首页 > 最新文献

Molecular Cancer Research最新文献

英文 中文
Metabolic Inhibition Induces Pyroptosis in Uveal Melanoma. 代谢抑制诱导葡萄膜黑色素瘤热下垂。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0508
Scott D Varney, Dan A Erkes, Glenn L Mersky, Manal U Mustafa, Vivian Chua, Inna Chervoneva, Timothy J Purwin, Emad Alnemri, Andrew E Aplin

Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.

转移性葡萄膜黑色素瘤(UM)患者的治疗选择很少。尽管双特异性tebentafusp已获得fda批准,但免疫治疗在很大程度上失败了,可能是由于UM的免疫原性较差。改善免疫系统对UM的识别的治疗方案可能是减轻疾病负担的关键。我们研究了UM是否有能力经历焦亡,一种免疫原性细胞死亡的形式。公开的患者数据和细胞系分析表明,UM表达了焦亡所需的机制,包括gasdermins D和E (GSDMD和E), caspases 1、3、4和8 (CASP1、3、4和8)和ninjurin1 (NINJ1)。我们用代谢抑制剂诱导UM细胞系的气真皮分裂。特别是,CPT1抑制剂乙托莫西诱导碘化丙啶摄取、caspase 3裂解以及HMGB1和IL-1β的释放,表明观察到的裂解导致了焦亡。重要的是,反映CPT1A活性的基因标记与UM患者预后不良相关,CPT1A的敲低也会引起焦亡。在一组UM患者中,依托莫西诱导的焦亡依赖于gsdme,但不依赖于gsdmd,并且焦亡基因特征与免疫浸润和对免疫检查点阻断的改善反应相关。总之,这些数据表明,代谢抑制剂可以诱导UM细胞系焦亡,可能为增强转移性UM患者炎症介导的免疫靶向提供了一种方法。意义:通过代谢抑制诱导焦亡可能改变肿瘤免疫微环境,提高免疫治疗葡萄膜黑色素瘤的疗效。
{"title":"Metabolic Inhibition Induces Pyroptosis in Uveal Melanoma.","authors":"Scott D Varney, Dan A Erkes, Glenn L Mersky, Manal U Mustafa, Vivian Chua, Inna Chervoneva, Timothy J Purwin, Emad Alnemri, Andrew E Aplin","doi":"10.1158/1541-7786.MCR-24-0508","DOIUrl":"10.1158/1541-7786.MCR-24-0508","url":null,"abstract":"<p><p>Few treatment options are available for patients with metastatic uveal melanoma. Although the bispecific tebentafusp is FDA approved, immunotherapy has largely failed, likely given the poorly immunogenic nature of uveal melanoma. Treatment options that improve the recognition of uveal melanoma by the immune system may be key to reducing disease burden. We investigated whether uveal melanoma has the ability to undergo pyroptosis, a form of immunogenic cell death. Publicly available patient data and cell line analysis showed that uveal melanoma expressed the machinery needed for pyroptosis, including gasdermins D and E (GSDMD and E), caspases 1, 3, 4, and 8, and ninjurin-1. We induced cleavage of GSDMs in uveal melanoma cell lines treated with metabolic inhibitors. In particular, the carnitine palmitoyltransferase 1 (CPT1) inhibitor, etomoxir, induced propidium iodide uptake, caspase 3 cleavage, and the release of HMGB1 and IL-1β, indicating that the observed cleavage of GSDMs led to pyroptosis. Importantly, a gene signature reflecting CPT1A activity correlated with poor prognosis in patients with uveal melanoma and knockdown of CPT1A also induced pyroptosis. Etomoxir-induced pyroptosis was dependent on GSDME but not on GSDMD, and a pyroptosis gene signature correlated with immune infiltration and improved response to immune checkpoint blockade in a set of patients with uveal melanoma. Together, these data show that metabolic inhibitors can induce pyroptosis in uveal melanoma cell lines, potentially offering an approach to enhance inflammation-mediated immune targeting in patients with metastatic uveal melanoma. Implications: Induction of pyroptosis by metabolic inhibition may alter the tumor immune microenvironment and improve the efficacy of immunotherapy in uveal melanoma.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"350-362"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142818668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intracellular Retention of Estradiol Is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells. 乳腺癌细胞中含有GRAM结构域的蛋白ASTER-B介导雌二醇的细胞内滞留。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0533
Hyung Bum Kim, W Lee Kraus

Elevated blood levels of estrogens have been associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating hormone levels in the blood and intracellular hormone concentrations is not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon the removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. Although circulating E2 is sequestered by sex hormone binding globulin, the potential mechanisms of intracellular E2 retention are poorly understood. We found that mislocalization of a steroid-binding GRAM domain-containing protein, ASTER-B, to the nucleus, which is observed in a subset of patients with breast cancer, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2 and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERα chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes. Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.

