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Spatial analysis of hereditary diffuse gastric cancer reveals indolent phenotype of signet ring cell precursors.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-07 DOI: 10.1158/1541-7786.MCR-24-1039
Amber F Gallanis, Lauren A Gamble, Cihan Oguz, Sarah G Samaranayake, Noemi Kedei, Maria O Hernandez, Madeline Wong, Desiree Tillo, Benjamin L Green, Paul McClelland, Cassidy Bowden, Irene Gullo, Mark Raffeld, Liqiang Xi, Michael Kelly, Markku Miettinen, Martha Quezado, Sun A Kim, Andrew M Blakely, Justin Lack, Theo Heller, Jonathan M Hernandez, Jeremy L Davis

Germline CDH1 loss-of-function mutations are causally linked to an increased lifetime risk of diffuse gastric cancer (DGC). Early, multifocal signet ring cell (SRC) lesions are ubiquitous among CDH1 variant carriers, yet only a subset of patients will develop advanced DGC. A multi-omics analysis was performed to establish the molecular phenotype of early SRC lesions and how they differ from advanced DGC using 20 samples from human total gastrectomy specimens of germline CDH1 variant carriers. Spatial transcriptomic analysis demonstrated reduced CDH1 gene expression and increased expression of ECM remodeling in SRC lesions compared to unaffected adjacent gastric epithelium. Single cell RNA sequencing revealed an SRC-enriched signature with markers REG1A, VIM, AQP5, PRR4, MUC6, and AGR2. Importantly, SRC lesions lacked alterations in known drivers of gastric cancer (TP53, ARID1A, KRAS) and activation of associated signal transduction pathways. Advanced DGC demonstrated E-cadherin re-expression, somatic TP53 and ERBB3 mutations, and upregulated CTNNA1, MYC, and MET expression when compared to SRC lesions. Implications: The marked differences in genomic and transcriptomic profile of SRC lesions and advanced DGC support the consideration of SRC lesions as precancers in patients with germline CDH1 mutations.

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引用次数: 0
Emerging Roles of ACTL6A as an Oncogenic Hub: Transcriptional Regulation and Beyond.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-07 DOI: 10.1158/1541-7786.MCR-25-0059
Kelvin K Tsai, Li-Hsin Cheng, Chung-Chi Hsu, Pei-Ming Yang, Chih-Pin Chuu

The malignant progression of human cancer is dictated by specific regulatory hubs coordinating multiple signaling modules. Identifying key oncogenic hubs of human cancers may lay the groundwork for developing breakthrough therapeutic strategies. Actin-like 6A (ACTL6A; BAF53A) was originally identified as a chromatin remodeling factor involved in the transcriptional regulation of genes, especially in stem and progenitor cells. The preponderance of evidence revealed the overexpression of ACTL6A in most cancers and its crucial role in various malignant phenotypes, including cell cycle progression, cancer stemness, epithelial-to-mesenchymal transition, redox and glucose metabolism, and DNA replication and repair. Interestingly, emerging data suggest that the oncogenic function of ACTL6A is mediated through diverse mechanisms beyond its canonical function in transcriptional regulation, including notably the stabilization of oncoproteins and stemness factors, such as YAP, VPS72, and MYC. Here, we describe the isoforms and the putative functional domains of ACTL6A. We summarize the expression pattern and prognostic significance of ACTL6A in human cancers and the upstream regulatory mechanisms of its expression. We summarize recent progress in understanding the diverse pro-oncogenic functions of ACTL6A and emphasize its pleiotropic mechanisms of action as a regulatory hub of cancer stemness and progression. The review highlights the importance and the potential utilities of characterizing ACTL6A, which may imply molecularly informed diagnostics and therapeutics to improve the outcome of cancer patients.

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引用次数: 0
VAV2 drives EGFR-mediated Rac1 responses in prostate cancer.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-04 DOI: 10.1158/1541-7786.MCR-24-0957
Martin J Baker, Suli Zhang, Daniel Zhang, Joshua Searle, Priti Lal, Cornelis P Vlaar, Suranganie Dharmawardhane, Martín C Abba, Marcelo G Kazanietz, Mariana Cooke

