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Genomic and transcriptomic profiling of pre- and postneoadjuvant chemotherapy triple negative breast cancer tumors. 新辅助化疗前后三阴性乳腺癌肿瘤的基因组和转录组分析。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-07 DOI: 10.1111/cas.16339
Tomomi Nishimura, Ravi Velaga, Norikazu Masuda, Kosuke Kawaguchi, Shuji Kawaguchi, Masahiro Takada, Yurina Maeshima, Sunao Tanaka, Yuichiro Kikawa, Takayuki Kadoya, Hiroko Bando, Rikiya Nakamura, Yutaka Yamamoto, Takayuki Ueno, Hiroyuki Yasojima, Hiroshi Ishiguro, Satoshi Morita, Shinji Ohno, Hironori Haga, Fumihiko Matsuda, Seishi Ogawa, Masakazu Toi

Our understanding of neoadjuvant treatment with microtubule inhibitors (MTIs) for triple negative breast cancer (TNBC) remains limited. To advance our understanding of the role of breast cancer driver genes' mutational status with pathological complete response (pCR; ypT0/isypN0) prediction and to identify distinct gene sets for MTIs like eribulin and paclitaxel, we carried out targeted genomic (n = 50) and whole transcriptomic profiling (n = 64) of TNBC tumor samples from the Japan Breast Cancer Research Group 22 (JBCRG-22) clinical trial. Lower PIK3CA, PTEN, and HRAS mutations were found in homologous recombination deficiency (HRD)-high (HRD score ≥ 42) tumors with higher pCR rates. When HRD-high tumors were stratified by tumor BRCA mutation status, the pCR rates in BRCA2-mutated tumors were higher (83% vs. 36%). Transcriptomic profiling of TP53-positive tumors identified downregulation of FGFR2 (false discovery rate p value = 2.07e-7), which was also the only common gene between HRD-high and -low tumors with pCR/quasi-pCR treated with paclitaxel and eribulin combined with carboplatin, respectively. Differential enrichment analysis of the HRD-high group posttreatment tumors revealed significant correlation (p = 0.006) of the glycan degradation pathway. FGFR2 expression and the differentially enriched pathways play a role in the response and resistance to MTIs containing carboplatin treatment in TNBC patients.

我们对使用微管抑制剂(MTIs)对三阴性乳腺癌(TNBC)进行新辅助治疗的了解仍然有限。为了进一步了解乳腺癌驱动基因的突变状态对病理完全反应(pCR;ypT0/isypN0)预测的作用,并确定艾瑞布林和紫杉醇等MTIs的不同基因集,我们对日本乳腺癌研究小组22(JBCRG-22)临床试验中的TNBC肿瘤样本进行了靶向基因组(n = 50)和全转录组分析(n = 64)。同源重组缺陷(HRD)高(HRD评分≥42分)肿瘤的PIK3CA、PTEN和HRAS突变率较低,pCR率较高。当根据肿瘤 BRCA 突变状态对 HRD 高肿瘤进行分层时,BRCA2 突变肿瘤的 pCR 率更高(83% 对 36%)。TP53阳性肿瘤的转录组分析发现了FGFR2的下调(假发现率p值=2.07e-7),这也是分别接受紫杉醇和艾瑞布林联合卡铂治疗的pCR/准pCR的HRD-高和-低肿瘤之间唯一的共同基因。对HRD-高组治疗后肿瘤的差异富集分析表明,糖降解途径与HRD-高组有显著相关性(p = 0.006)。FGFR2的表达和差异富集通路在TNBC患者对含卡铂的MTIs治疗的反应和耐药性中起着作用。
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引用次数: 0
Leveraging non-coding regions to guarantee the accuracy of small-sized panel-based tumor mutational burden estimates. 利用非编码区保证基于小样本组的肿瘤突变负荷估计的准确性。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-10-01 DOI: 10.1111/cas.16342
Takahiro Nishino, Mio Yumura, Kuniko Sunami, Takashi Kubo, Hitoshi Ichikawa, Tomoyo Yasuda, Eisaku Furukawa, Momoko Nagai, Yasushi Yatabe, Mamoru Kato, Takashi Kohno