雌激素受体阳性(ER+)乳腺癌患者血中雌激素水平升高与预后不良相关,但循环血中激素水平与细胞内激素浓度之间的关系尚不清楚。我们观察到,即使从培养基中去除激素,经17β-雌二醇(E2)急性处理的MCF-7细胞仍保留了大量的激素。此外,E2依赖性基因表达的全局模式在急性E2治疗和激素去除后持续数小时。虽然循环中的E2被性激素结合球蛋白(SHBG)隔离,但细胞内E2滞留的潜在机制尚不清楚。我们发现,在一部分乳腺癌患者中观察到的含有类固醇结合克结构域的蛋白ASTER-B在细胞核中的错误定位与较高的细胞E2保留有关。E2的积累和保留与E2的甾体特性有关,并且需要细胞核定位和与ASTER-B的类固醇结合,如图所示为一组突变的ASTER-B蛋白。最后,我们观察到核aster - b介导的E2保留是持续激素诱导的er - α染色质占用增强子和基因表达以及随后的细胞生长反应所必需的。我们的研究结果表明细胞内激素保留是控制e2依赖基因表达和下游生物学结果的机制。结论:错定位的核ASTER-B结合雌二醇支持ER的功能,可以提供一种增强E2在乳腺癌中的生物学效应的替代方法,并且可能是解决雌激素生物利用度多个方面的潜在治疗靶点。
{"title":"Intracellular Retention of Estradiol Is Mediated by GRAM Domain-Containing Protein ASTER-B in Breast Cancer Cells.","authors":"Hyung Bum Kim, W Lee Kraus","doi":"10.1158/1541-7786.MCR-24-0533","DOIUrl":"10.1158/1541-7786.MCR-24-0533","url":null,"abstract":"<p><p>Elevated blood levels of estrogens have been associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating hormone levels in the blood and intracellular hormone concentrations is not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon the removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. Although circulating E2 is sequestered by sex hormone binding globulin, the potential mechanisms of intracellular E2 retention are poorly understood. We found that mislocalization of a steroid-binding GRAM domain-containing protein, ASTER-B, to the nucleus, which is observed in a subset of patients with breast cancer, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2 and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERα chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes. Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"313-326"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142971681","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis. 非典型BRAF和KRAS突变在结直肠肿瘤发生中的共同进化。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0464
Connor E Woolley, Enric Domingo, Juan Fernandez-Tajes, Kathryn A F Pennel, Patricia Roxburgh, Joanne Edwards, Susan D Richman, Tim S Maughan, David J Kerr, Ignacio Soriano, Ian P M Tomlinson

BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non-class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2-mutant and class 3-mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.

结直肠癌(CRC)中的BRAF突变包括三个功能类别:具有强组成激活的1类(V600E),致病激酶活性低于1类的2类,以及矛盾地缺乏激酶活性的3类。非1类突变与更好的预后、微卫星稳定性、远端肿瘤位置和更好的抗egfr反应相关。对13个CRC队列(n= 6605个肿瘤)进行分析,比较1类(n=709,占CRC的10.7%)、2类(n=31, 0.47%)和3类(n=81, 1.22%)突变。2类和3类突变型crc经常与其他Ras通路突变同时发生(分别为29.0%和45.7%,而1类为2.40%,p
{"title":"Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis.","authors":"Connor E Woolley, Enric Domingo, Juan Fernandez-Tajes, Kathryn A F Pennel, Patricia Roxburgh, Joanne Edwards, Susan D Richman, Tim S Maughan, David J Kerr, Ignacio Soriano, Ian P M Tomlinson","doi":"10.1158/1541-7786.MCR-24-0464","DOIUrl":"10.1158/1541-7786.MCR-24-0464","url":null,"abstract":"<p><p>BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non-class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2-mutant and class 3-mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"300-312"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7617415/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142922372","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}
引用次数: 0
The Role of WDR77 in Cancer: More than a PRMT5 Interactor.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0933
Isaac Silverman, Aaron Shaykevich, Radhashree Maitra

