Neoplasia最新文献_第5页

EGFL6 is a novel HER3 ligand, inducing HER3/integrin heterodimers to induce pERK centrosomal deposition and therapeutic resistance EGFL6是一种新的HER3配体，可诱导HER3/整合素异源二聚体诱导pERK中心体沉积和治疗耐药性。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-27 DOI: 10.1016/j.neo.2025.101246

Shoumei Bai , Navneet Gupta , Victoria Liu , Adetunji Fayomi , Stacy McGonigal , Ronald J. Buckanovich

EGF-like domain multiple-6 (EGFL6) is a secreted tumor growth/migration factor linked with poor outcomes in many tumor types. While EGFL6 is known to signal, in part, via its integrin-binding RGD domain, little else is known about EGFL6 receptors. We evaluated putative EGFL6 receptors and found that EGFL6 treatment of ovarian cancer cells leads to both transient phosphorylation of EGFR and prolonged phosphorylation of HER2 and HER3 and subsequent phosphorylation of ERK (pERK). We found that EGFL6 directly binds HER3. However, EGFL6-driven prolonged activation of HER3 is dependent on an intact EGFL6 integrin-binding RGD domain. Immunoprecipitation and proximity ligation assays confirmed that EGFL6 treatment of cancer cells induces HER2/3-integrin-β3 heterocomplexes. Suggesting EGFL6 could play a role in resistance to HER targeting therapies, EGFL6 is upregulated in EGFR/HER receptor inhibitor-resistant cells, and EGFL6 treatment increases resistance to EGFR/HER inhibitors in vitro. Interestingly, we found that, in EGFL6-treated ovarian cancer cells undergoing mitosis, pERK localizes to the centrosome. Both EGFL6-neutralizing antibodies and HER protein-targeted inhibitors resulted in aberrant pERK centrosomal localization with associated altered mitotic spindle alignment and mitotic catastrophe. Furthermore, combination anti-EGFL6 therapy with the pan-EGFR receptor inhibitor neratinib, compared to either therapy alone, led to an increase in aberrant pERK localization and cancer cell death in vitro and significant restricted tumor growth in vivo. Combined, our data suggests that EGFL6 is a new ligand for HER3 and that dual targeting of the EGFL6/HER signaling axis, via altered pERK localization, may be an effective therapeutic strategy in ovarian cancer.

Significance

This work reveals that EGFL6 is a previously unrecognized ligand for HER3 which can increase resistance to HER family-targeted therapy. We also reveal a novel function of pERK downstream of pHER3 at the centrosome in mitosis. Importantly, we show that EGFL6 is an important therapeutic target to enhance the efficacy of EGFR/HER-targeted therapy.

egf样结构域多重6 （EGFL6）是一种分泌性肿瘤生长/迁移因子，与许多肿瘤类型的不良预后相关。虽然已知EGFL6部分通过其整合素结合RGD结构域发出信号，但对EGFL6受体的其他信息知之甚少。我们评估了可能的EGFL6受体，发现EGFL6治疗卵巢癌细胞会导致EGFR的短暂磷酸化和HER2和HER3的延长磷酸化以及随后的ERK （pERK）磷酸化。我们发现EGFL6直接结合HER3。然而，EGFL6驱动的HER3的延长激活依赖于完整的EGFL6整合素结合RGD结构域。免疫沉淀和接近结扎实验证实，EGFL6对癌细胞的处理可诱导her2 /3-整合素-β3异质复合物。EGFL6在EGFR/HER受体抑制剂耐药细胞中上调，EGFL6治疗增加了体外对EGFR/HER抑制剂的耐药性，这表明EGFL6可能在HER靶向治疗的耐药中发挥作用。有趣的是，我们发现，在egfl6处理的有丝分裂的卵巢癌细胞中，pERK定位于中心体。egfl6中和抗体和HER蛋白靶向抑制剂都导致pERK中心体定位异常，并伴有有丝分裂纺锤体排列改变和有丝分裂突变。此外，与单独治疗相比，抗egfl6与泛egfr受体抑制剂neratinib联合治疗在体外导致异常pERK定位和癌细胞死亡增加，并在体内显著限制肿瘤生长。综上所述，我们的数据表明，EGFL6是HER3的新配体，通过改变pERK定位，双重靶向EGFL6/HER信号轴可能是卵巢癌的有效治疗策略。意义：这项工作揭示了EGFL6是一种以前未被识别的HER3配体，它可以增加对HER家族靶向治疗的耐药性。我们还揭示了pERK在有丝分裂中位于中心体ph3下游的新功能。重要的是，我们发现EGFL6是提高EGFR/ her靶向治疗疗效的重要治疗靶点。

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引用次数: 0

Age-diet interactions significantly influence intratumoral gene expression, gut microbiome signature and tumor microenvironment in colorectal cancer 年龄-饮食相互作用显著影响结直肠癌肿瘤内基因表达、肠道微生物组特征和肿瘤微环境