Accurate estimation of tumor mutational burden (TMB) as a predictor of responsiveness to immune checkpoint inhibitors in gene panel assays requires an adequate panel size. The current calculations of TMB only consider coding regions, while most of gene panel assays interrogate non-coding regions. Leveraging the non-coding regions is a potential solution to address this panel size limitation. However, the impact of including non-coding regions on the accuracy of TMB estimates remains unclear. This study investigated the validity of leveraging non-coding regions to supplement panel size using the OncoGuide NCC Oncopanel System (NOP). The aim of this study was to evaluate test performance against orthogonal assays and the association with responsiveness to immune checkpoint inhibitors was not included in the evaluation. We compared TMB status and values between TMB calculated only from coding regions (NOP-coding) and from both coding and non-coding regions (NOP-overall) using whole exome sequencing (WES) and FoundationOne®CDx (F1CDx) assay. Our findings revealed that NOP-overall significantly improved the overall percent agreement (OPA) with TMB status compared with NOP-coding for both WES (OPA: 96.7% vs. 73.3%, n = 30) and F1CDx (OPA: 90.0% vs. 73.3%). Additionally, the mean difference in TMB values compared with WES was lower for NOP-overall (3.55 [95% CI: 0.98-6.13]) than for NOP-coding (6.22 [95% CI: 3.73-8.70]). These results exemplify the utility of incorporating non-coding regions to maintain accurate TMB estimates in small-sized panels.

要准确估算肿瘤突变负荷(TMB),并将其作为免疫检查点抑制剂反应性的预测指标,需要足够的基因组规模。目前对 TMB 的计算只考虑编码区,而大多数基因面板检测都会询问非编码区。利用非编码区是解决面板规模限制的一个潜在解决方案。然而,纳入非编码区对 TMB 估计准确性的影响仍不清楚。本研究使用 OncoGuide NCC Oncopanel System (NOP) 调查了利用非编码区补充面板规模的有效性。本研究的目的是评估正交检测的测试性能,与免疫检查点抑制剂反应性的关联不在评估范围内。我们使用全外显子测序(WES)和FoundationOne®CDx(F1CDx)检测法比较了仅从编码区(NOP-编码)和从编码区及非编码区(NOP-overall)计算的TMB状态和数值。我们的研究结果表明,在 WES(OPA:96.7% vs. 73.3%,n = 30)和 F1CDx(OPA:90.0% vs. 73.3%)中,与 NOP 编码相比,NOP-overall 显著提高了与 TMB 状态的总体一致性百分比(OPA)。此外,与 WES 相比,NOP-整体(3.55 [95% CI: 0.98-6.13])的 TMB 值平均差异低于 NOP 编码(6.22 [95% CI: 3.73-8.70])。这些结果体现了纳入非编码区以保持小规模面板中准确的 TMB 估计值的实用性。
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引用次数: 0
SNRPB2 promotes triple-negative breast cancer progression by controlling alternative splicing of MDM4 pre-mRNA. SNRPB2通过控制MDM4前mRNA的替代剪接促进三阴性乳腺癌的进展。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-27 DOI: 10.1111/cas.16356
Shiyi Yu, Yue Si, Jianzhong Yu, Chengyang Jiang, Fei Cheng, Miao Xu, Zhehao Fan, Fangchen Liu, Chang Liu, Ying Wang, Ning Wang, Chenxu Liu, Caili Bi, Haibo Sun

Alternative splicing generates cancer-specific transcripts and is now recognized as a hallmark of cancer. However, the critical oncogenic spliceosome-related proteins involved in triple-negative breast cancer (TNBC) remain elusive. Here, we explored the expression pattern of spliceosome-related proteins in TNBC, non-TNBC, and normal breast tissues from The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort, revealing higher expression of nearly half of spliceosome-related proteins in TNBC than their counterparts. Among these TNBC-specific spliceosome-related proteins, the expression of SNRPB2 was associated with poor prognosis in patients with TNBC. In TNBC cells, the knockdown of SNRPB2 strongly suppressed cell proliferation and invasion and induced cell cycle arrest. Mechanistically, transcriptome data showed that SNRPB2 knockdown inactivated E2F1 signaling, which regulated the cell cycle. We further validated the downregulation of several cell cycle genes in SNRPB2 knockdown cells. Moreover, the analysis showed that SNRPB2 knockdown triggered the alteration of many alternative splicing events, most of which were skipping of exon. In TNBC cells, it was found that SNRPB2 knockdown led to the skipping of exon 6 in MDM4 pre-mRNA, generating MDM4-S transcript and downregulating MDM4 protein expression. More importantly, downregulation of MDM4 decreased retinoblastoma 1 (Rb1) protein expression, which is a target of MDM4 and a regulator of E2F1 signaling. In summary, the current study revealed an SNRPB2/MDM4/Rb axis in promoting the progression of TNBC, providing novel insights and novel targets for combating TNBC.

