa, Kento Hirotaka, Pingshan Zhong, Satomi Date, Haizhen Luo, Akihiro Kubo, Nobuhiro Higashijima, Yutaka Yamada, Toshiya Abe, Noboru Ideno, Kazuhiro Koikawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Hideya Onishi, Takashi Morisaki, Keiji Kuba, Yoshinao Oda, Masafumi Nakamura

{"title":"Combined Autophagy Inhibition and Dendritic Cell Recruitment Induces Antitumor Immunity and Enhances Immune Checkpoint Blockade Sensitivity in Pancreatic Cancer","authors":"Koki Oyama, Kohei Nakata, Chikanori Tsutsumi, Masataka Hayashi, Bo Zhang, Yuki Mochida, Tomohiko Shinkawa, Kento Hirotaka, Pingshan Zhong, Satomi Date, Haizhen Luo, Akihiro Kubo, Nobuhiro Higashijima, Yutaka Yamada, Toshiya Abe, Noboru Ideno, Kazuhiro Koikawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Hideya Onishi, Takashi Morisaki, Keiji Kuba, Yoshinao Oda, Masafumi Nakamura","doi":"10.1158/0008-5472.can-24-0830","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0830","url":null,"abstract":"The effect of immune checkpoint inhibitors is extremely limited in patients with pancreatic ductal adenocarcinoma (PDAC) due to the suppressive tumor immune microenvironment (TIME). Autophagy, which has been shown to play a role in anti-tumor immunity, has been proposed as a therapeutic target for PDAC. Here, single-cell RNA-sequencing of autophagy-deficient murine PDAC tumors revealed that autophagy inhibition in cancer cells induced dendritic cell (DC) activation. Analysis of human PDAC tumors substantiated a negative correlation between autophagy and DC activation signatures. Mechanistically, autophagy inhibition increased intracellular accumulation of tumor antigens, which could activate DCs. Administration of chloroquine (CQ), an autophagy inhibitor, in combination with Flt3 ligand (Flt3L)-induced DC infiltration inhibited tumor growth and increased tumor-infiltrating T lymphocytes. However, autophagy inhibition in cancer cells also induced CD8+ T cell exhaustion with high expression of immune checkpoint LAG3. A triple therapy comprising CQ, Flt3L, and an anti-LAG3 antibody markedly reduced tumor growth in orthotopic syngeneic PDAC mouse models. Thus, targeting autophagy in cancer cells and activating DCs sensitizes PDAC tumors to immune checkpoint inhibitor therapy, warranting further development of this treatment approach to overcome immunosuppression in pancreatic cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236159","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}

引用次数: 0

CD24-Targeted NIR-II Fluorescence Imaging Enables Early Detection of Colorectal Neoplasia CD24靶向近红外-II荧光成像可实现结直肠肿瘤的早期检测

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-17 DOI: 10.1158/0008-5472.can-24-0012

Xiaoyong Guo, Shuangling Luo, Xiaofeng Wang, Yingying Cui, Miaomiao Li, Zeyu Zhang, Lidan Fu, Caiguang Cao, Xiaojing Shi, Haifeng Liu, Yawei Qu, Xiangyu Gao, Zhenhua Hu, Jie Tian

{"title":"CD24-Targeted NIR-II Fluorescence Imaging Enables Early Detection of Colorectal Neoplasia","authors":"Xiaoyong Guo, Shuangling Luo, Xiaofeng Wang, Yingying Cui, Miaomiao Li, Zeyu Zhang, Lidan Fu, Caiguang Cao, Xiaojing Shi, Haifeng Liu, Yawei Qu, Xiangyu Gao, Zhenhua Hu, Jie Tian","doi":"10.1158/0008-5472.can-24-0012","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0012","url":null,"abstract":"Colorectal cancer (CRC) continues to be a major health issue even though screening methods have facilitated early detection. Despite the high sensitivity of white-light colonoscopy, it frequently overlooks invasive flat or depressed lesions, which can lead to the development of larger, advanced tumors. Fluorescence molecular imaging (FMI) offers a promising approach for early tumor detection by targeting specific molecular characteristics of lesions. CD24 is upregulated during the adenoma-to-CRC transition, providing a potential target for FMI. Here, we developed a second near-infrared window (NIR-II) fluorescent probe with a high affinity for CD24 and evaluated its efficacy and targeting ability in cellular models, murine models, and clinical samples of CRC. CD24 expression was elevated in 76% of adenomas and 80% of CRCs. In a colitis-associated cancer mouse model, NIR-II imaging with the CD24-targeted probe achieved a significantly higher tumor-to-background ratio compared to conventional NIR-I imaging. The probe demonstrated exceptional sensitivity (92%) and specificity (92%) for detecting CRC, including small lesions less than 1 mm in size. This led to the identification of precancerous lesions missed by white-light detection and lesions missed by NIR-I imaging. Moreover, ex vivo human tissue incubation with the probe supported the potential for intraprocedural lesion identification via topical probe application during colonoscopy. In conclusion, this study successfully demonstrates the potential of CD24-targeted NIR-II imaging for identifying colorectal neoplasia, highlighting its significance for early CRC detection in the gastrointestinal tract.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236215","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}

