Pub Date : 2025-10-25DOI: 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.
{"title":"Age-diet interactions significantly influence intratumoral gene expression, gut microbiome signature and tumor microenvironment in colorectal cancer","authors":"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","doi":"10.1016/j.neo.2025.101245","DOIUrl":"10.1016/j.neo.2025.101245","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101245"},"PeriodicalIF":7.7,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363830","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}
Pub Date : 2025-10-23DOI: 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.
{"title":"Targeting Wnt/β-catenin signaling enhances the efficacy of anti-CD38 immunotherapy in multiple myeloma","authors":"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","doi":"10.1016/j.neo.2025.101242","DOIUrl":"10.1016/j.neo.2025.101242","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>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 <em>in vivo</em>.</div></div><div><h3>Results</h3><div>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 <em>in vitro</em> as well as in an <em>in vivo</em> mouse model.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101242"},"PeriodicalIF":7.7,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145363835","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}
Pub Date : 2025-10-19DOI: 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.
{"title":"FER kinase governs invasive growth of head and neck squamous cell carcinoma through dynamic control of growth factor receptor activity","authors":"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","doi":"10.1016/j.neo.2025.101241","DOIUrl":"10.1016/j.neo.2025.101241","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101241"},"PeriodicalIF":7.7,"publicationDate":"2025-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145325541","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}
Pub Date : 2025-10-17DOI: 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.
{"title":"Adverse prognosis of GM-CSF expression in human cutaneous melanoma","authors":"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","doi":"10.1016/j.neo.2025.101240","DOIUrl":"10.1016/j.neo.2025.101240","url":null,"abstract":"<div><h3>Background</h3><div>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.</div></div><div><h3>Methods</h3><div>A stage II-IV primary melanoma cohort (<em>n</em> = 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.</div></div><div><h3>Results</h3><div>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 (<em>p</em> < 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.</div></div><div><h3>Conclusions</h3><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101240"},"PeriodicalIF":7.7,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318647","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}
Pub Date : 2025-10-11DOI: 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.
{"title":"6-aminonicotinamide, a G6PD inhibitor, mitigates CAPS1 reduction mediated HCC metastasis via ERK and GSK3β signals","authors":"Xiahui Lin , Yingying Xu , Encheng Bai , Yiran Deng , Wei Zhang , Ruyi Xue , Si Zhang , Li Zhang , Wenqing Tang , Ling Dong , She Chen","doi":"10.1016/j.neo.2025.101239","DOIUrl":"10.1016/j.neo.2025.101239","url":null,"abstract":"<div><div>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 <em>in vitro</em> and <em>in vivo</em> 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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101239"},"PeriodicalIF":7.7,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287275","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}
Pub Date : 2025-10-08DOI: 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.
{"title":"RANKL and CSF-1 are elevated in periovulatory follicular fluid of BRCA1 mutation carriers and increase proinflammatory signaling in fallopian tube epithelial cells","authors":"Alexandra Kollara , Vidushi Madaan , Jianhong Zhang , Ellen M. Greenblatt , Theodore J. Brown","doi":"10.1016/j.neo.2025.101237","DOIUrl":"10.1016/j.neo.2025.101237","url":null,"abstract":"<div><div>Pathogenic germline mutations in <em>BRCA1</em> 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 <em>BRCA1</em> 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 <em>BRCA1</em> mutation carriers to that of non-<em>BRCA1</em> 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 <em>BRCA1</em> mutations, 15 patients with mutations in other susceptibility genes and 31 patients confirmed as non-<em>BRCA1</em> 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 <em>BRCA1</em> mutation carriers clustered separately from other samples, indicating <em>BRCA1</em> 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 <em>BRCA1</em> 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 <em>BRCA1</em> mutation carriers.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101237"},"PeriodicalIF":7.7,"publicationDate":"2025-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145259703","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}
Pub Date : 2025-10-07DOI: 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.
{"title":"Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer","authors":"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","doi":"10.1016/j.neo.2025.101235","DOIUrl":"10.1016/j.neo.2025.101235","url":null,"abstract":"<div><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101235"},"PeriodicalIF":7.7,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145253296","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}
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.
{"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}
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.
{"title":"PD-L1(+) tumor-associated macrophages induce CD8(+) T Cell exhaustion in hepatocellular carcinoma","authors":"Takuto Nosaka , Masahiro Ohtani , Junki Yamashita , Yosuke Murata , Yu Akazawa , Tomoko Tanaka , Kazuto Takahashi , Tatsushi Naito , Yoshiaki Imamura , Kenji Koneri , Takanori Goi , Yasunari Nakamoto","doi":"10.1016/j.neo.2025.101234","DOIUrl":"10.1016/j.neo.2025.101234","url":null,"abstract":"<div><div>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, <em>in vitro</em> functional assays, and <em>in vivo</em> 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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101234"},"PeriodicalIF":7.7,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145201187","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}
Pub Date : 2025-09-25DOI: 10.1016/j.neo.2025.101233
Thi-Anh-Thuy Tran , Sinae An , Junghyun Lim , Young-Hee Kim , Ahyeon Shim , Taewoo Han , Hawsan Kim , Sue-Jee Park , Yeong Jin Kim , Kyung-Sub Moon , In-Young Kim , Shin Jung , Chul Won Lee , Kyung-Hwa Lee , Ae Kyung Park , Tae-Young Jung
Background
This study aimed to establish orthotopic intracranial patient-derived xenograft (PDX) models to investigate molecular and pathological features and to evaluate potential preclinical therapeutic approaches in glioblastoma (GBM).
