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Perivascular NOTCH3+ Stem Cells Drive Meningioma Tumorigenesis and Resistance to Radiotherapy. 血管周围NOTCH3+干细胞驱动脑膜瘤肿瘤发生并对放疗产生抗药性。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/2159-8290.CD-23-1459
Abrar Choudhury, Martha A Cady, Calixto-Hope G Lucas, Hinda Najem, Joanna J Phillips, Brisa Palikuqi, Naomi Zakimi, Tara Joseph, Janeth O Birrueta, William C Chen, Nancy A Oberheim Bush, Shawn L Hervey-Jumper, Ophir D Klein, Christine M Toedebusch, Craig M Horbinski, Stephen T Magill, Aparna Bhaduri, Arie Perry, Peter J Dickinson, Amy B Heimberger, Alan Ashworth, Elizabeth E Crouch, David R Raleigh

Meningiomas are the most common primary intracranial tumors. Treatments for patients with meningiomas are limited to surgery and radiotherapy, and systemic therapies remain ineffective or experimental. Resistance to radiotherapy is common in high-grade meningiomas and the cell types and signaling mechanisms that drive meningioma tumorigenesis and resistance to radiotherapy are incompletely understood. Here, we report that NOTCH3 drives meningioma tumorigenesis and resistance to radiotherapy and find that perivascular NOTCH3+ stem cells are conserved across meningiomas from humans, dogs, and mice. Integrating single-cell transcriptomics with lineage tracing and imaging approaches in genetically engineered mouse models and xenografts, we show NOTCH3 drives tumor-initiating capacity, cell proliferation, angiogenesis, and resistance to radiotherapy to increase meningioma growth and reduce survival. To translate these findings to patients, we show that an antibody stabilizing the extracellular negative regulatory region of NOTCH3 blocks meningioma tumorigenesis and sensitizes meningiomas to radiotherapy, reducing tumor growth and improving survival. Significance: There are no effective systemic therapies to treat meningiomas, and meningioma stem cells are poorly understood. Here, we report perivascular NOTCH3+ stem cells to drive meningioma tumorigenesis and resistance to radiotherapy. Our results identify a conserved mechanism and a therapeutic vulnerability to treat meningiomas that are resistant to standard interventions.

脑膜瘤是最常见的原发性颅内肿瘤。对脑膜瘤患者的治疗仅限于手术和放射治疗,全身治疗仍然无效或处于试验阶段。高分化脑膜瘤普遍存在放疗耐药性,而驱动脑膜瘤肿瘤发生和放疗耐药性的细胞类型和信号机制尚不完全清楚。在这里,我们报告了NOTCH3驱动脑膜瘤肿瘤发生和对放疗的耐受性,并发现血管周围NOTCH3+干细胞在人类、狗和小鼠的脑膜瘤中是保守的。在基因工程小鼠模型和异种移植物中,我们将单细胞转录组学与系谱追踪和成像方法相结合,结果表明NOTCH3驱动肿瘤的始发能力、细胞增殖、血管生成和对放疗的耐受性,从而增加脑膜瘤的生长并降低存活率。为了将这些发现应用到患者身上,我们证明了稳定 NOTCH3 细胞外负调控区的抗体可以阻止脑膜瘤的肿瘤发生,并使脑膜瘤对放疗敏感,从而减少肿瘤生长,提高生存率。
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引用次数: 0
Clonal Lineage Tracing with Somatic Delivery of Recordable Barcodes Reveals Migration Histories of Metastatic Prostate Cancer. 通过体细胞传递可记录条形码进行克隆系谱追踪,揭示转移性前列腺癌的迁移历史。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/2159-8290.CD-23-1332
Ryan N Serio, Armin Scheben, Billy Lu, Domenic V Gargiulo, Lucrezia Patruno, Caroline L Buckholtz, Ryan J Chaffee, Megan C Jibilian, Steven G Persaud, Stephen J Staklinski, Rebecca Hassett, Lise M Brault, Daniele Ramazzotti, Christopher E Barbieri, Adam C Siepel, Dawid G Nowak