引用次数: 0

mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer mLumiOpto 是一种治疗癌症的线粒体靶向基因疗法

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-17 DOI: 10.1158/0008-5472.can-24-0984

Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D. Ringel, Xiaoguang Liu, Lufang Zhou

{"title":"mLumiOpto is a Mitochondrial-Targeted Gene Therapy for Treating Cancer","authors":"Kai Chen, Patrick Ernst, Anusua Sarkar, Seulhee Kim, Yingnan Si, Tanvi Varadkar, Matthew D. Ringel, Xiaoguang Liu, Lufang Zhou","doi":"10.1158/0008-5472.can-24-0984","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0984","url":null,"abstract":"Mitochondria are important in various aspects of cancer development and progression. Targeting mitochondria in cancer cells holds great therapeutic promise, yet current strategies to specifically and effectively destroy cancer mitochondria in vivo are limited. Here, we developed mLumiOpto, an innovative mitochondrial-targeted luminoptogenetics gene therapy designed to directly disrupt the inner mitochondrial membrane (IMM) potential and induce cancer cell death. The therapeutic approach included synthesis of a blue light-gated cationic channelrhodopsin (CoChR) in the IMM and co-expression of a blue bioluminescence-emitting nanoluciferase (NLuc) in the cytosol of the same cells. The mLumiOpto genes were selectively delivered to cancer cells in vivo by an adeno-associated virus (AAV) carrying a cancer-specific promoter or cancer-targeted monoclonal antibody-tagged exosome-associated AAV (mAb-Exo-AAV). Induction with NLuc luciferin elicited robust endogenous bioluminescence, which activated CoChR, triggering cancer cell mitochondrial depolarization and subsequent cell death. Importantly, mLumiOpto demonstrated remarkable efficacy in reducing tumor burden and killing tumor cells in glioblastoma and triple-negative breast cancer xenograft mouse models. Furthermore, the approach induced an anti-tumor immune response, increasing infiltration of dendritic cells and CD8+ T cells in the tumor microenvironment. These findings establish mLumiOpto as a promising therapeutic strategy by targeting cancer cell mitochondria in vivo.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236260","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}

引用次数: 0

Precise In Situ Delivery of a Photo-enhanceable Inflammasome-Activating Nanovaccine Activates Anti-cancer Immunity 可光照增强的炎症体激活纳米疫苗的精确原位递送激活了抗癌免疫力

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-17 DOI: 10.1158/0008-5472.can-24-0220

Yang Zhou, Li Pang, Tao Ding, Kang Chen, Jinzhao Liu, Meicen Wu, Weiping Wang, Kwan Man

{"title":"Precise In Situ Delivery of a Photo-enhanceable Inflammasome-Activating Nanovaccine Activates Anti-cancer Immunity","authors":"Yang Zhou, Li Pang, Tao Ding, Kang Chen, Jinzhao Liu, Meicen Wu, Weiping Wang, Kwan Man","doi":"10.1158/0008-5472.can-24-0220","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0220","url":null,"abstract":"A variety of state-of-the-art nanovaccines (NVs) combined with immunotherapies have recently been developed to treat malignant tumors, showing promising results. However, immunosuppression in the tumor microenvironment (TME) restrains cytotoxic T cells infiltration and limits the efficacy of immunotherapies in solid tumors. Therefore, tactics for enhancing antigen cross-presentation and reshaping the TME need to be explored to enhance the activity of NV. Here, we developed a photo-enhanceable inflammasome-activating NV (PIN) to achieve precise in situ delivery of a tumor antigen and a hydrophobic small molecule activating the NLRP3-inflammasome pathway. Near-infrared light irradiation promoted PIN accumulation in tumor sites through photo-triggered charge reversal of the nanocarrier. Systematic PIN administration facilitated intratumoral NLRP3 inflammasome activation and antigen cross-presentation in antigen-presenting cells upon light irradiation at tumor sites. Furthermore, PIN treatment triggered immune responses by promoting the production of proinflammatory cytokines and activated of anti-tumor immunity without significant systematic toxicity. Importantly, the PIN enhanced the efficacy of immune checkpoint blockade and supported the establishment of long-term immune memory in mouse models of melanoma and hepatocellular carcinoma. Collectively, this study reports a safe and efficient photoresponsive system for co-delivery of antigens and immune modulators into tumor tissues with promising therapeutic potential.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236160","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}