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-25 DOI: 10.1016/j.neo.2025.101245

Shivani Soni , Pooja Mittal , Jae Ho Lo , Yan Yang , Goar Smbatyan , Keehoon Lee , Junxiang Wan , Hiroshi Kumagai , Kelvin Yen , Hemal H. Mehta , Brendan Miller , Lesly Torres-Gonzalez , Francesca Battaglin , Unnati Hemant Shah , Michela Bartolini , Wu Zhang , David W. Craig , Josh Millstein , Pinchas Cohen , Heinz-Josef Lenz

Colorectal Cancer (CRC) is the third most prevalent malignancy, leading to significant morbidity and mortality globally. Epidemiological studies suggest that chronological age and diet are among the major contributing factors correlated with the incidence of CRC. Our study aimed to provide insights into the association between age, diet, and gut microbiome in CRC using molecular techniques including RNA sequencing, cytokine analysis, and metagenomic analysis. We used syngeneic MC38 mice model divided into two age groups (old and young) and three diet groups (standard chow, calorie-restricted and high-fat). The major findings of this study are that age and diet impact intratumoral gene signaling (nuclear and mitochondrial), and hub genes we identified are associated with prognosis in CRC. Fecal microbiome analysis showed that old microbiomes have higher alpha diversity compared to young mice. Our results demonstrate that interactions between host (age) and external (diet) factors regulate tumor growth mediated by cytokines, mitochondrial derived proteins, and the gut microbiome. Collectively, our findings advance current understanding of the mechanisms by which aging, diet and gut microbiota impact CRC onset and progression though further investigation is warranted.

结直肠癌（CRC）是第三大最常见的恶性肿瘤，在全球范围内导致显著的发病率和死亡率。流行病学研究表明，实足年龄和饮食是与结直肠癌发病率相关的主要因素。我们的研究旨在通过RNA测序、细胞因子分析和宏基因组分析等分子技术，深入了解结直肠癌患者的年龄、饮食和肠道微生物组之间的关系。采用同基因MC38小鼠模型，分为老幼两组和标准饮食组、限热量饮食组和高脂肪饮食组。本研究的主要发现是年龄和饮食影响肿瘤内基因信号（核和线粒体），我们发现的枢纽基因与结直肠癌的预后相关。粪便微生物组分析表明，与年轻小鼠相比，老年小鼠的微生物组具有更高的α多样性。我们的研究结果表明，宿主（年龄）和外部（饮食）因素之间的相互作用通过细胞因子、线粒体衍生蛋白和肠道微生物组调节肿瘤生长。总的来说，我们的发现促进了目前对衰老、饮食和肠道微生物群影响结直肠癌发病和进展的机制的理解，但需要进一步的研究。

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引用次数: 0

Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma 靶向Wnt/β-catenin信号通路可提高抗cd38免疫治疗多发性骨髓瘤的疗效

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-23 DOI: 10.1016/j.neo.2025.101242

Heng Li , Yunguang Chen , Michaela Gregorova , Tingting Yang , Xiayi Zhang , Xiaoyu Yu , Zhen Wang , Haiying Hua , Long Ye , Xiaowei Qi , Marcel Spaargaren , Steven T. Pals , Zemin Ren

Background

Previous studies have shown that the Wnt/β-catenin signaling pathway is aberrantly activated in multiple myeloma (MM) and regulates the growth of MM cells, while recent studies reported crosstalk between Wnt and STAT3 signaling in various non-MM systems. In addition, it has been shown that STAT3 regulates the expression of CD38, the key target of current antibody therapies in MM. Therefore, we aimed to investigate the impact of inhibiting the Wnt signaling on the efficacy of anti-CD38 immunotherapy.

Methods

We utilized dnTCF overexpression and β-catenin knockout to inhibit the Wnt signaling. Flow cytometry was used to analyze the expression of CD38. NK92MI-CD16 and CB-derived NK cells were used to conduct ADCC in cell lines and patient-derived MM. A xenograft mouse model was used to evaluate the therapeutic efficacy of inhibiting Wnt signaling in combination with daratumumab in vivo.

Results

We demonstrate that inhibition of Wnt signaling results in reduced STAT3 activity in both MM cell lines and primary MM samples. The suppression of STAT3 activity by Wnt signaling inhibition significantly enhances the expression of CD38, which is a crucial determinant of the clinical response to anti-CD38 treatment, viz. daratumumab. In accordance, targeting of Wnt signaling with the Wnt inhibitor ICG-001 greatly enhanced the anti-MM efficacy of daratumumab in vitro as well as in an in vivo mouse model.

Conclusions

These findings demonstrated that targeting Wnt signaling enhances the efficacy of daratumumab and provide a strong rationale for combining daratumumab with Wnt-signaling inhibition as a therapeutic strategy in MM.