The patterns by which primary tumors spread to metastatic sites remain poorly understood. Here, we define patterns of metastatic seeding in prostate cancer using a novel injection-based mouse model-EvoCaP (Evolution in Cancer of the Prostate), featuring aggressive metastatic cancer to bone, liver, lungs, and lymph nodes. To define migration histories between primary and metastatic sites, we used our EvoTraceR pipeline to track distinct tumor clones containing recordable barcodes. We detected widespread intratumoral heterogeneity from the primary tumor in metastatic seeding, with few clonal populations instigating most migration. Metastasis-to-metastasis seeding was uncommon, as most cells remained confined within the tissue. Migration patterns in our model were congruent with human prostate cancer seeding topologies. Our findings support the view of metastatic prostate cancer as a systemic disease driven by waves of aggressive clones expanding their niche, infrequently overcoming constraints that otherwise keep them confined in the primary or metastatic site. Significance: Defining the kinetics of prostate cancer metastasis is critical for developing novel therapeutic strategies. This study uses CRISPR/Cas9-based barcoding technology to accurately define tumor clonal patterns and routes of migration in a novel somatically engineered mouse model (EvoCaP) that recapitulates human prostate cancer using an in-house developed analytical pipeline (EvoTraceR).

人们对原发性肿瘤向转移部位扩散的模式仍然知之甚少。在这里,我们利用一种新型注射小鼠模型--EvoCaP(前列腺癌进化),确定了前列腺癌(PCa)的转移播种模式,该模型的特点是侵袭性癌症向骨、肝、肺和淋巴结转移。为了确定原发部位和转移部位之间的迁移历史,我们使用 EvoTraceR 管道追踪含有可记录条形码的不同肿瘤克隆。我们在转移播种中检测到了原发肿瘤广泛的瘤内异质性,少数克隆群(CP)引发了大部分迁移。转移瘤之间的播种并不常见,因为大多数细胞仍局限在组织内。我们模型中的迁移模式与人类 PCa 的播种拓扑结构一致。我们的研究结果支持这样一种观点,即转移性 PCa 是一种由侵袭性克隆波驱动的系统性疾病,它们不断扩大自己的生态位,很少能克服使它们局限在原发或转移部位的限制因素。
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引用次数: 0
CD28 Costimulation Augments CAR Signaling in NK Cells via the LCK/CD3ζ/ZAP70 Signaling Axis. CD28 成本刺激可通过 LCK/CD3Z/ZAP70 信号轴增强 NK 细胞中的 CAR 信号。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/2159-8290.CD-24-0096
Sunil Acharya, Rafet Basar, May Daher, Hind Rafei, Ping Li, Nadima Uprety, Emily Ensley, Mayra Shanley, Bijender Kumar, Pinaki P Banerjee, Luciana Melo Garcia, Paul Lin, Vakul Mohanty, Kun H Kim, Xianli Jiang, Yuchen Pan, Ye Li, Bin Liu, Ana K Nunez Cortes, Chenyu Zhang, Mohsen Fathi, Ali Rezvan, Melisa J Montalvo, Sophia L Cha, Francia Reyes-Silva, Rejeena Shrestha, Xingliang Guo, Kiran Kundu, Alexander Biederstädt, Luis Muniz-Feliciano, Gary M Deyter, Mecit Kaplan, Xin R Jiang, Enli Liu, Antrix Jain, Janos Roszik, Natalie W Fowlkes, Luisa M Solis Soto, Maria G Raso, Joseph D Khoury, Pei Lin, Francisco Vega, Navin Varadarajan, Ken Chen, David Marin, Elizabeth J Shpall, Katayoun Rezvani