引用次数: 0

CircRREB1 Mediates Metabolic Reprogramming and Stemness Maintenance to Facilitate Pancreatic Ductal Adenocarcinoma Progression CircRREB1 介导代谢重编程和干性维持，促进胰腺导管腺癌进展

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-17 DOI: 10.1158/0008-5472.can-23-3596

Zeyin Rong, Jin Xu, Jianhui Yang, Wei Wang, Rong Tang, Zifeng Zhang, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Chen Liang, Xianjun Yu, Si Shi

{"title":"CircRREB1 Mediates Metabolic Reprogramming and Stemness Maintenance to Facilitate Pancreatic Ductal Adenocarcinoma Progression","authors":"Zeyin Rong, Jin Xu, Jianhui Yang, Wei Wang, Rong Tang, Zifeng Zhang, Zhen Tan, Qingcai Meng, Jie Hua, Jiang Liu, Bo Zhang, Chen Liang, Xianjun Yu, Si Shi","doi":"10.1158/0008-5472.can-23-3596","DOIUrl":"https://doi.org/10.1158/0008-5472.can-23-3596","url":null,"abstract":"Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal tumor with limited treatment options and poor patient survival. Circular RNAs (circRNAs) play crucial regulatory roles in the occurrence and development of various cancers, including PDAC. Here, using circRNA sequencing of diverse PDAC samples, we identified circRREB1 as an oncogenic circRNA that is significantly upregulated in PDAC and is correlated with an unfavorable patient prognosis. Functionally, loss of circRREB1 markedly inhibited glycolysis and stemness, while elevated circRREB1 elicited the opposite effects. Mechanistically, circRREB1 interacted with PGK1, disrupting the association between PTEN and PGK1 and increasing PGK1 phosphorylation to activate glycolytic flux. Moreover, circRREB1 promoted WNT7B transcription by directly interacting with YBX1 and facilitating its nuclear translocation, consequently activating the Wnt/β-catenin signaling pathway to maintain PDAC stemness. Overall, these results highlight circRREB1 as a key regulator of metabolic and stemness properties of PDAC.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236157","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}

引用次数: 0

The Pivotal Role of Germline BRCA2 Pathogenic Variants in “Apparently Sporadic” Pancreatic Cancer 种系 BRCA2 致病性变异在 "表面散发性 "胰腺癌中的关键作用

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-16 DOI: 10.1158/0008-5472.can-24-2730

Jonathan R. Brody, Alison P. Klein

{"title":"The Pivotal Role of Germline BRCA2 Pathogenic Variants in “Apparently Sporadic” Pancreatic Cancer","authors":"Jonathan R. Brody, Alison P. Klein","doi":"10.1158/0008-5472.can-24-2730","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-2730","url":null,"abstract":"In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360–4","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236207","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}

引用次数: 0

Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling. 同时靶向 NQO1 和 SOD1 可通过线粒体氧化还原循环消灭乳腺癌干细胞

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-12 DOI: 10.1158/0008-5472.can-24-0800

Ming Luo,Na Shen,Li Shang,Zeng Fang,Ying Xin,Yuxi Ma,Min Du,Yuan Yuan,Chenchen Hu,Yun Tang,Jing Huang,Wei Wei,Myung Ryul Lee,Paul J Hergenrother,Max S Wicha