WD repeat domain 77 protein (WDR77), a WD-40 domain-containing protein, is a crucial regulator of cellular pathways in cancer progression. Although much of the past research on WDR77 has focused on its interaction with protein arginine methyltransferase 5 (PRMT5) in histone methylation, WDR77's regulatory functions extend beyond this pathway, influencing diverse mechanisms such as mRNA translation, chromatin assembly, cell-cycle regulation, and apoptosis. WDR77 is a key regulator of cell-cycle progression, regulating the transition from the G1 phase. WDR77 regulates many signaling pathways such as TGFβ in which its role in these cellular pathways underscores its broad oncogenic potential. WDR77 also assists and promotes certain transcription factors such as E2F. Furthermore, in certain cancers, WDR77 enhances steroid hormone receptor activity, uniquely linking it to hormone-driven malignancies. WDR77 often translocates between the nucleus and the cytoplasm, with its location dictating its role in the cell. WDR77 has the ability to adapt its function depending on its location that emphasizes its dynamic role in both promoting and inhibiting tumor growth, depending on cellular context. This dual function makes WDR77 an attractive therapeutic target, as disrupting its interactions with critical signaling pathways or modulating its translocation could yield novel strategies for cancer treatment. Given WDR77's role in oncogenic pathways independent of PRMT5, further exploration of WDR77 and its non-PRMT5-related activities may reveal additional therapeutic opportunities in an array of cancers.

{"title":"The Role of WDR77 in Cancer: More than a PRMT5 Interactor.","authors":"Isaac Silverman, Aaron Shaykevich, Radhashree Maitra","doi":"10.1158/1541-7786.MCR-24-0933","DOIUrl":"10.1158/1541-7786.MCR-24-0933","url":null,"abstract":"<p><p>WD repeat domain 77 protein (WDR77), a WD-40 domain-containing protein, is a crucial regulator of cellular pathways in cancer progression. Although much of the past research on WDR77 has focused on its interaction with protein arginine methyltransferase 5 (PRMT5) in histone methylation, WDR77's regulatory functions extend beyond this pathway, influencing diverse mechanisms such as mRNA translation, chromatin assembly, cell-cycle regulation, and apoptosis. WDR77 is a key regulator of cell-cycle progression, regulating the transition from the G1 phase. WDR77 regulates many signaling pathways such as TGFβ in which its role in these cellular pathways underscores its broad oncogenic potential. WDR77 also assists and promotes certain transcription factors such as E2F. Furthermore, in certain cancers, WDR77 enhances steroid hormone receptor activity, uniquely linking it to hormone-driven malignancies. WDR77 often translocates between the nucleus and the cytoplasm, with its location dictating its role in the cell. WDR77 has the ability to adapt its function depending on its location that emphasizes its dynamic role in both promoting and inhibiting tumor growth, depending on cellular context. This dual function makes WDR77 an attractive therapeutic target, as disrupting its interactions with critical signaling pathways or modulating its translocation could yield novel strategies for cancer treatment. Given WDR77's role in oncogenic pathways independent of PRMT5, further exploration of WDR77 and its non-PRMT5-related activities may reveal additional therapeutic opportunities in an array of cancers.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"269-276"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143033758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor Microenvironment: Obstacles and Opportunities for T Cell-Based Tumor Immunotherapies.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0747
Miao-Miao Hu, Ying Zhao, Nan Zhang, Fang-Yuan Gong, Wei Zhang, Chun-Sheng Dong, Jian-Feng Dai, Jun Wang

The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.