Multiple factors in the design of a chimeric antigen receptor (CAR) influence CAR T-cell activity, with costimulatory signals being a key component. Yet, the impact of costimulatory domains on the downstream signaling and subsequent functionality of CAR-engineered natural killer (NK) cells remains largely unexplored. Here, we evaluated the impact of various costimulatory domains on CAR-NK cell activity, using a CD70-targeting CAR. We found that CD28, a costimulatory molecule not inherently present in mature NK cells, significantly enhanced the antitumor efficacy and long-term cytotoxicity of CAR-NK cells both in vitro and in multiple xenograft models of hematologic and solid tumors. Mechanistically, we showed that CD28 linked to CD3ζ creates a platform that recruits critical kinases, such as lymphocyte-specific protein tyrosine kinase (LCK) and zeta-chain-associated protein kinase 70 (ZAP70), initiating a signaling cascade that enhances CAR-NK cell function. Our study provides insights into how CD28 costimulation enhances CAR-NK cell function and supports its incorporation in NK-based CARs for cancer immunotherapy. Significance: We demonstrated that incorporation of the T-cell-centric costimulatory molecule CD28, which is normally absent in mature natural killer (NK) cells, into the chimeric antigen receptor (CAR) construct recruits key kinases including lymphocyte-specific protein tyrosine kinase and zeta-chain-associated protein kinase 70 and results in enhanced CAR-NK cell persistence and sustained antitumor cytotoxicity.

嵌合抗原受体(CAR)设计中的多种因素会影响 CAR T 细胞的活性,其中成本调控信号是一个关键因素。然而,成本调控域对 CAR 工程自然杀伤(NK)细胞的下游信号转导和后续功能的影响在很大程度上仍未得到探讨。在这里,我们使用一种 CD70 靶向 CAR 评估了各种成本调控域对 CAR-NK 细胞活性的影响。我们发现,CD28是成熟NK细胞中并不固有的一种协同调控分子,它能显著增强CAR-NK细胞在体外以及多种血液肿瘤和实体瘤异种移植模型中的抗肿瘤疗效和长期细胞毒性。从机理上讲,我们发现 CD28 与 CD3Z 连接形成了一个平台,它能招募 LCK 和 ZAP70 等关键激酶,启动信号级联,增强 CAR-NK 细胞的功能。我们的研究深入揭示了 CD28 成本刺激如何增强 CAR-NK 细胞功能,并支持将其纳入基于 NK 的 CAR 用于癌症免疫疗法。
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引用次数: 0
Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth. 致癌基因 KRAS 依赖性基质白细胞介素-33 引导胰腺微环境促进肿瘤生长。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-04 DOI: 10.1158/2159-8290.CD-24-0100
Katelyn L Donahue, Hannah R Watkoske, Padma Kadiyala, Wenting Du, Kristee Brown, Michael K Scales, Ahmed M Elhossiny, Carlos E Espinoza, Emily L Lasse Opsahl, Brian D Griffith, Yukang Wen, Lei Sun, Ashley Velez-Delgado, Nur M Renollet, Jacqueline Morales, Nicholas M Nedzesky, Rachael K Baliira, Rosa E Menjivar, Paola I Medina-Cabrera, Arvind Rao, Benjamin Allen, Jiaqi Shi, Timothy L Frankel, Eileen S Carpenter, Filip Bednar, Yaqing Zhang, Marina Pasca di Magliano

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.

胰腺癌的特点是具有广泛的纤维炎症微环境。在癌变过程中,正常基质细胞会转化为细胞因子含量较高的癌相关成纤维细胞(CAF)。人们对这种转化的机制,包括成纤维细胞衍生细胞因子的调节和功能,还知之甚少。因此,以 CAFs 为治疗目标的努力至今仍未成功。在这里,我们发现来自表达致癌 KRAS(一种标志性的胰腺癌突变)的上皮细胞的信号激活了成纤维细胞的自分泌信号,从而驱动了细胞因子白细胞介素-33(IL-33)的表达。在整个癌变过程中,基质 IL-33 的表达仍然很高,并依赖于上皮 KRAS;反过来,环境压力也会诱导 IL-33 的分泌。我们利用特异性IL-33基因敲除小鼠观察到,基质IL-33的缺乏会导致胰腺肿瘤微环境的多种成分发生深刻的重编程,包括CAFs、髓样细胞和淋巴细胞。值得注意的是,基质 IL-33 的缺失会导致 CD8+ T 细胞浸润和活化的增加,并最终导致肿瘤生长的减少。
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引用次数: 0
TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells. TIMP1 在脑转移中介导星形胶质细胞依赖性局部免疫抑制,作用于浸润的 CD8+ T 细胞。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-10-02 DOI: 10.1158/2159-8290.CD-24-0134
Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente

Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.