交替剪接产生癌症特异性转录本,现已被公认为癌症的标志。然而,三阴性乳腺癌(TNBC)中涉及的关键致癌剪接体相关蛋白仍然难以确定。在这里,我们探讨了剪接体相关蛋白在TNBC、非TNBC和正常乳腺组织中的表达模式,发现近一半的剪接体相关蛋白在TNBC中的表达高于其同类组织。在这些TNBC特异性剪接体相关蛋白中,SNRPB2的表达与TNBC患者的不良预后有关。在TNBC细胞中,敲除SNRPB2可强烈抑制细胞增殖和侵袭,并诱导细胞周期停滞。从机理上讲,转录组数据显示,SNRPB2的敲除使E2F1信号失活,而E2F1信号调控细胞周期。我们进一步验证了 SNRPB2 敲除细胞中多个细胞周期基因的下调。此外,分析表明,SNRPB2敲除引发了许多替代剪接事件的改变,其中大部分是跳过外显子。在TNBC细胞中,研究发现SNRPB2敲除会导致MDM4前mRNA第6外显子的跳过,产生MDM4-S转录本,并下调MDM4蛋白的表达。更重要的是,MDM4的下调降低了视网膜母细胞瘤1(Rb1)蛋白的表达,而Rb1是MDM4的靶标,也是E2F1信号转导的调控因子。总之,本研究揭示了促进 TNBC 进展的 SNRPB2/MDM4/Rb 轴,为抗击 TNBC 提供了新的见解和新的靶点。
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引用次数: 0
Dynamic single-cell sequencing unveils the tumor microenvironment evolution of gastric cancer abdominal wall metastases during radiotherapy. 动态单细胞测序揭示放疗期间胃癌腹壁转移灶的肿瘤微环境演变
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-26 DOI: 10.1111/cas.16308
Qianqian Mao, Zhenzhen Wu, Yonghong Lai, Ling Wang, Qiongzhi Zhao, Xi Xu, Xiansheng Lu, Wenjun Qiu, Zhihua Zhang, Jiani Wu, Gaofeng Wang, Rui Zhou, Jianhua Wu, Huiying Sun, Na Huang, Xiatong Huang, Luyang Jiang, Yiran Fang, Yuyun Kong, Li Liang, Jianping Bin, Yulin Liao, Min Shi, Wangjun Liao, Dongqiang Zeng

Although the combination of immunotherapy and radiotherapy (RT) for the treatment of malignant tumors has shown rapid development, the insight of how RT remodels the tumor microenvironment to prime antitumor immunity involves a complex interplay of cell types and signaling pathways, much of which remains to be elucidated. Four tumor samples were collected from the same abdominal wall metastasis site of the patient with gastric cancer at baseline and during fractionated RT for single-cell RNA and T-cell receptor sequencing. The Seurat analysis pipeline and immune receptor analysis were used to characterize the gastric cancer metastasis ecosystem and investigated its dynamic changes of cell proportion, cell functional profiles and cell-to-cell communication during RT. Immunohistochemical and immunofluorescent staining and bulk RNA sequencing were applied to validate the key results. We found tumor cells upregulated immune checkpoint genes in response to RT. The infiltration and clonal expansion of T lymphocytes declined within tumors undergoing irradiation. Moreover, RT led to the accumulation of proinflammatory macrophages and natural killer T cells with enhanced cytotoxic gene expression signature. In addition, subclusters of dendritic cells and endothelial cells showed decrease in the expression of antigen present features in post-RT samples. More ECM component secreted by myofibroblasts during RT. These findings indicate that RT induced the dynamics of the immune response that should be taken into consideration when designing and clinically implementing innovative multimodal cancer treatment regimens of different RT and immunotherapy approaches.