以往的研究表明，Wnt/β-catenin信号通路在多发性骨髓瘤（MM）中异常激活并调节MM细胞的生长，而最近的研究报道了Wnt和STAT3信号通路在各种非MM系统中的串扰。此外，已有研究表明STAT3调节CD38的表达，而CD38是目前MM抗体治疗的关键靶点。因此，我们旨在研究抑制Wnt信号传导对抗CD38免疫治疗效果的影响。方法采用dnTCF过表达和敲除β-catenin抑制Wnt信号通路。流式细胞术检测CD38的表达。使用NK92MI-CD16和cb来源的NK细胞在细胞系和患者来源的MM中进行ADCC。使用异种移植小鼠模型来评估联合达拉单抗抑制Wnt信号传导的体内治疗效果。结果Wnt信号的抑制导致MM细胞系和原代MM样品中STAT3活性降低。Wnt信号抑制对STAT3活性的抑制显著增强了CD38的表达，这是抗CD38治疗（即达拉单抗）临床反应的关键决定因素。因此，用Wnt抑制剂ICG-001靶向Wnt信号，在体外和体内小鼠模型中，大大增强了daratumumab的抗mm功效。这些发现表明，靶向Wnt信号通路可增强daratumumab的疗效，并为daratumumab联合Wnt信号通路抑制作为MM治疗策略提供了强有力的理论依据。

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引用次数: 0

FER kinase governs invasive growth of head and neck squamous cell carcinoma through dynamic control of growth factor receptor activity FER激酶通过动态调控生长因子受体活性调控头颈部鳞状细胞癌的侵袭性生长

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-19 DOI: 10.1016/j.neo.2025.101241

Peter D. Haughton , Lotte N.F.L. Enserink , Sandra Tavares , Wisse Haakma , Garik Galustjan , Sjors Koppes , Lorenza Casasanta , Else Driehuis , Hans Clevers , Yanchun Zhang , Gaofeng Fan , Stefan Willems , Xiaobao Yang , Patrick W.B. Derksen

Promiscuous activation of growth factor receptors drives sustained MAP kinase signaling, which reinforces oncogene addiction in HPV-negative head and neck squamous cell carcinoma (HNSCC). This feature promotes invasive growth, complicating surgical resection and contributing to high rates of local relapse and poor patient outcomes. Current treatment strategies for locally advanced or non-resectable tumors targeting single growth factor receptors offer limited therapeutic benefit, underscoring the need for alternative targets. Using patient-derived tumor organoid (PDO) models of invasive HNSCC, we demonstrate that FER, a non-receptor tyrosine kinase that correlates with poor survival in HNSCC patients, is essential for growth factor receptor dependent invasive growth in Collagen-I extracellular matrix (ECM) networks. In this setting, FER promotes phosphorylation of EGFR-Y1068 and MET-Y1234/5. Additionally, FER controls ligand-dependent endocytic transport velocity, demonstrating a multifactorial regulation of proximal GFR activation during HNSCC invasion. Finally, genetic loss of function experiments or a FER-specific PROteolysis-TArgeting Chimera (PROTAC) strategy in PDO-based xenograft mouse models, demonstrate that FER is essential for invasive growth and metastasis of HNSCC. In sum, we propose that FER is an indiscriminate regulator of proximal GFR activation in HNSCC, a mechanism that may foster oncogene addition, thereby leading to invasive growth and metastasis. Based on its oncogenic roles and correlations with poor patient prognosis, we nominate FER as a potential candidate for targeted clinical intervention of HNSCC.

生长因子受体的混杂激活驱动持续的MAP激酶信号传导，增强了hpv阴性头颈部鳞状细胞癌（HNSCC）的癌基因依赖。这一特征促进了侵袭性生长，使手术切除复杂化，并导致局部复发率高和患者预后差。目前针对单一生长因子受体的局部晚期或不可切除肿瘤的治疗策略提供有限的治疗效果，强调需要替代靶点。利用侵袭性HNSCC的患者源性肿瘤类器官（PDO）模型，我们证明了与HNSCC患者生存率低相关的非受体酪氨酸激酶FER对于胶原- i细胞外基质（ECM）网络中生长因子受体依赖的侵袭性生长至关重要。在这种情况下，FER促进EGFR-Y1068和MET-Y1234/5的磷酸化。此外，FER控制配体依赖的内吞运输速度，表明在HNSCC侵袭期间近端GFR激活的多因子调节。最后，在基于pdo的异种移植小鼠模型中进行的基因功能缺失实验或FER特异性蛋白水解靶向嵌合体（PROTAC）策略表明，FER对于HNSCC的侵袭性生长和转移至关重要。总之，我们提出，在HNSCC中，FER是近端GFR激活的不加区分的调节因子，这一机制可能促进癌基因的添加，从而导致侵袭性生长和转移。基于其致癌作用和与患者预后不良的相关性，我们推荐FER作为针对HNSCC的靶向临床干预的潜在候选者。