针对脑转移瘤的免疫疗法在应用于无症状患者时已显示出临床疗效,但在有症状的病例中却大多无效,原因不明。在这里,我们利用 scRNAseq 对转移相关星形胶质细胞的异质性进行了剖析,并报告了一个阻止浸润 T 细胞抗肿瘤活性的群体。这种促肿瘤活性是由一组 pSTAT3+ 星形胶质细胞分泌的 TIMP1 介导的,TIMP1 作用于 CD63+ CD8+ T 细胞以调节其功能。通过在小鼠和人类脑转移模型中使用基因和药理学方法,我们证明将免疫检查点阻断抗体与抑制星形胶质细胞介导的局部免疫抑制相结合,可能会使有症状的脑转移患者受益。我们进一步发现,液体活检中 TIMP1 的存在为选择接受这种联合免疫疗法的患者提供了一种生物标志物。总之,我们的研究结果表明,星形胶质细胞在脑转移瘤中发挥着意想不到的免疫调节作用,并具有临床意义。
{"title":"TIMP1 mediates astrocyte-dependent local immunosuppression in brain metastasis acting on infiltrating CD8+ T cells.","authors":"Neibla Priego, Ana de Pablos-Aragoneses, Maria Perea-García, Valentina Pieri, Carolina Hernandez-Oliver, Laura Alvaro-Espinosa, Andrea Rojas, Oliva Sanchez, Ariane Steindl, Eduardo Caleiras, Fernando Garcia, Santiago Garcia-Martin, Osvaldo Grana-Castro, Sandra Garcia-Mulero, Diego Serrano, Paloma Velasco-Beltran, Borja Jimenez-Lasheras, Leire Egia-Mendikute, Luise Rupp, Antonia Stammberger, Matthias Meinhardt, Anas Chaachou-Charradi, Elena Martínez-Saez, Luca Bertero, Paola Cassoni, Luca Mangherini, Alessia Pellerino, Roberta Ruda, Riccardo Soffietti, Fatima Al-Shahrour, Paul Saftig, Rebeca Sanz-Pamplona, Marc Schmitz, Stephen J Crocker, Alfonso Calvo, Asis Palazon, Renacer Group, Manuel Valiente","doi":"10.1158/2159-8290.CD-24-0134","DOIUrl":"https://doi.org/10.1158/2159-8290.CD-24-0134","url":null,"abstract":"<p><p>Immunotherapies against brain metastases have shown clinical benefits when applied to asymptomatic patients, but they are largely ineffective in symptomatic cases for unknown reasons. Here we dissect the heterogeneity in metastasis-associated astrocytes using scRNAseq and report a population that blocks the antitumoral activity of infiltrating T cells. This pro-tumoral activity is mediated by the secretion of TIMP1 from a cluster of pSTAT3+ astrocytes that acts on CD63+ CD8+ T cells to modulate their function. Using genetic and pharmacologic approaches in mouse and human brain metastasis models, we demonstrate that combining immune checkpoint blockade antibodies with the inhibition of astrocyte-mediated local immunosuppression may benefit patients with symptomatic brain metastases. We further reveal that the presence of TIMP1 in liquid biopsies provides a biomarker to select patients for this combined immunotherapy. Overall, our findings demonstrate an unexpected immunomodulatory role for astrocytes in brain metastases with clinical implications.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142361163","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 KRAS inhibition and immune therapy generates durable complete responses in an autochthonous PDAC model. 联合 KRAS 抑制和免疫疗法可在自体 PDAC 模型中产生持久的完全应答。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-30 DOI: 10.1158/2159-8290.CD-24-0489
Yonghong Liu, Jincheng Han, Wen-Hao Hsu, Kyle A LaBella, Pingna Deng, Xiaoying Shang, Paulino Tallon de Lara, Li Cai, Shan Jiang, Ronald A DePinho