The small G-protein Rac1 is a central player in cancer progression and metastatic dissemination. Rac1 has been established as a bona fide effector of receptor tyrosine kinases, acting as a signaling node for motility, invasiveness, mitogenesis, and gene expression. Previous studies demonstrated that Rac1 is hyperactivated in aggressive cellular models of prostate cancer. Here, we show that CRISPR/Cas9-based knockout of Rac1 leads to impaired prostate cancer cell proliferation and migration. Rac1-null cells display profound alterations in transcriptional programs, particularly those associated with cell adhesion and extracellular matrix (ECM) regulation. Combined expression profiling and unbiased RNAi screening of Rac1 Guanine nucleotide Exchange Factors (Rac-GEFs) identified VAV2 as the foremost mediator of epidermal growth factor (EGF)-induced GTP loading onto Rac1 in prostate cancer cells. VAV2 depletion from prostate cancer cells significantly reduced their proliferative and migratory capacities without affecting the expression of Rac1-regulated genes, suggesting that VAV2 controls a discrete subset of Rac1-dependent cellular responses. Immunohistochemical assessment in human prostate biopsies showed significant VAV2 overexpression in tumor areas. Bioinformatic analysis revealed a strong correlation between VAV2 expression and poor clinical prognosis. In addition to uncovering a prominent role for VAV2-Rac1 as an effector pathway mediating EGFR-driven proliferative and migratory responses in prostate cancer cells, our findings underscore the potential prognostic value of VAV2 in human prostate cancer progression. Implications: This study highlights VAV2's central role in prostate cancer cell proliferation and migration and its potential prognostic value in disease progression.

小 G 蛋白 Rac1 是癌症进展和转移扩散的核心参与者。Rac1 已被确定为受体酪氨酸激酶的真正效应因子,是运动性、侵袭性、有丝分裂和基因表达的信号节点。以前的研究表明,在侵袭性前列腺癌细胞模型中,Rac1 被过度激活。在这里,我们发现基于 CRISPR/Cas9 的 Rac1 基因敲除会导致前列腺癌细胞增殖和迁移受损。Rac1 基因缺失细胞的转录程序发生了深刻的变化,尤其是那些与细胞粘附和细胞外基质(ECM)调控相关的转录程序。对Rac1鸟嘌呤核苷酸交换因子(Rac-GEFs)的表达谱分析和无偏见RNAi筛选发现,VAV2是前列腺癌细胞中表皮生长因子(EGF)诱导的GTP加载到Rac1上的最主要介质。删除前列腺癌细胞中的 VAV2 能显著降低其增殖和迁移能力,而不影响 Rac1 调控基因的表达,这表明 VAV2 控制着一个独立的 Rac1 依赖性细胞反应子集。人体前列腺活检组织的免疫组化评估显示,VAV2在肿瘤区域显著过表达。生物信息学分析表明,VAV2 的表达与不良临床预后之间存在很强的相关性。除了发现 VAV2-Rac1 在前列腺癌细胞中作为介导表皮生长因子受体驱动的增殖和迁移反应的效应通路的重要作用外,我们的研究结果还强调了 VAV2 在人类前列腺癌进展中的潜在预后价值。影响:本研究强调了 VAV2 在前列腺癌细胞增殖和迁移中的核心作用及其在疾病进展中的潜在预后价值。
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引用次数: 0
m6A modified SFTA1P acts as a tumor suppressor in non-small cell lung cancer by regulating TGFBR2 and P-TEFb.
IF 4.1 2区 医学 Q2 CELL BIOLOGY Pub Date : 2025-04-01 DOI: 10.1158/1541-7786.MCR-24-0499
Tingting Xia, Menglei Chen, Meiyu Zhou, Weiping Wan, Yifan Shan, Weijia Xie, Na Wu, Chengying Li, Zhiquan Yuan, Tongjian Cai, Zubin Yu, Ying Xiang, Li Bai, Yafei Li

SFTA1P is a pseudogene-derived lncRNA and has become a master regulator in tumor carcinogenesis and progression processes. SFTA1P has been reported as a potential diagnostic and prognostic biomarker in non-small cell lung cancer (NSCLC). The down-regulation of SFTA1P in tumor tissue has been associated with poor prognosis, however, the detailed molecular mechanism and biological functions still need to be investigated. We demonstrated that SFTA1P inhibited the growth and metastasis of NSCLC in vitro and in vivo. SFTA1P played dual functions in the cytoplasm and nucleus: in the cytoplasm, SFTA1P can serve as a "sponge" for miR-665 to increase the expression level of TGFBR2; in the nucleus, SFTA1P can bind the P-TEFb and subsequently inhibit the transcriptase activity of RNA polymerase II. The regulation of TGFBR2 and P-TEFb via SFTA1P depends on its subcellular localization, which was affected by the status of the N6-methyladenosine (m6A) RNA modification of SFTA1P. Our research demonstrated that the candidate tumor suppressor SFTA1P is extensively involved in NSCLC, which may offer novel insight into NSCLC oncogenesis. Implications: SFTA1P is down regulated in non-small cell lung cancer and played dual functions in the cytoplasm and nucleus.

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引用次数: 0
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。
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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。
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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
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Molecular Cancer Research
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