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引用次数: 0

Adverse prognosis of GM-CSF expression in human cutaneous melanoma 人皮肤黑色素瘤中GM-CSF表达的不良预后。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-17 DOI: 10.1016/j.neo.2025.101240

Elena García-Martínez , Alicia Nieto-Valle , Celia Barrio-Alonso , Baltasar López-Navarro , José Antonio Avilés-Izquierdo , Verónica Parra-Blanco , Alba Gutiérrez-Seijo , Paloma Sánchez-Mateos , Rafael Samaniego

Background

GM-CSF, a myeloid-priming cytokine, exhibits context-dependent effects on tumor growth and, despite its clinical use, its role in human melanoma remains undefined.

Methods

A stage II-IV primary melanoma cohort (n = 80) was interrogated for GM-CSF/GM-CSFR expression at the single-cell level in tumor-associated macrophages (TAMs) and tumor cells (TCs). Invasion, survival and lung colonization assays were used to determine the pro-tumoral role of GM-CSF, and RNA-seq to analyze transcriptomic profiles.

Results

GM-CSF was significantly enriched in TAMs and TCs of primary cutaneous melanoma samples from patients who subsequently developed metastasis, compared with non-metastasizing ones, correlating with reduced disease-free and overall survival (p < 0.0001). GM-CSF receptor subunits were present in both cell types and their expression did not correlate with clinical outcomes. GM-CSF activated non-canonical signaling pathways in TCs, promoted their invasiveness and enhanced in vivo lung colonization in a murine model. GM-CSF–primed macrophages secreted higher levels of inflammatory cytokines upon interaction with melanoma cells than those unprimed or primed with M-CSF. Reciprocally, RNA-seq analyses revealed a broader transcriptional reprogramming in melanoma cells exposed to GM-CSF-primed macrophages.

Conclusions

Our findings highlight a potentially pro-tumorigenic GM-CSF-driven paracrine axis in patients with poor-prognosis melanoma, supporting therapeutic strategies aimed at disrupting this signaling network.

背景：GM-CSF是一种髓细胞启动细胞因子，对肿瘤生长表现出环境依赖性作用，尽管其临床应用，但其在人类黑色素瘤中的作用仍不明确。方法：对II-IV期原发性黑色素瘤队列（n = 80）进行了肿瘤相关巨噬细胞（tam）和肿瘤细胞（tc）单细胞水平的GM-CSF/GM-CSFR表达检测。侵袭、生存和肺部定植试验用于确定GM-CSF的促肿瘤作用，RNA-seq用于分析转录组谱。结果：与未发生转移的患者相比，来自随后发生转移的患者的原发性皮肤黑色素瘤样本的tam和tc中GM-CSF显著富集，与降低的无病生存期和总生存期相关（p < 0.0001）。两种细胞类型中均存在GM-CSF受体亚基，其表达与临床结果无关。在小鼠模型中，GM-CSF激活TCs中的非规范信号通路，促进其侵袭性并增强其在体内肺定植。与未引物或引物M-CSF的巨噬细胞相比，gm - csf引物的巨噬细胞在与黑色素瘤细胞相互作用时分泌更高水平的炎症细胞因子。相反，RNA-seq分析揭示了暴露于gm - csf引发的巨噬细胞的黑色素瘤细胞中更广泛的转录重编程。结论：我们的研究结果强调了预后不良黑色素瘤患者中潜在的促瘤性gm - csf驱动的旁分泌轴，支持旨在破坏该信号网络的治疗策略。

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引用次数: 0

6-aminonicotinamide, a G6PD inhibitor, mitigates CAPS1 reduction mediated HCC metastasis via ERK and GSK3β signals 6-氨基烟碱酰胺，一种G6PD抑制剂，通过ERK和GSK3β信号减轻CAPS1减少介导的HCC转移。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-11 DOI: 10.1016/j.neo.2025.101239

Xiahui Lin , Yingying Xu , Encheng Bai , Yiran Deng , Wei Zhang , Ruyi Xue , Si Zhang , Li Zhang , Wenqing Tang , Ling Dong , She Chen

Redirecting glucose into the pentose phosphate pathway (PPP) is a strategy used by cancer cells to facilitate accelerated proliferation and dissemination. Glucose-6-phosphate dehydrogenase (G6PD) is a rate-limiting enzyme of PPP. However, the regulation of G6PD in hepatocellular carcinoma (HCC) has not been well understood. Here we found that G6PD activity was induced in HCC tissues. G6PD inhibition, by its inhibitor 6-aminonicotinamide (6-AN) or siRNA, attenuated HCC metastasis. CAPS1 (calcium-dependent activator protein for secretion 1) was identified as a novel regulator of G6PD. CAPS1 C2 domain directly interacted with the N-terminus of G6PD. This interaction disrupted G6PD dimer formation and inhibited G6PD activity. In HCC, CAPS1 down-regulation, primarily due to miR-30d-5p elevation, accumulated metabolic products in PPP. Loss of CAPS1 elevated ROS level, an event that induced epithelial-mesenchymal transition (EMT) process and HCC metastasis via ERK and GSK3β signals. Importantly, these effects could be reversed in vitro and in vivo by G6PD inhibitors, 6-AN, or siRNA. Our studies revealed CAPS1 as a novel regulator of G6PD and suggested that G6PD inhibition, such as 6-AN, represented a strategy for HCC therapy in patients with low CAPS1 expression.