Pancreatic ductal adenocarcinoma (PDAC) resists conventional chemo/radiation and immunotherapy. In PDAC, oncogenic KRAS (KRAS*) drives glycolysis in cancer cells to consume available glucose and produce abundant lactate, creating profound immune suppression in the tumor microenvironment. Here, we combined KRAS* inhibition with agents targeting the major arms of the immunity cycle: CXCR1/2 inhibitor for myeloid cells, antagonistic anti-LAG3 antibody for T cells, and agonistic anti-41BB antibody for dendritic cells. This combination elicited robust anti-tumor regression in iKPC mice bearing large autochthonous tumors. While untreated mice succumbed within 3 weeks, sustained treatment led to durable complete tumor regression and prolonged survival in 36% of mice at 6 months. Mechanistic analyses revealed enhanced T cell infiltration and activation, depletion of immunosuppressive myeloid cells, and increased antigen cross-presentation by dendritic cells within the tumor core. These findings highlight the promise of KRAS* inhibitors alongside immunotherapy as a potential PDAC treatment avenue, warranting clinical investigation.

胰腺导管腺癌(PDAC)对传统的化疗/放疗和免疫疗法有抵抗力。在 PDAC 中,致癌基因 KRAS(KRAS*)驱动癌细胞中的糖酵解消耗可用葡萄糖并产生大量乳酸,从而在肿瘤微环境中造成严重的免疫抑制。在这里,我们将 KRAS* 抑制与针对免疫循环主要臂膀的药物相结合:针对骨髓细胞的 CXCR1/2 抑制剂、针对 T 细胞的拮抗剂抗 LAG3 抗体以及针对树突状细胞的激动剂抗 41BB 抗体。这种组合能在携带巨大自体肿瘤的 iKPC 小鼠中产生强大的抗肿瘤消退作用。未经治疗的小鼠会在 3 周内死亡,而持续治疗可使肿瘤持久完全消退,并延长 36% 的小鼠在 6 个月后的存活时间。机理分析表明,T 细胞浸润和活化增强,免疫抑制性髓细胞耗竭,肿瘤核心内树突状细胞的抗原交叉呈递增加。这些发现凸显了 KRAS* 抑制剂与免疫疗法一起作为潜在的 PDAC 治疗途径的前景,值得进行临床研究。
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引用次数: 0
Early detection of ovarian cancer using cell-free DNA fragmentomes and protein biomarkers 利用无细胞 DNA 片段组和蛋白质生物标记物早期检测卵巢癌
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-30 DOI: 10.1158/2159-8290.cd-24-0393
Jamie E. Medina, Akshaya V. Annapragada, Pien Lof, Sarah Short, Adrianna L. Bartolomucci, Dimitrios Mathios, Shashikant Koul, Noushin Niknafs, Michael Noe, Zachariah H. Foda, Daniel C. Bruhm, Carolyn Hruban, Nicholas A. Vulpescu, Euihye Jung, Renu Dua, Jenna V. Canzoniero, Stephen Cristiano, Vilmos Adleff, Heather Symecko, Daan van den Broek, Lori J. Sokoll, Stephen B. Baylin, Michael F. Press, Dennis J. Slamon, Gottfried E. Konecny, Christina Therkildsen, Beatriz Carvalho, Gerrit A. Meijer, Claus Lindbjerg. Andersen, Susan M. Domchek, Ronny Drapkin, Robert B. Scharpf, Jillian Phallen, Christine A.R. Lok, Victor E. Velculescu
Ovarian cancer is a leading cause of death for women worldwide in part due to ineffective screening methods. In this study, we used whole-genome cell-free DNA (cfDNA) fragmentome and protein biomarker (CA-125 and HE4) analyses to evaluate 591 women with ovarian cancer, benign adnexal masses, or without ovarian lesions. Using a machine learning model with the combined features, we detected ovarian cancer with specificity &gt;99% and sensitivity of 72%, 69%, 87%, and 100% for stages I–IV, respectively. At the same specificity, CA-125 alone detected 34%, 62%, 63%, and 100% of ovarian cancers for stages I–IV. Our approach differentiated benign masses from ovarian cancers with high accuracy (AUC=0.88, 95% CI=0.83-0.92). These results were validated in an independent population. These findings show that integrated cfDNA fragmentome and protein analyses detect ovarian cancers with high performance, enabling a new accessible approach for noninvasive ovarian cancer screening and diagnostic evaluation.