{"title":"Tumor Microenvironment: Obstacles and Opportunities for T Cell-Based Tumor Immunotherapies.","authors":"Miao-Miao Hu, Ying Zhao, Nan Zhang, Fang-Yuan Gong, Wei Zhang, Chun-Sheng Dong, Jian-Feng Dai, Jun Wang","doi":"10.1158/1541-7786.MCR-24-0747","DOIUrl":"10.1158/1541-7786.MCR-24-0747","url":null,"abstract":"<p><p>The complex composition and dynamic change of the tumor microenvironment (TME), mainly consisting of tumor cells, immune cells, stromal cells, and extracellular components, significantly impede the effector function of cytotoxic T lymphocytes (CTL), thus representing a major obstacle for tumor immunotherapies. In this review, we summarize and discuss the impacts and underlying mechanisms of major elements in the TME (different cell types, extracellular matrix, nutrients and metabolites, etc.) on the infiltration, survival, and effector functions of T cells, mainly CD8+ CTLs. Moreover, we also highlight recent advances that may potentiate endogenous antitumor immunity and improve the efficacy of T cell-based immunotherapies in patients with cancer by manipulating components inside/outside of the TME. A deeper understanding of the effects and action mechanisms of TME components on the tumor-eradicating ability of CTLs may pave the way for discovering new targets to augment endogenous antitumor immunity and for designing combinational therapeutic regimens to enhance the efficacy of tumor immunotherapies in the clinic.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"277-287"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143079821","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Bmal1-Mediated Circadian MELK Expression Potentiates MELK Inhibitor Chronotherapy for Esophageal Cancer. bmal1介导的MELK昼夜表达增强了MELK抑制剂对食管癌的时间治疗。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0498
Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang

Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model, and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in patients with ESCC and were accompanied by altered expression of core clock genes, especially, since Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, whereas the knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumors, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.

食管鳞状细胞癌(ESCC)仍然是一个全球性的健康挑战。生物钟和母体胚胎亮氨酸拉链激酶(MELK)在肿瘤发生中起关键作用。然而,在ESCC的发生和发展过程中,生物钟失调和MELK功能之间的联系仍然是未知的。在体内和体外系统中,我们首次发现MELK在小鼠食管组织、异种移植模型和人ESCC细胞中表现出明显的昼夜节律表达。正常食管组织中峰(ZT0)与谷(ZT12)点的日表达差异接近10倍。Bmal1通过结合MELK启动子调控ESCC细胞中MELK的昼夜表达。支持这一观点的是,ESCC患者的MELK水平显著升高,并伴有核心时钟基因的表达改变,尤其是Bmal1显著上调。最重要的是,bmal1的缺失消除了MELK的节律性表达,而敲低其他核心基因对MELK的表达没有影响。此外,在移植瘤裸鼠中,ZT0给药OTS167的抗癌作用是ZT12的两倍。我们的研究结果表明,MELK代表了一个治疗靶点,并且可以作为昼夜节律控制ESCC生长的调节剂,这些发现促进了我们对时间疗法的临床潜力的理解,以及基于时间的MELK抑制在癌症治疗中的重要性。
{"title":"Bmal1-Mediated Circadian MELK Expression Potentiates MELK Inhibitor Chronotherapy for Esophageal Cancer.","authors":"Boning Zeng, Chao Sun, Qian Tang, Nan Li, Siying Chen, Yili Yang, Xiao Wang, Shaoxiang Wang","doi":"10.1158/1541-7786.MCR-24-0498","DOIUrl":"10.1158/1541-7786.MCR-24-0498","url":null,"abstract":"<p><p>Esophageal squamous cell carcinoma (ESCC) remains a global health challenge. Circadian clock and maternal embryonic leucine zipper kinase (MELK) play a key role in tumorigenesis. However, a link between circadian clock dysregulation and MELK function in the occurrence and development of ESCC remains elusive. Here, In the in vivo and in vitro systems, we found for the first time that MELK exhibits pronounced circadian rhythms expression in mice esophageal tissue, xenograft model, and human ESCC cells. The diurnal differences expression between peak (ZT0) and trough (ZT12) points in normal esophageal tissue is nearly 10-fold. Circadian expression of MELK in ESCC cells was regulated by Bmal1 through binding to the MELK promoter. Supporting this, the levels of MELK were increased significantly in patients with ESCC and were accompanied by altered expression of core clock genes, especially, since Bmal1 is prominently upregulated. Most importantly, Bmal1-deleted eliminated the rhythmic expression of MELK, whereas the knockdown of other core genes had no effect on MELK expression. Furthermore, in nude mice with transplanted tumors, the anticancer effect of OTS167 at ZT0 administration is twice that of ZT12. Implications: Our findings suggest that MELK represents a therapeutic target, and can as a regulator of circadian control ESCC growth, with these findings advance our understanding of the clinical potential of chronotherapy and the importance of time-based MELK inhibition in cancer treatment.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"288-299"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck. 溶酶体/线粒体相互作用促进头颈部鳞状细胞癌的肿瘤生长。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0337
Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri

Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal-mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A-expressing SCCHN.