将葡萄糖重定向到戊糖磷酸途径（PPP）是癌细胞加速增殖和传播的一种策略。葡萄糖-6-磷酸脱氢酶（G6PD）是PPP的限速酶。然而，G6PD在肝细胞癌（HCC）中的调控作用尚不清楚。我们发现G6PD活性在HCC组织中被诱导。G6PD抑制剂6-氨基烟碱酰胺（6-AN）或siRNA抑制G6PD可减轻HCC转移。CAPS1（钙依赖性分泌激活蛋白1）被确定为G6PD的一种新的调节因子。CAPS1 C2结构域直接与G6PD的n端相互作用。这种相互作用破坏了G6PD二聚体的形成，抑制了G6PD的活性。在HCC中，CAPS1下调，主要是由于miR-30d-5p升高，在PPP中积累代谢产物。CAPS1缺失会升高ROS水平，这一事件通过ERK和GSK3β信号诱导上皮-间质转化（EMT）过程和HCC转移。重要的是，这些作用可以通过G6PD抑制剂、6-AN或siRNA在体外和体内逆转。我们的研究表明CAPS1是G6PD的一种新的调节因子，并表明G6PD抑制，如6-AN，代表了低CAPS1表达患者的HCC治疗策略。

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引用次数: 0

RANKL and CSF-1 are elevated in periovulatory follicular fluid of BRCA1 mutation carriers and increase proinflammatory signaling in fallopian tube epithelial cells BRCA1突变携带者的卵泡液中RANKL和CSF-1升高，并增加输卵管上皮细胞的促炎信号。

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-08 DOI: 10.1016/j.neo.2025.101237

Alexandra Kollara , Vidushi Madaan , Jianhong Zhang , Ellen M. Greenblatt , Theodore J. Brown

Pathogenic germline mutations in BRCA1 predispose individuals to high-grade serous tubo-ovarian cancer (HGSTOC), which originates in the fallopian tube epithelium (FTE). Identified non-genetic risk factors are consistent with a potential role for repetitive exposure of FTE cells to follicular fluid during ovulation in the development of this disease. We previously showed that BRCA1 deficiency in non-malignant FTE cells associates with increased proinflammatory NFκB signaling, which could contribute to the development of HGSTOC. Additionally, exposure of BRCA1 mutated primary FTE cells to periovulatory follicular fluid resulted in further increased levels of proinflammatory gene transcripts as compared to cells isolated from control patients. In this study, we compared cytokine levels in periovulatory follicular fluid collected from BRCA1 mutation carriers to that of non-BRCA1 mutation carriers. Follicular fluid was collected from 59 patients diagnosed with breast cancer undergoing controlled ovarian stimulation and oocyte retrieval as part of their oncofertility treatment. Samples included 13 patients with confirmed BRCA1 mutations, 15 patients with mutations in other susceptibility genes and 31 patients confirmed as non-BRCA1 mutation carriers. Levels of 92 inflammatory proteins were measured using an antibody array with a proximity extension assay. Partial Least-Squares Discriminant Analysis indicated that samples from BRCA1 mutation carriers clustered separately from other samples, indicating BRCA1 mutation status influences cytokine levels in follicular fluid. RANKL and CSF-1 were among 7 proteins found to be statistically elevated in follicular fluid from BRCA1 mutation carriers. Treatment of an immortalized FTE cell line with RANKL and CSF-1 increased NFκB signaling and levels of proteins encoded by type I interferon-stimulated genes. These findings support further investigation exploring the potential of targeting RANKL and CSF-1 for HGSTOC prevention strategies in BRCA1 mutation carriers.