卵巢癌是全球妇女死亡的主要原因之一,部分原因是筛查方法无效。在这项研究中,我们利用全基因组无细胞DNA(cfDNA)片段组和蛋白质生物标志物(CA-125和HE4)分析,对591名患有卵巢癌、良性附件肿块或无卵巢病变的妇女进行了评估。利用具有综合特征的机器学习模型,我们检测出卵巢癌的特异性&gt;99%,对I-IV期的敏感性分别为72%、69%、87%和100%。在相同的特异性下,单独使用 CA-125 检测 I-IV 期卵巢癌的特异性分别为 34%、62%、63% 和 100%。我们的方法能准确区分良性肿块和卵巢癌(AUC=0.88,95% CI=0.83-0.92)。这些结果在一个独立人群中得到了验证。这些研究结果表明,cfDNA片段组和蛋白质综合分析能高效检测卵巢癌,为无创卵巢癌筛查和诊断评估提供了一种新的便捷方法。
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引用次数: 0
DNAJB1-PRKACA fusion drives fibrolamellar liver cancer through impaired SIK signaling and CRTC2/p300-mediated transcriptional reprogramming DNAJB1-PRKACA融合通过受损的SIK信号和CRTC2/p300介导的转录重编程驱动纤维细胞肝癌的发生
IF 28.2 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-26 DOI: 10.1158/2159-8290.cd-24-0634
Ilaria Gritti, Jinkai Wan, Vajira Weeresekara, Joel M. Vaz, Giuseppe Tarantino, Tenna Holgersen. Bryde, Vindhya Vijay, Ashwin V. Kammula, Prabhat Kattel, Songli Zhu, Phuong Vu, Marina Chan, Meng-Ju Wu, John D. Gordan, Krushna C. Patra, Vanessa S. Silveira, Robert T. Manguso, Marc N. Wein, Christopher J. Ott, Jun Qi, David Liu, Kei Sakamoto, Taranjit S. Gujral, Nabeel Bardeesy
Fibrolamellar carcinoma (FLC) is a liver cancer of adolescents and young adults characterized by fusions of the genes encoding the protein kinase A catalytic subunit, PRKACA, and heat shock protein, DNAJB1. The chimeric DNAJB1-PRKACA protein has increased kinase activity and is essential for FLC xenograft growth. Here, we explore the critical oncogenic pathways controlled by DNAJB1-PRKACA using patient-derived FLC models, engineered systems, and patient samples. We show that a core function of DNAJB1-PRKACA is the phosphorylation and inactivation of Salt-inducible kinases (SIKs). This leads to deregulation of the CRTC2 transcriptional co-activator and p300 acetyltransferase, resulting in transcriptional reprogramming and increased global histone acetylation, driving malignant growth. Our studies establish a central oncogenic mechanism of DNAJB1-PRKACA and suggest the potential of targeting CRTC2/p300 in FLC. Notably, these findings link this rare cancer’s signature fusion oncoprotein to more common cancer gene alterations involving STK11 and GNAS, which also function via SIK suppression.
纤维母细胞瘤(FLC)是一种青少年肝癌,其特征是编码蛋白激酶 A 催化亚基 PRKACA 和热休克蛋白 DNAJB1 的基因融合。DNAJB1-PRKACA 嵌合蛋白具有更强的激酶活性,对 FLC 异种移植的生长至关重要。在这里,我们利用源自患者的 FLC 模型、工程系统和患者样本来探索 DNAJB1-PRKACA 控制的关键致癌通路。我们发现,DNAJB1-PRKACA 的一个核心功能是磷酸化和失活盐诱导激酶(SIKs)。这导致 CRTC2 转录共激活因子和 p300 乙酰转移酶的失调,从而导致转录重编程和全局组蛋白乙酰化增加,推动恶性生长。我们的研究确立了DNAJB1-PRKACA的核心致癌机制,并提出了在FLC中靶向CRTC2/p300的可能性。值得注意的是,这些发现将这种罕见癌症的标志性融合肿瘤蛋白与涉及 STK11 和 GNAS 的更常见癌症基因改变联系起来,而 STK11 和 GNAS 也通过 SIK 抑制发挥作用。
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引用次数: 0
Advancing Global Health Equity in Oncology Clinical Trial Access. 在肿瘤学临床试验中促进全球健康公平。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-24 DOI: 10.1158/2159-8290.CD-24-1288