包括溶酶体和线粒体在内的胞内细胞器之间的通信最近被证明可以调节细胞增殖和适应性。溶酶体和线粒体相互沟通的方式(溶酶体/线粒体相互作用,LMI)正在成为肿瘤增殖和生长的主要决定因素。约30%的鳞状癌(包括头颈部鳞状细胞癌,SCCHN)过表达TMEM16A,这是一种钙活化的氯离子通道,促进细胞生长并与患者生存负相关。我们最近表明TMEM16A驱动溶酶体的生物发生,但其对线粒体功能的影响尚未探讨。在这里,我们表明,在高TMEM16A SCCHN的背景下,(1)患者显示线粒体含量增加,特别是复合物I;(2)体外和体内模型的生长和存活完全依赖线粒体复合体I的活性;(3) NRF2信号是驱动线粒体功能的关键关键;(4)线粒体复合体I和溶酶体功能在增殖过程中相互依赖。综上所述,我们的数据表明,通过LMI协调的溶酶体和线粒体活性和生物发生驱动肿瘤增殖,并促进溶酶体和线粒体网络之间的功能相互作用。因此,抑制LMI恢复可能是SCCHN患者的一种治疗策略。意义:干预溶酶体-线粒体相互作用可能是治疗高TMEM16A表达SCCHN患者的一种方法。
{"title":"Lysosomal-Mitochondrial Interaction Promotes Tumor Growth in Squamous Cell Carcinoma of the Head and Neck.","authors":"Avani Gopalkrishnan, Nathaniel Wang, Silvia Cruz-Rangel, Abdul Yassin-Kassab, Sruti Shiva, Chareeni Kurukulasuriya, Satdarshan P Monga, Ralph J DeBerardinis, Heath D Skinner, Kirill Kiselyov, Umamaheswar Duvvuri","doi":"10.1158/1541-7786.MCR-24-0337","DOIUrl":"10.1158/1541-7786.MCR-24-0337","url":null,"abstract":"<p><p>Communication between intracellular organelles including lysosomes and mitochondria has recently been shown to regulate cellular proliferation and fitness. The way lysosomes and mitochondria communicate with each other [lysosomal-mitochondrial interaction (LMI)] is emerging as a major determinant of tumor proliferation and growth. About 30% of squamous carcinomas [including squamous cell carcinoma of the head and neck (SCCHN)] overexpress transmembrane member 16A (TMEM16A), a calcium-activated chloride channel, which promotes cellular growth and negatively correlates with patient survival. We have recently shown that TMEM16A drives lysosomal biogenesis; however, its impact on mitochondrial function has not been explored. In this study, we show that in the context of high-TMEM16A SCCHN, (i) patients display increased mitochondrial content, specifically complex I; (ii) in vitro and in vivo models uniquely depend on mitochondrial complex I activity for growth and survival; (iii) NRF2 signaling is a critical linchpin that drives mitochondrial function, and (iv) mitochondrial complex I and lysosomal function are codependent for proliferation. Taken together, our data demonstrate that coordinated lysosomal and mitochondrial activity and biogenesis via LMI drive tumor proliferation and facilitate a functional interaction between lysosomal and mitochondrial networks. Therefore, inhibition of LMI instauration may serve as a therapeutic strategy for patients with SCCHN. Implications: Intervention of LMI may serve as a therapeutic approach for patients with high TMEM16A-expressing SCCHN.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"339-349"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142854576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities. 探讨B7-H4在前列腺癌雄激素剥夺治疗后休眠中的作用:细胞外基质相互作用和治疗机会。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0958
Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang

Prostate cancer is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique prostate cancer patient-derived xenograft dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of patients with prostate cancer treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within the dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during prostate cancer dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.