虽然免疫疗法与放射治疗(RT)相结合治疗恶性肿瘤的方法发展迅速,但RT如何重塑肿瘤微环境以增强抗肿瘤免疫力涉及到细胞类型和信号通路的复杂相互作用,其中大部分仍有待阐明。研究人员从胃癌患者同一腹壁转移部位采集了四份肿瘤样本,分别在基线和分次RT期间进行单细胞RNA和T细胞受体测序。利用Seurat分析管道和免疫受体分析来描述胃癌转移生态系统的特征,并研究其在RT过程中细胞比例、细胞功能谱和细胞间通讯的动态变化。免疫组化和免疫荧光染色以及大量 RNA 测序被用于验证主要结果。我们发现肿瘤细胞对RT的免疫检查点基因上调。在接受辐照的肿瘤内,T淋巴细胞的浸润和克隆扩增下降。此外,RT导致促炎性巨噬细胞和自然杀伤T细胞聚集,并增强了细胞毒性基因表达特征。此外,在 RT 后样本中,树突状细胞和内皮细胞亚群的抗原呈递特征表达减少。肌成纤维细胞在 RT 期间分泌更多的 ECM 成分。这些研究结果表明,RT 会诱导免疫反应的动态变化,在设计和临床实施不同 RT 和免疫疗法的创新多模式癌症治疗方案时应考虑到这一点。
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引用次数: 0
Loss of USP10 promotes hepatocellular carcinoma proliferation by regulating the serine synthesis pathway through inhibition of LKB1 activity. USP10 的缺失通过抑制 LKB1 的活性调节丝氨酸合成途径,从而促进肝细胞癌的增殖。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-26 DOI: 10.1111/cas.16336
Chi Ma, Zhikun Lin, Jiaqi Yao, Wangshu Qin, Xiaolin Wang, Qi Li, Yaorui Ye, Xinyu Liu, Fating Chen, Jinlong Hu, Guowang Xu, Guang Tan

Metabolic dysregulation is emerging as a critical factor in tumorigenesis, and reprogramming of serine metabolism has been identified as an essential factor in the progression of hepatocellular carcinoma (HCC). Studies have shown that LKB1 deficiency can activate mTOR to upregulate the serine synthesis pathway (SSP) and promote tumor progression. Our team discovered that ubiquitin-specific protease 10 (USP10) can inhibit HCC proliferation through mTOR, but its relationship with SSP needs further investigation. The metabolite assays revealed a significant increase in serine content in HCC tissues. Through the LKB1/mTOR/activating transcription factor 4 (ATF4) axis, loss of USP10 may increase serine biosynthesis and promote the proliferation of HCC in vitro and in vivo. Furthermore, it was found that USP10 could activate LKB1 through deubiquitination. Analyzing clinical HCC tissues revealed a positive correlation between USP10 and LKB1. Additionally, those with high expression of USP10 in HCC tissues showed a better degree of tumor differentiation and longer overall survival time. Moreover, we found increased expression of both serine and its synthase in liver tumor tissues of USP10 liver-specific KO mice. Loss of USP10 inhibits the activity of LKB1, contributing to the stimulation of the mTOR/ATF4 axis and SSP and then promoting the proliferation of HCC. This work presents a novel approach for serine-targeted treatment in HCC.

代谢失调正在成为肿瘤发生的一个关键因素,而丝氨酸代谢的重编程已被确定为肝细胞癌(HCC)进展的一个重要因素。研究表明,LKB1 缺乏可激活 mTOR,上调丝氨酸合成途径(SSP),促进肿瘤进展。我们的团队发现泛素特异性蛋白酶10(USP10)可以通过mTOR抑制HCC增殖,但其与SSP的关系还需要进一步研究。代谢物检测显示,HCC 组织中丝氨酸含量显著增加。通过 LKB1/mTOR/ 激活转录因子 4 (ATF4) 轴,USP10 的缺失可能会增加丝氨酸的生物合成,促进 HCC 在体外和体内的增殖。此外,研究还发现 USP10 可通过去泛素化激活 LKB1。分析临床 HCC 组织发现,USP10 与 LKB1 呈正相关。此外,HCC 组织中 USP10 高表达者的肿瘤分化程度更高,总生存时间更长。此外,我们发现在 USP10 肝特异性 KO 小鼠的肝肿瘤组织中,丝氨酸及其合成酶的表达均有所增加。USP10 的缺失会抑制 LKB1 的活性,从而刺激 mTOR/ATF4 轴和 SSP,进而促进 HCC 的增殖。这项研究为丝氨酸靶向治疗 HCC 提供了一种新方法。
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引用次数: 0
Specific cancer types and prognosis in patients with variations in the KEAP1-NRF2 system: A retrospective cohort study. KEAP1-NRF2系统变异患者的特定癌症类型和预后:一项回顾性队列研究。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-26 DOI: 10.1111/cas.16355
Tomoyuki Iwasaki, Hidekazu Shirota, Keiju Sasaki, Kota Ouchi, Yuki Nakayama, Hiroyuki Oshikiri, Akihito Otsuki, Takafumi Suzuki, Masayuki Yamamoto, Chikashi Ishioka