{"title":"Simultaneous Targeting of NQO1 and SOD1 Eradicates Breast Cancer Stem Cells via Mitochondrial Futile Redox Cycling.","authors":"Ming Luo,Na Shen,Li Shang,Zeng Fang,Ying Xin,Yuxi Ma,Min Du,Yuan Yuan,Chenchen Hu,Yun Tang,Jing Huang,Wei Wei,Myung Ryul Lee,Paul J Hergenrother,Max S Wicha","doi":"10.1158/0008-5472.can-24-0800","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-0800","url":null,"abstract":"Triple negative breast cancer (TNBC) contains the highest proportion of cancer stem-like cells (CSCs), which display intrinsic resistance to currently available cancer therapies. This therapeutic resistance is partially mediated by an antioxidant defense coordinated by the transcription factor NRF2 and its downstream targets including NQO1. Here, we identified the antioxidant enzymes NQO1 and SOD1 as therapeutic vulnerabilities of ALDH+ epithelial-like CSCs and CD24-/loCD44+/hi mesenchymal-like CSCs in TNBC. Effective targeting of these CSC states was achieved by utilizing IB-DNQ, a potent and specific NQO1-bioactivatable futile redox cycling molecule, which generated large amounts of reactive oxygen species (ROS) including superoxide and hydrogen peroxide. Furthermore, the CSC killing effect was specifically enhanced by genetic or pharmacological inhibition of SOD1, a copper-containing superoxide dismutase highly expressed in TNBC. Mechanistically, a significant portion of NQO1 resided in the mitochondrial intermembrane space, catalyzing futile redox cycling from IB-DNQ to generate high levels of mitochondrial superoxide, and SOD1 inhibition markedly potentiated this effect resulting in mitochondrial oxidative injury, cytochrome c release, and activation of the caspase 3-mediated apoptotic pathway. Treatment with IB-DNQ alone or together with SOD1 inhibition effectively suppressed tumor growth, metastasis, and tumor-initiating potential in xenograft models of TNBC expressing different levels of NQO1. This futile oxidant-generating strategy, which targets CSCs across the epithelial-mesenchymal continuum, could be a promising therapeutic approach for treating TNBC patients.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174534","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}

引用次数: 0

Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1. 前列腺癌的神经内分泌分化需要 ASCL1

IF 11.2 1区医学

Cancer research Pub Date : 2024-09-12 DOI: 10.1158/0008-5472.can-24-1388

Kathia E Rodarte,Shaked Nir Heyman,Lei Guo,Lydia Flores,Trisha K Savage,Juan Villarreal,Su Deng,Lin Xu,Rajal B Shah,Trudy G Oliver,Jane E Johnson

{"title":"Neuroendocrine Differentiation in Prostate Cancer Requires ASCL1.","authors":"Kathia E Rodarte,Shaked Nir Heyman,Lei Guo,Lydia Flores,Trisha K Savage,Juan Villarreal,Su Deng,Lin Xu,Rajal B Shah,Trudy G Oliver,Jane E Johnson","doi":"10.1158/0008-5472.can-24-1388","DOIUrl":"https://doi.org/10.1158/0008-5472.can-24-1388","url":null,"abstract":"Most patients with prostate adenocarcinoma develop resistance to therapies targeting the androgen receptor (AR). Consequently, a portion of these patients develop AR-independent neuroendocrine prostate cancer (NEPC), a rapidly progressing cancer with limited therapies and poor survival outcomes. Current research to understand the progression to NEPC suggests a model of lineage plasticity whereby AR-dependent luminal-like tumors progress towards an AR-independent NEPC state. Genetic analysis of human NEPC identified frequent loss of RB1 and TP53, and the loss of both genes in experimental models mediates the transition to a neuroendocrine lineage. Transcriptomics studies have shown that lineage transcription factors ASCL1 and NEUROD1 are present in NEPC. In this study, we modeled the progression of prostate adenocarcinoma to NEPC by establishing prostate organoids and subsequently generating subcutaneous allograft tumors from genetically-engineered mouse models harboring Cre-induced loss of Rb1 and Trp53 with Myc overexpression (RPM). These tumors were heterogeneous and displayed adenocarcinoma, squamous, and neuroendocrine features. ASCL1 and NEUROD1 were expressed within neuroendocrine-defined regions, with ASCL1 being predominant. Genetic loss of Ascl1 in this model did not decrease tumor incidence, growth, or metastasis; however, there was a notable decrease in neuroendocrine identity and an increase in basal-like identity. This study provides an in vivo model to study progression to NEPC and establishes the requirement for ASCL1 in driving neuroendocrine differentiation in prostate cancer.","PeriodicalId":9441,"journal":{"name":"Cancer research","volume":null,"pages":null},"PeriodicalIF":11.2,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142174533","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}

引用次数: 0