前列腺癌(PCa)主要通过雄激素剥夺疗法(ADT)进行治疗,但这通常导致休眠状态并随后复发为致命的去势抵抗性前列腺癌(CRPC)。利用我们独特的PCa患者来源的异种移植物(PDX)休眠模型,我们研究了这一关键休眠阶段,并发现在小鼠宿主去势后的休眠期间B7-H4表达选择性增加。这一发现得到了用ADT治疗的PCa患者临床标本观察结果的支持。差异表达分析显示b7 - h4阳性细胞中细胞外基质(ECM)-细胞相互作用通路富集。功能分析表明B7-H4在维持ECM生态位内的休眠中起着至关重要的作用。具体来说,LNCaP细胞中B7-H4的表达减少了体外休眠ECM的增殖,并显著延缓了体内阉割宿主的复发。这些结果揭示了B7-H4在PCa休眠期间的动态调控,并强调了其作为预防CRPC复发的治疗靶点的潜力。意义:我们的研究发现了adt诱导的休眠期间膜性B7-H4的表达,突出了其作为治疗休眠前列腺癌和预防致命CRPC复发的治疗靶点的潜力。
{"title":"Exploring B7-H4's Role in Prostate Cancer Dormancy after Androgen Deprivation Therapy: Extracellular Matrix Interactions and Therapeutic Opportunities.","authors":"Ning Kang, Hui Xue, Nelson K Y Wong, Yen-Yi Lin, Adam Classen, Rebecca Wu, Htoo Zarni Oo, Xin Dong, Angela Trinh, Dong Lin, Mads Daugaard, Christopher Ong, Colin Collins, Martin Gleave, Yuzhuo Wang","doi":"10.1158/1541-7786.MCR-24-0958","DOIUrl":"10.1158/1541-7786.MCR-24-0958","url":null,"abstract":"<p><p>Prostate cancer is mainly managed with androgen deprivation therapy (ADT), but this often leads to a dormant state and subsequent relapse as lethal castration-resistant prostate cancer (CRPC). Using our unique prostate cancer patient-derived xenograft dormancy models, we investigated this critical dormant phase and discovered a selective increase in B7-H4 expression during the dormancy period following mouse host castration. This finding is supported by observations in clinical specimens of patients with prostate cancer treated with ADT. Differential expression analyses revealed the enrichment of extracellular matrix (ECM)-cell interaction pathways in B7-H4-positive cells. Functional assays demonstrated a crucial role of B7-H4 in maintaining dormancy within the ECM niche. Specifically, B7-H4 expression in LNCaP cells reduced proliferation within the dormant ECM in vitro and significantly delayed relapse in castrated hosts in vivo. These results shed light on the dynamic regulation of B7-H4 during prostate cancer dormancy and underscore its potential as a therapeutic target for preventing CRPC relapse. Implications: Our study identified membranous B7-H4 expression during ADT-induced dormancy, highlighting its potential as a therapeutic target for managing dormant prostate cancer and preventing fatal CRPC relapse.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":"327-338"},"PeriodicalIF":4.1,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142951495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Single-cell and spatial transcriptomics reveal a tumor-associated macrophage subpopulation that mediates prostate cancer progression and metastasis.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-03-19 DOI: 10.1158/1541-7786.MCR-24-0791
Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl

Tumor-associated macrophages (TAMs) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA-sequencing, spatial transcriptomics and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their pro-tumorigenic role. Blocking SPP1 in RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment, and increased CD8 T cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition (ICI) in advanced prostate cancer. Implications: This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.