The KEAP1-NRF2 system induces the expression of antioxidant genes in response to various types of oxidative stress. Some cancer cells activate this system, which increases their malignancy through genetic mutations. We performed a retrospective cohort study using the C-CAT database, which contains the gene-panel sequence data from 60,056 cases of diagnosed solid tumors. We analyzed somatic mutations in NRF2 and KEAP1 genes and their associations with clinical outcomes. Variants in the NRF2 gene were clustered in exon 2, which encodes the DLG and ETGE motifs essential for KEAP1 interaction. The NRF2 variants were frequently observed in esophageal and lung squamous cell carcinoma with frequencies of 35.9% and 19.6%, respectively. Among these mutations, the NRF2 variants in the ETGE motif were indicators of a worse prognosis. KEAP1 variants were found in 2.5% of all cases. The variants were frequent in lung cancer and showed a worse prognosis in lung and other types of adenocarcinomas. We then conducted gene expression analysis using TCGA data. While cancers with DLG and ETGE variants were similar in terms of gene expression profiles, there were significant differences between cancers with KEAP1 and NRF2 variants. Our results indicate that genetic alteration of the KEAP1-NRF2 pathway is a major factor in patient prognosis for each cancer type and its genetic variant. Variants in NRF2 and KEAP1 genes can characterize the biological basis of each cancer type and are involved in carcinogenesis, resistance to therapy, and other biological differences.

KEAP1-NRF2 系统会诱导抗氧化基因的表达,以应对各种类型的氧化应激。一些癌细胞会激活这一系统,从而通过基因突变增加其恶性程度。我们利用 C-CAT 数据库进行了一项回顾性队列研究,该数据库包含 60,056 例确诊实体瘤患者的基因组序列数据。我们分析了 NRF2 和 KEAP1 基因的体细胞突变及其与临床结果的关系。NRF2 基因的变异集中在第 2 号外显子,该外显子编码 KEAP1 相互作用所必需的 DLG 和 ETGE 基序。NRF2基因变异在食管癌和肺鳞癌中出现频率分别为35.9%和19.6%。在这些变异中,ETGE基序的NRF2变异是预后较差的指标。2.5%的病例中发现了KEAP1变异。这种变异在肺癌中很常见,并显示肺癌和其他类型腺癌的预后较差。随后,我们利用 TCGA 数据进行了基因表达分析。虽然具有 DLG 和 ETGE 变异的癌症在基因表达谱方面相似,但具有 KEAP1 和 NRF2 变异的癌症之间存在显著差异。我们的研究结果表明,KEAP1-NRF2通路的基因改变是影响每种癌症类型及其基因变异患者预后的主要因素。NRF2和KEAP1基因的变异可以描述每种癌症类型的生物学基础,并参与致癌、抗药性和其他生物学差异。
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引用次数: 0
Selective killing of castration-resistant prostate cancer cells by formycin A via the ATF4-CHOP axis. 甲霉素 A 通过 ATF4-CHOP 轴选择性杀死耐阉割前列腺癌细胞
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-26 DOI: 10.1111/cas.16349
Tomoki Takei, Yuki Hamamura, Hiroshi Hongo, Etsu Tashiro, Masaya Imoto, Takeo Kosaka, Mototsugu Oya

Prostate cancer is initially androgen-dependent but often relapses to an androgen-independent state called castration-resistant prostate cancer (CRPC). Currently approved therapies have limited efficacy against CRPC, highlighting the need for novel therapeutic strategies. To address this need, we conducted a drug screen in our previously established aggressive CRPC cell model. We found that formycin A induced cell death in CRPC model cells but not in parental prostate cancer cells. In addition, formycin A upregulated death receptor 5 through the induction of endoplasmic reticulum stress, activating the "extrinsic" apoptosis pathway in CRPC model cells. Moreover, formycin A showed in vivo antitumor efficacy against CRPC xenografts in castrated nude mice. Thus, our findings highlight the potential of formycin A as a CRPC therapeutic.