Methods
Fresh or cryopreserved patient tumor tissues were first expanded as subcutaneous PDXs and subsequently used to generate orthotopic intracranial PDXs. Tumor growth and similarity to patient tumors were assessed by magnetic resonance imaging (MRI), pathological analyses, and multi-omics profiling. A selected intracranial PDX was further used to evaluate the potential preclinical efficacy of natural killer (NK) cells combined with Avastin® and irinotecan. The cytotoxic effects of this combination were also examined in primary GBM cells obtained from the original tumor of the same PDX.
Results
Subcutaneous PDX engraftment was successful in 13 out of 16 cases (81.3 %), and orthotopic intracranial PDXs were established from six of these with a 100 % success rate. Subcutaneous tumors expanded within 9 to 31 weeks, while intracranial tumors formed within 4 to 14 weeks. Subcutaneous growth was influenced by the Ki-67 index and the cryopreservation duration. Multi-omics analysis revealed extrachromosomal DNA (ecDNA)-driven amplifications of MYC(N), PDGFRA, CDK4, and MDM2 in PDXs from two patients. PDGFRA, CDK4, and MDM2 amplifications were consistent with those in the primary tumors, whereas MYC(N) amplification, initially minimal or absent in patient samples, was markedly enriched in the PDXs. Of the multiple PDXs from a single patient, the one PDX harboring ecDNA-driven MYCN amplification showed a greatly accelerated growth rate. Notably, PDXs containing ecDNA-driven MYC amplification exhibited a histological transformation toward primitive embryonal features. Combining NK cells with Avastin® and irinotecan enhanced cytotoxicity in vitro and prolonged survival in intracranial PDXs harboring ecDNA-driven MYC and PDGFRA amplifications.
Conclusion
Intracranial PDX models were successfully established from cryopreserved GBM tissues through subcutaneous expansion. These models offer a clinically relevant platform for investigating GBM biology and evaluating the therapeutic efficacy of chemoimmunotherapy.
{"title":"Generation of orthotopic intracranial glioblastoma patient-derived xenograft models: insights into extrachromosomal DNA-driven MYC(N) and PDGFRA oncogene amplification and preliminary therapeutic evaluation","authors":"Thi-Anh-Thuy Tran , Sinae An , Junghyun Lim , Young-Hee Kim , Ahyeon Shim , Taewoo Han , Hawsan Kim , Sue-Jee Park , Yeong Jin Kim , Kyung-Sub Moon , In-Young Kim , Shin Jung , Chul Won Lee , Kyung-Hwa Lee , Ae Kyung Park , Tae-Young Jung","doi":"10.1016/j.neo.2025.101233","DOIUrl":"10.1016/j.neo.2025.101233","url":null,"abstract":"<div><h3>Background</h3><div>This study aimed to establish orthotopic intracranial patient-derived xenograft (PDX) models to investigate molecular and pathological features and to evaluate potential preclinical therapeutic approaches in glioblastoma (GBM).</div></div><div><h3>Methods</h3><div>Fresh or cryopreserved patient tumor tissues were first expanded as subcutaneous PDXs and subsequently used to generate orthotopic intracranial PDXs. Tumor growth and similarity to patient tumors were assessed by magnetic resonance imaging (MRI), pathological analyses, and multi-omics profiling. A selected intracranial PDX was further used to evaluate the potential preclinical efficacy of natural killer (NK) cells combined with Avastin® and irinotecan. The cytotoxic effects of this combination were also examined in primary GBM cells obtained from the original tumor of the same PDX.</div></div><div><h3>Results</h3><div>Subcutaneous PDX engraftment was successful in 13 out of 16 cases (81.3 %), and orthotopic intracranial PDXs were established from six of these with a 100 % success rate. Subcutaneous tumors expanded within 9 to 31 weeks, while intracranial tumors formed within 4 to 14 weeks. Subcutaneous growth was influenced by the Ki-67 index and the cryopreservation duration. Multi-omics analysis revealed extrachromosomal DNA (ecDNA)-driven amplifications of MYC(N), PDGFRA, CDK4, and MDM2 in PDXs from two patients. PDGFRA, CDK4, and MDM2 amplifications were consistent with those in the primary tumors, whereas MYC(N) amplification, initially minimal or absent in patient samples, was markedly enriched in the PDXs. Of the multiple PDXs from a single patient, the one PDX harboring ecDNA-driven MYCN amplification showed a greatly accelerated growth rate. Notably, PDXs containing ecDNA-driven MYC amplification exhibited a histological transformation toward primitive embryonal features. Combining NK cells with Avastin® and irinotecan enhanced cytotoxicity in vitro and prolonged survival in intracranial PDXs harboring ecDNA-driven MYC and PDGFRA amplifications.</div></div><div><h3>Conclusion</h3><div>Intracranial PDX models were successfully established from cryopreserved GBM tissues through subcutaneous expansion. These models offer a clinically relevant platform for investigating GBM biology and evaluating the therapeutic efficacy of chemoimmunotherapy.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101233"},"PeriodicalIF":7.7,"publicationDate":"2025-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145154853","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}
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