{"title":"Single-cell and spatial transcriptomics reveal a tumor-associated macrophage subpopulation that mediates prostate cancer progression and metastasis.","authors":"Shenglin Mei, Hanyu Zhang, Taghreed Hirz, Nathan Elias Jeffries, Yanxin Xu, Ninib Baryawno, Shulin Wu, Chin-Lee Wu, Akash Patnaik, Philip J Saylor, David B Sykes, Douglas M Dahl","doi":"10.1158/1541-7786.MCR-24-0791","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0791","url":null,"abstract":"<p><p>Tumor-associated macrophages (TAMs) are a transcriptionally heterogeneous population, and their abundance and function in prostate cancer is poorly defined. We integrated parallel datasets from single-cell RNA-sequencing, spatial transcriptomics and multiplex immunofluorescence to reveal the dynamics of TAMs in primary and metastatic prostate cancer. Four TAM subpopulations were identified. Notably, one of these TAM subsets was defined by the co-expression of SPP1+ and TREM2+ and was significantly enriched in metastatic tumors. The SPP1+/TREM2+ TAMs were enriched in the metastatic tumor microenvironment in both human patient samples and murine models of prostate cancer. The abundance of these SPP1+/TREM2+ macrophages was associated with patient progression free survival. Spatially, TAMs within prostate cancer bone metastases were highly enriched within the tumor region, consistent with their pro-tumorigenic role. Blocking SPP1 in RM1 prostate cancer mouse model led to improved efficacy of anti-PD-1 treatment, and increased CD8 T cell infiltration in tumor. These findings suggest that targeting SPP1+ TAMs may offer a promising therapeutic strategy and potentially enhance the effects of immune checkpoint inhibition (ICI) in advanced prostate cancer. Implications: This study expands our understanding of the diverse roles of macrophage populations in prostate cancer metastases and highlights new therapeutic targets.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143657868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1. Empty spiracles homeobox 2 (EMX2) 转录因子通过靶向 CADM1 在肾细胞癌中发挥肿瘤抑制因子的功能。
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-03-17 DOI: 10.1158/1541-7786.MCR-24-0496
Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang

Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of EMX2 in RCC patients and revealed a significant reduction of EMX2 expression, correlating with poor RCC patient prognosis. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA-seq and chromatin immunoprecipitation sequencing analyses, we have identified Cell Adhesion Molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates Caspase-3-dependent apoptosis in attached RCC cells. Furthermore, EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by EMX2-CADM1 axis promote RCC cell death and suppresse its growth and invasion, providing potential intervention strategies for combating RCC. Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in renal cell carcinoma, which could lead to more effective treatment strategies for this aggressive malignancy.

{"title":"Empty spiracles homeobox 2 (EMX2) transcription factor functions as a tumor suppressor in renal cell carcinoma by targeting CADM1.","authors":"Zhibin Fu, Wenqi Chen, Di Gu, Juan Li, Kai Dong, Yuying Lan, Tao Liu, Bianhong Zhang, Lei Li, Ethan Lee, Chenghua Yang, Tao P Zhong, Linhui Wang","doi":"10.1158/1541-7786.MCR-24-0496","DOIUrl":"https://doi.org/10.1158/1541-7786.MCR-24-0496","url":null,"abstract":"<p><p>Renal cell carcinoma (RCC), a prevalent urinary system malignancy, often metastasizes at an early stage. Characterized by a complex pathogenesis and high mortality rate, RCC poses a significant clinical challenge. We evaluated the expression level of EMX2 in RCC patients and revealed a significant reduction of EMX2 expression, correlating with poor RCC patient prognosis. EMX2 functions as a tumor suppressor and inhibits RCC cell proliferation and migration, accompanied by programmed cell death. Implantation of EMX2-transduced RCC cells beneath the mouse kidney capsule or subcutaneous injection of transduced RCC cells results in a reduction in tumor growth and size. Through RNA-seq and chromatin immunoprecipitation sequencing analyses, we have identified Cell Adhesion Molecule 1 (CADM1) as a direct transcriptional target of EMX2's suppressive effects. CADM1 induction by EMX2 triggers PARP1-mediated parthanatos, a specific type of cell death due to mitochondrial oxidation reduction, in migrating RCC cells. Concurrently, EMX2-CADM1 upregulation instigates Caspase-3-dependent apoptosis in attached RCC cells. Furthermore, EMX2-CADM1 transcriptional axis also inhibits the PI3K-AKT pathway to impair RCC cell growth. Hence, the orchestrated effects mediated by EMX2-CADM1 axis promote RCC cell death and suppresse its growth and invasion, providing potential intervention strategies for combating RCC. Implications: The EMX2-CADM1 transcriptional axis offers a promising therapeutic target for inducing cell death and inhibiting growth and invasion in renal cell carcinoma, which could lead to more effective treatment strategies for this aggressive malignancy.</p>","PeriodicalId":19095,"journal":{"name":"Molecular Cancer Research","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
期刊
Molecular Cancer Research
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1