前列腺癌最初是雄激素依赖性的,但往往会复发为雄激素非依赖性状态,称为阉割抗性前列腺癌(CRPC)。目前已获批准的疗法对 CRPC 的疗效有限,这凸显了对新型治疗策略的需求。为了满足这一需求,我们在之前建立的侵袭性 CRPC 细胞模型中进行了药物筛选。我们发现,福霉素 A 能诱导 CRPC 模型细胞死亡,但不能诱导亲代前列腺癌细胞死亡。此外,福霉素 A 通过诱导内质网应激上调死亡受体 5,激活了 CRPC 模型细胞的 "外源性 "凋亡途径。此外,甲霉素 A 对阉割裸鼠体内的 CRPC 异种移植物具有体内抗肿瘤疗效。因此,我们的研究结果凸显了甲霉素 A 作为 CRPC 治疗药物的潜力。
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引用次数: 0
Decreased PU.1 expression in mature B cells induces lymphomagenesis. 成熟 B 细胞中 PU.1 表达减少会诱发淋巴瘤。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-25 DOI: 10.1111/cas.16344
Shinya Endo, Nao Nishimura, Kosuke Toyoda, Yoshihiro Komohara, Joaquim Carreras, Hiromichi Yuki, Takafumi Shichijo, Shikiko Ueno, Niina Ueno, Shinya Hirata, Yawara Kawano, Kisato Nosaka, Masashi Miyaoka, Naoya Nakamura, Ai Sato, Kiyoshi Ando, Hiroaki Mitsuya, Koichi Akashi, Daniel G Tenen, Jun-Ichirou Yasunaga, Masao Matsuoka, Yutaka Okuno, Hiro Tatetsu

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma, accounting for 30% of non-Hodgkin lymphomas. Although comprehensive analysis of genetic abnormalities has led to the classification of lymphomas, the exact mechanism of lymphomagenesis remains elusive. The Ets family transcription factor, PU.1, encoded by Spi1, is essential for the development of myeloid and lymphoid cells. Our previous research illustrated the tumor suppressor function of PU.1 in classical Hodgkin lymphoma and myeloma cells. In the current study, we found that patients with DLBCL exhibited notably reduced PU.1 expression in their lymphoma cells, particularly in the non-germinal center B-cell-like (GCB) subtype. This observation suggests that downregulation of PU.1 may be implicated in DLBCL tumor growth. To further assess PU.1's role in mature B cells in vivo, we generated conditional Spi1 knockout mice using Cγ1-Cre mice. Remarkably, 13 of the 23 knockout mice (56%) showed splenomegaly, lymphadenopathy, or masses, with some having histologically confirmed B-cell lymphomas. In contrast, no wild-type mice developed B-cell lymphoma. In addition, RNA-seq analysis of lymphoma cells from Cγ1-Cre Spi1F/F mice showed high frequency of each monoclonal CDR3 sequence, indicating that these lymphoma cells were monoclonal tumor cells. When these B lymphoma cells were transplanted into immunodeficient recipient mice, all mice died within 3 weeks. Lentiviral-transduced Spi1 rescued 60% of the recipient mice, suggesting that PU.1 has a tumor suppressor function in vivo. Collectively, PU.1 is a tumor suppressor in mature B cells, and decreased PU.1 results in mature B-cell lymphoma development.