BRCA1的致病种系突变使个体易患起源于输卵管上皮（FTE）的高级别浆液性输卵管卵巢癌（HGSTOC）。已确定的非遗传风险因素与排卵期间FTE细胞反复暴露于卵泡液在该病发展中的潜在作用一致。我们之前的研究表明，非恶性FTE细胞中的BRCA1缺失与促炎NFκB信号的增加有关，这可能有助于HGSTOC的发展。此外，与从对照患者中分离的细胞相比，将BRCA1突变的原代FTE细胞暴露于排卵周卵泡液中导致促炎基因转录物水平进一步升高。在这项研究中，我们比较了BRCA1突变携带者和非BRCA1突变携带者收集的卵泡液中细胞因子的水平。收集了59例诊断为乳腺癌的患者的卵泡液，这些患者接受了控制性卵巢刺激和卵母细胞回收，作为其肿瘤生育治疗的一部分。样本包括13例确诊BRCA1突变患者，15例其他易感基因突变患者和31例确诊非BRCA1突变携带者。使用抗体阵列和接近扩展法测量92种炎症蛋白的水平。偏最小二乘判别分析表明，BRCA1突变携带者的样本与其他样本分开聚集，表明BRCA1突变状态影响卵泡液中细胞因子的水平。在BRCA1突变携带者的卵泡液中，RANKL和CSF-1等7种蛋白在统计学上升高。用RANKL和CSF-1处理永生化FTE细胞系可增加NFκB信号传导和I型干扰素刺激基因编码的蛋白水平。这些发现支持进一步探索靶向RANKL和CSF-1在BRCA1突变携带者中预防HGSTOC策略的潜力。

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引用次数: 0

Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer 前列腺癌中与RB1和TP53缺失相关的代谢和影像学表型

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-07 DOI: 10.1016/j.neo.2025.101235

Fahim Ahmad , Margaret White , Kazutoshi Yamamoto , Daniel R. Crooks , Supreet Agarwal , Ye Yang , Brian Capaldo , Sonam Raj , Aian Neil Alilin , Anita Ton , Stephen Adler , Jurgen Seidel , Colleen Olkowski , Murali Krishna Cherukuri , Peter L Choyke , Kathleen Kelly , Jeffrey R. Brender

Advanced prostate cancer is treated with androgen receptor (AR) signaling inhibitors, which are initially effective, but most patients eventually develop resistance and progress to castrate-resistant prostate cancer (CRPC). Loss of RB1 in CRPC tumors is correlated with rapid progression and poor patient survival and, in combination with TP53 loss, predisposes patients to the development of transitional neuroendocrine prostate cancer (NEPC). Although progressive CRPC is clinically associated with higher 18FDG-PET SUVmax values, it is unknown whether inactivation of RB1 and/or TP53 is a driver of increased glucose import. Using a cohort of patient-derived xenograft (PDX)-derived CRPC organoids, we found that NEPC could not be conclusively distinguished from adenocarcinoma by 18FDG uptake alone, and PSMA protein levels did not correlate with cancer phenotype or 18FDG uptake. Castration-resistant models showed higher 18FDG uptake, but lower pyruvate-to-lactate conversion compared to their castration-sensitive counterparts. In parallel studies using castration-sensitive prostate cancer models, RB1/TP53 knockdown did not affect 18FDG uptake, but increased basal respiration and glycolytic activity, with combined depletion leading to glucose diversion into glycogenesis. These metabolic changes were reflected in increased lactate dehydrogenase flux detected by 13C-hyperpolarized magnetic resonance spectroscopy upon RB1 loss, but not in 18FDG uptake. The metabolic heterogeneity revealed here suggests that a multimodal molecular imaging approach can improve tumor characterization, potentially leading to a better prognosis in cancer treatment.

晚期前列腺癌采用雄激素受体（AR）信号抑制剂治疗，最初有效，但大多数患者最终产生耐药性并进展为去势抵抗性前列腺癌（CRPC）。CRPC肿瘤中RB1的缺失与快速进展和较差的患者生存相关，并与TP53缺失相结合，使患者易发展为过渡性神经内分泌前列腺癌（NEPC）。尽管进行性CRPC在临床上与更高的18FDG-PET SUVmax值相关，但尚不清楚RB1和/或TP53失活是否是葡萄糖进口增加的驱动因素。通过一组患者来源的异种移植（PDX）来源的CRPC类器官，我们发现仅通过18FDG摄取不能将NEPC与腺癌明确区分开来，PSMA蛋白水平与癌症表型或18FDG摄取无关。与去势敏感的模型相比，抗去势模型显示更高的18FDG摄取，但更低的丙酮酸-乳酸转化。在对去雄敏感的前列腺癌模型进行的平行研究中，RB1/TP53敲低并不影响18FDG的摄取，但增加了基础呼吸和糖酵解活性，联合消耗导致葡萄糖转移到糖生成。这些代谢变化反映在RB1损失时，13c超极化磁共振波谱检测到乳酸脱氢酶通量增加，但不反映在18FDG摄取上。本文揭示的代谢异质性表明，多模态分子成像方法可以改善肿瘤特征，可能导致更好的癌症治疗预后。

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引用次数: 0

Ovulation releases G-CSF to induce peritoneal neutrophil influx and netosis, facilitating peritoneal seeding of high-grade serous carcinoma 排卵释放G-CSF诱导腹膜中性粒细胞内流和网状，促进高级别浆液性癌的腹膜播种

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-10-04 DOI: 10.1016/j.neo.2025.101236

Tang-Yuan Chu , Pao-Chu Chen , Aye Aye Khine , Ying-Hsi Chen , Sung-Chao Chu , Hsuan-Shun Huang

Introduction

High-grade serous ovarian cancer (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), often originates from serous tubal intraepithelial carcinoma (STIC) and is typically diagnosed at advanced stages. However, the mechanisms underlying the dissemination of STIC cells into the peritoneal cavity remain poorly understood. This study aims to clarify whether the immune microenvironment triggered by physiological ovulation contributes to this early metastatic process.