Despite exponentially increased industry investment in oncology research and development with more than $80 billion spent annually, patient enrollment in clinical trials remains below 5% globally. Our multistakeholder international cancer coalition envisions ecosystem transformation with capacity building through a global "hub-and-spoke" network model to expand access to and accelerate clinical trials, thus ending cancer as a major cause of death in this lifetime.

尽管业界对肿瘤研发的投资呈指数级增长,每年投入超过 800 亿美元,但全球临床试验的患者注册率仍低于 5%。我们的多方利益相关者国际癌症联盟设想通过全球 "枢纽-辐条 "网络模式进行能力建设,实现生态系统转型,以扩大临床试验的可及性并加快临床试验的进程,从而终结癌症这一主要致死原因。
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引用次数: 0
AMG 193, a Clinical Stage MTA-Cooperative PRMT5 Inhibitor, Drives Antitumor Activity Preclinically and in Patients With MTAP-Deleted Cancers. AMG 193 是一种处于临床阶段的 MTA-Cooperative PRMT5 抑制剂,在临床前和 MTAP 缺失的癌症患者中具有抗肿瘤活性。
IF 29.7 1区 医学 Q1 ONCOLOGY Pub Date : 2024-09-16 DOI: 10.1158/2159-8290.CD-24-0887
Brian Belmontes, Katherine K Slemmons, Chun Su, Siyuan Liu, Antonia N Policheni, Jodi Moriguchi, Hong Tan, Fang Xie, Daniel Andrew Aiello, Yajing Yang, Raul Lazaro, Famke Aeffner, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Mikkel Vestergaard, Sanne Cowland, Jan Andersson, Ian Sarvary, Qing Chen, Pooja Sharma, Patricia Lopez, Nuria Tamayo, Liping H Pettus, Sudipa Ghimire-Rijal, Susmith Mukund, Jennifer R Allen, Jason DeVoss, Angela Coxon, Jordi Rodon, Francois Ghiringhelli, Nicolas Penel, Hans Prenen, Sanne Glad, Chen-Hua Chuang, Kiana Keyvanjah, Danielle M Townsley, John R Butler, Matthew P Bourbeau, Sean Caenepeel, Paul E Hughes

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

在多个功能基因组筛选中观察到的最强大的合成致死相互作用之一是 MTAP 缺失的癌细胞对 PRMT5 的依赖性。我们报告发现了处于临床阶段的 MTA 协同 PRMT5 抑制剂 AMG 193,它在 MTA 存在的情况下优先结合 PRMT5,并在多个癌系的 MTAP 缺失细胞中具有强大的生化和细胞活性。在体外,抑制 PRMT5 可诱导 MTAP 缺失细胞的 DNA 损伤、细胞周期停滞和异常替代 mRNA 剪接。在人类细胞系和患者来源的异种移植模型中,AMG 193 可诱导强大的抗肿瘤活性,而且耐受性良好,对正常造血细胞系没有影响。AMG 193 在体外可与化疗或 KRAS G12C 抑制剂 sotorasib 协同增效,在体内联合治疗可显著抑制肿瘤生长。AMG 193 正在显示出良好的临床活性,包括正在进行的一项 1 / 2 期研究中证实的 MTAP 缺失实体瘤患者的部分应答。
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Cancer discovery
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