弥漫大 B 细胞淋巴瘤(DLBCL)是淋巴瘤中最常见的亚型,占非霍奇金淋巴瘤的 30%。虽然对基因异常的全面分析已促成了淋巴瘤的分类,但淋巴瘤发生的确切机制仍难以确定。Spi1编码的Ets家族转录因子PU.1对髓系细胞和淋巴细胞的发育至关重要。我们之前的研究表明,PU.1 在经典霍奇金淋巴瘤和骨髓瘤细胞中具有肿瘤抑制功能。在目前的研究中,我们发现DLBCL患者的淋巴瘤细胞中PU.1的表达明显减少,尤其是在非生殖中心B细胞样(GCB)亚型中。这一观察结果表明,PU.1 的下调可能与 DLBCL 肿瘤的生长有关。为了进一步评估PU.1在体内成熟B细胞中的作用,我们利用Cγ1-Cre小鼠产生了条件性Spi1基因敲除小鼠。值得注意的是,23 只基因敲除小鼠中有 13 只(56%)出现脾脏肿大、淋巴结病变或肿块,其中一些经组织学证实患有 B 细胞淋巴瘤。相比之下,野生型小鼠没有出现 B 细胞淋巴瘤。此外,对来自 Cγ1-Cre Spi1F/F 小鼠的淋巴瘤细胞进行的 RNA-seq 分析显示,每个单克隆 CDR3 序列的频率都很高,表明这些淋巴瘤细胞是单克隆肿瘤细胞。将这些 B 淋巴瘤细胞移植到免疫缺陷受体小鼠体内,所有小鼠均在 3 周内死亡。慢病毒转导的 Spi1 挽救了 60% 的受体小鼠,表明 PU.1 在体内具有肿瘤抑制功能。综上所述,PU.1是成熟B细胞的肿瘤抑制因子,PU.1的减少会导致成熟B细胞淋巴瘤的发生。
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引用次数: 0
Host ANGPTL2 establishes an immunosuppressive tumor microenvironment and resistance to immune checkpoint therapy. 宿主 ANGPTL2 可建立免疫抑制性肿瘤微环境,并对免疫检查点疗法产生抗药性。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-25 DOI: 10.1111/cas.16348
Shinsei Yumoto, Haruki Horiguchi, Tsuyoshi Kadomatsu, Taichi Horino, Michio Sato, Kazutoyo Terada, Keishi Miyata, Toshiro Moroishi, Hideo Baba, Yuichi Oike

Use of immune checkpoint inhibitors (ICIs) as cancer immunotherapy has advanced rapidly in the clinic; however, mechanisms underlying resistance to ICI therapy, including impaired T cell infiltration, low immunogenicity, and tumor "immunophenotypes" governed by the host, remain unclear. We previously reported that in some cancer contexts, tumor cell-derived angiopoietin-like protein 2 (ANGPTL2) has tumor-promoting functions. Here, we asked whether ANGPTL2 deficiency could enhance antitumor ICI activity in two inflammatory contexts: a murine syngeneic model of colorectal cancer and a mouse model of high-fat diet (HFD)-induced obesity. Systemic ANGPTL2 deficiency potentiated ICI efficacy in the syngeneic model, supporting an immunosuppressive role for host ANGPTL2. Relevant to the mechanism, we found that ANGPTL2 induces pro-inflammatory cytokine production in adipose tissues, driving generation of myeloid-derived suppressor cells (MDSCs) in bone marrow and contributing to an immunosuppressive tumor microenvironment and resistance to ICI therapy. Moreover, HFD-induced obese mice showed impaired responsiveness to ICI treatment, suggesting that obesity-induced chronic inflammation facilitated by high ANGPTL2 expression blocks ICI antitumor effects. Our findings overall provide novel insight into protumor ANGPTL2 functions and illustrate the essential role of the host system in ICI responsiveness.