Methods

We investigated the link between ovulation-induced peritoneal neutrophil extracellular trap (NET) formation, NETosis, and cancer cell seeding. Peritoneal fluid from humans and mice at various ovulatory stages was analyzed for immune cell composition. NETosis was assessed by neutrophil DNA staining and detection of PAD4 and citrullinated histone H3 (CitH3). STIC-mimicking and HGSC cells were used with or without NET inhibition to evaluate effects on early metastatic seeding.

Results

Ovulatory follicular fluid (FF) robustly induced peritoneal neutrophil recruitment and rapid NET formation via a G-CSF-mediated, ROS/NOX/PAD4-dependent mechanism. NETs promoted cell clustering and anchorage-independent growth through extracellular DNA, while NET-derived soluble factors enhanced cell adhesion and invasion. In vivo, exposure to FF enhanced early intraperitoneal tumor cell seeding, which was significantly reduced by PAD4 inhibition.

Conclusion

Physiological ovulation induces neutrophil influx and NETosis, creating a pro-metastatic peritoneal niche that facilitates both the dissemination and transformation of STIC cells. These findings reveal a novel mechanism linking ovulation to HGSC progression and suggest NETosis as a potential target for early intervention.

高级别浆液性卵巢癌（HGSC）是上皮性卵巢癌（EOC）中最致命的亚型，通常起源于浆液性输卵管上皮内癌（STIC），通常在晚期诊断出来。然而，STIC细胞扩散到腹腔的机制仍然知之甚少。本研究旨在阐明生理排卵触发的免疫微环境是否有助于这种早期转移过程。方法研究排卵诱导的腹膜中性粒细胞胞外陷阱（NET）形成、NETosis和癌细胞播种之间的关系。分析了人类和小鼠在不同排卵期的腹膜液中免疫细胞的组成。中性粒细胞DNA染色、PAD4和瓜氨酸组蛋白H3 （CitH3）检测NETosis。使用或不使用NET抑制的模拟stic细胞和HGSC细胞来评估对早期转移播种的影响。结果卵泡液（FF）通过g - csf介导的ROS/NOX/ pad4依赖性机制，强烈诱导腹膜中性粒细胞募集和快速NET形成。net通过细胞外DNA促进细胞聚集和非锚定生长，而net衍生的可溶性因子增强细胞粘附和侵袭。在体内，暴露于FF增强了早期腹膜内肿瘤细胞的播种，而PAD4抑制显著降低了肿瘤细胞的播种。结论生理性排卵诱导中性粒细胞内流和NETosis，形成促转移腹膜生态位，促进STIC细胞的传播和转化。这些发现揭示了一种将排卵与HGSC进展联系起来的新机制，并建议NETosis作为早期干预的潜在目标。

{"title":"Ovulation releases G-CSF to induce peritoneal neutrophil influx and netosis, facilitating peritoneal seeding of high-grade serous carcinoma","authors":"Tang-Yuan Chu , Pao-Chu Chen , Aye Aye Khine , Ying-Hsi Chen , Sung-Chao Chu , Hsuan-Shun Huang","doi":"10.1016/j.neo.2025.101236","DOIUrl":"10.1016/j.neo.2025.101236","url":null,"abstract":"<div><h3>Introduction</h3><div>High-grade serous ovarian cancer (HGSC), the most lethal subtype of epithelial ovarian cancer (EOC), often originates from serous tubal intraepithelial carcinoma (STIC) and is typically diagnosed at advanced stages. However, the mechanisms underlying the dissemination of STIC cells into the peritoneal cavity remain poorly understood. This study aims to clarify whether the immune microenvironment triggered by physiological ovulation contributes to this early metastatic process.</div></div><div><h3>Methods</h3><div>We investigated the link between ovulation-induced peritoneal neutrophil extracellular trap (NET) formation, NETosis, and cancer cell seeding. Peritoneal fluid from humans and mice at various ovulatory stages was analyzed for immune cell composition. NETosis was assessed by neutrophil DNA staining and detection of PAD4 and citrullinated histone H3 (CitH3). STIC-mimicking and HGSC cells were used with or without NET inhibition to evaluate effects on early metastatic seeding.</div></div><div><h3>Results</h3><div>Ovulatory follicular fluid (FF) robustly induced peritoneal neutrophil recruitment and rapid NET formation via a G-CSF-mediated, ROS/NOX/PAD4-dependent mechanism. NETs promoted cell clustering and anchorage-independent growth through extracellular DNA, while NET-derived soluble factors enhanced cell adhesion and invasion. In vivo, exposure to FF enhanced early intraperitoneal tumor cell seeding, which was significantly reduced by PAD4 inhibition.</div></div><div><h3>Conclusion</h3><div>Physiological ovulation induces neutrophil influx and NETosis, creating a pro-metastatic peritoneal niche that facilitates both the dissemination and transformation of STIC cells. These findings reveal a novel mechanism linking ovulation to HGSC progression and suggest NETosis as a potential target for early intervention.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101236"},"PeriodicalIF":7.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145223595","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