使用免疫检查点抑制剂(ICIs)作为癌症免疫疗法在临床上进展迅速;然而,ICI疗法的抗药性机制,包括T细胞浸润受损、免疫原性低以及受宿主控制的肿瘤 "免疫表型",仍不清楚。我们以前曾报道过,在某些癌症中,肿瘤细胞衍生的血管生成素样蛋白 2(ANGPTL2)具有促进肿瘤生长的功能。在此,我们探讨了 ANGPTL2 缺乏是否能在两种炎症环境中增强 ICI 的抗肿瘤活性:一种是结直肠癌小鼠合成模型,另一种是高脂饮食(HFD)诱导肥胖症小鼠模型。系统性 ANGPTL2 缺乏会增强 ICI 在合成模型中的疗效,从而支持宿主 ANGPTL2 的免疫抑制作用。与这一机制相关的是,我们发现 ANGPTL2 能诱导脂肪组织产生促炎细胞因子,推动骨髓中髓源性抑制细胞(MDSCs)的生成,并促成免疫抑制性肿瘤微环境和对 ICI 治疗的耐药性。此外,HFD诱导的肥胖小鼠对ICI治疗的反应性减弱,这表明ANGPTL2高表达导致的肥胖诱导的慢性炎症阻碍了ICI的抗肿瘤作用。我们的研究结果总体上提供了对原发肿瘤 ANGPTL2 功能的新见解,并说明了宿主系统在 ICI 反应性中的重要作用。
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引用次数: 0
Anti-tissue factor antibody conjugated with monomethyl auristatin E or deruxtecan in pancreatic cancer models. 在胰腺癌模型中使用与单甲基金丝桃素 E 或德鲁替康结合的抗组织因子抗体。
IF 5.7 2区 医学 Q1 Medicine Pub Date : 2024-09-25 DOI: 10.1111/cas.16335
Ryo Tsumura, Takahiro Anzai, Yoshikatsu Koga, Hiroki Takashima, Yasuhiro Matsumura, Masahiro Yasunaga

Antibody-drug conjugates (ADCs) have been recognized as a promising class of cancer therapeutics. Tissue factor (TF), an initiator of the blood coagulation pathway, has been investigated regarding its relationship with cancer, and several preclinical and clinical studies have presented data on anti-TF ADCs, including tisotumab vedotin, which was approved in 2021. However, the feasibility of other payloads in the design of anti-TF ADCs is still unclear because no reports have compared payloads with different cytotoxic mechanisms. For ADCs targeting other antigens, such as Her2, optimizing the payload is also an important issue in order to improve in vivo efficacy. In this study, we prepared humanized anti-TF Ab (clone.1084) conjugated with monomethyl auristatin E (MMAE) or deruxtecan (DXd), and evaluated the efficacy in several cell line- and patient-derived xenograft models of pancreatic cancer. As a result, optimizing the drug / Ab ratio was necessary for each payload in order to prevent pharmacokinetic deterioration and maximize delivery efficiency. In addition, MMAE-conjugated anti-TF ADC showed higher antitumor effects in tumors with strong and homogeneous TF expression, while DXd-conjugated anti-TF ADC was more effective in tumors with weak and heterogeneous TF expression. Analysis of a pancreatic cancer tissue array showed weak and heterogeneous TF expression in most TF-positive specimens, indicating that the response rate to pancreatic cancer might be higher for DXd- than MMAE-conjugated anti-TF ADC. Nevertheless, our findings indicated that optimizing the ADC payloads individually in each patient could maximize the potential of ADC therapeutics.

抗体药物共轭物(ADCs)已被公认为是一类很有前景的癌症治疗药物。组织因子(TF)是血液凝固通路的启动因子,人们一直在研究它与癌症的关系,一些临床前和临床研究提供了抗TF ADCs的数据,包括2021年获批的tisotumab vedotin。然而,其他有效载荷在抗TF ADC设计中的可行性仍不清楚,因为没有报告对具有不同细胞毒性机制的有效载荷进行了比较。对于靶向 Her2 等其他抗原的 ADC,优化有效载荷也是提高体内疗效的一个重要问题。在这项研究中,我们制备了与单甲基乌司他丁 E(MMAE)或德克替康(DXd)共轭的人源化抗-TF Ab(clone.1084),并评估了其在多种胰腺癌细胞系和患者来源异种移植模型中的疗效。因此,有必要优化每种有效载荷的药物/抗体比例,以防止药代动力学恶化并最大限度地提高递送效率。此外,MMAE共轭的抗TF ADC在TF表达强且均匀的肿瘤中显示出更高的抗肿瘤效果,而DXd共轭的抗TF ADC在TF表达弱且不均匀的肿瘤中更有效。对胰腺癌组织阵列的分析表明,大多数TF阳性标本的TF表达较弱且不均匀,这表明DXd-结合型抗TF ADC对胰腺癌的反应率可能高于MMAE-结合型抗TF ADC。尽管如此,我们的研究结果表明,对每位患者的 ADC 有效载荷进行单独优化可最大限度地发挥 ADC 疗法的潜力。
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引用次数: 0
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Cancer Science
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