PD-L1(+) tumor-associated macrophages induce CD8(+) T Cell exhaustion in hepatocellular carcinoma PD-L1（+）肿瘤相关巨噬细胞在肝细胞癌中诱导CD8(+) T细胞衰竭

IF 7.7 2区医学 Q1 Biochemistry, Genetics and Molecular Biology

Neoplasia

Pub Date : 2025-09-29 DOI: 10.1016/j.neo.2025.101234

Takuto Nosaka , Masahiro Ohtani , Junki Yamashita , Yosuke Murata , Yu Akazawa , Tomoko Tanaka , Kazuto Takahashi , Tatsushi Naito , Yoshiaki Imamura , Kenji Koneri , Takanori Goi , Yasunari Nakamoto

The therapeutic efficacy of immune checkpoint inhibitors (ICIs) in patients with hepatocellular carcinoma (HCC) is profoundly influenced by the tumor immune microenvironment (TIME), where tumor-associated macrophages (TAMs) expressing programmed death-ligand 1 (PD-L1) serve as key modulators of immune suppression and tumor progression. Although PD-L1(+) TAMs have attracted increasing attention, their precise immunological functions in patients with HCC remain incompletely understood. In this study, we conducted an integrated analysis combining single-cell transcriptomics, spatial profiling, in vitro functional assays, and in vivo therapeutic modeling to clarify the role of PD-L1(+) TAMs in HCC. Single-cell RNA sequencing of tumor samples from patients with HCC (GSE189903) revealed that intratumoral PD-L1(+) TAMs were enriched for immune-related signaling pathways and expressed chemokines including CXCL9, CXCL10, and CXCL11. In vitro, GM-CSF–induced PD-L1(+) macrophages promoted CD8(+) T cell exhaustion, characterized by increased expression of TIM3 and suppression of cytotoxic molecules such as GZMB. Spatial analysis using multiplex immunofluorescence staining of surgical specimens from 113 patients with HCC demonstrated that close proximity between PD-L1(+) TAMs and CD8(+) T cells within tumors was an independent predictor of early postoperative recurrence and poor outcome. Moreover, in a murine orthotopic liver cancer model, the combination of anti–GM-CSF and anti–PD-L1 antibodies inhibited the differentiation of PD-L1(+) TAMs, reduced their contact with CD8(+) T cells, alleviated T cell exhaustion, and potentiated antitumor immunity. These findings highlight the critical contribution of PD-L1(+) TAMs to immune evasion in patients with HCC and support their therapeutic targeting as a strategy to enhance ICI responses.

免疫检查点抑制剂（ICIs）对肝细胞癌（HCC）患者的治疗效果受到肿瘤免疫微环境（TIME）的深刻影响，其中表达程序性死亡配体1 （PD-L1）的肿瘤相关巨噬细胞（tam）是免疫抑制和肿瘤进展的关键调节剂。尽管PD-L1(+) tam引起了越来越多的关注，但它们在HCC患者中的确切免疫功能仍不完全清楚。在这项研究中，我们进行了一项综合分析，结合单细胞转录组学、空间分析、体外功能分析和体内治疗模型，以阐明PD-L1(+) tam在HCC中的作用。肝癌患者肿瘤样本（GSE189903）的单细胞RNA测序显示，肿瘤内PD-L1(+) tam富集免疫相关信号通路，表达趋化因子包括CXCL9、CXCL10和CXCL11。在体外，gm - csf诱导的PD-L1（+）巨噬细胞促进CD8(+) T细胞衰竭，其特征是TIM3的表达增加和GZMB等细胞毒性分子的抑制。对113例HCC患者的手术标本进行多重免疫荧光染色的空间分析表明，肿瘤内PD-L1(+) tam和CD8(+) T细胞的密切接近是术后早期复发和预后不良的独立预测因子。此外，在小鼠原位肝癌模型中，抗gm - csf和抗PD-L1抗体联合使用可抑制PD-L1(+) tam的分化，减少其与CD8(+) T细胞的接触，减轻T细胞衰竭，增强抗肿瘤免疫。这些发现强调了PD-L1(+) tam对HCC患者免疫逃避的重要贡献，并支持其治疗靶向作为增强ICI反应的策略。

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引用次数: 0