A comprehensive understanding of the mechanisms by which air pollutant exposure drives cancer progression remains incomplete. Particulate matter has been shown to induce genotoxicity and mutagenesis through oxidative stress both in vivo and in vitro. However, its impact on the pulmonary immune microenvironment and its role in modulating anti-tumour immune responses remains poorly characterized.
Here, we report that chronic exposure to diesel exhaust particles (DEPs), a major component of PM2.5, induces an immunosuppressive lung microenvironment that promotes tumour progression in a KRAS-driven lung adenocarcinoma model (KrasLSL-G12D/+-Trp53lox/lox or KP mice). This environment is characterized by the emergence of PMN-MDSC (CD14pos PMNs) that exhibit NET formation and an immunosuppressive gene expression and functional profile. Additionally, we observed increased infiltration of regulatory T cells (Tregs), and upregulation of exhaustion/activation and immunosuppressive markers on T cells, factors that likely contribute to the increased tumour burden and enhanced tumour cell proliferation seen in DEP-exposed KP mice.
Our study reveals how chronic DEP exposure reshapes the lung microenvironment in ways that may impair the ability to mount effective anti-tumour immune responses. These findings highlight the need for stronger public and occupational health policies aimed at reducing air pollution and its associated disease burden.
{"title":"Exposure to diesel particulates induces an immunosuppressive microenvironment that promotes the progression of lung cancer","authors":"Marie-Laure Delhez , Maëlle Bosmans , Lucia Rodriguez Rodriguez , Alison Gillard , Silvia Blacher , Arnaud Blomme , Pierre Close , Bénédicte Machiels , Marie-Julie Nokin , Didier Cataldo","doi":"10.1016/j.neo.2025.101255","DOIUrl":"10.1016/j.neo.2025.101255","url":null,"abstract":"<div><div>A comprehensive understanding of the mechanisms by which air pollutant exposure drives cancer progression remains incomplete. Particulate matter has been shown to induce genotoxicity and mutagenesis through oxidative stress both <em>in vivo</em> and <em>in vitro</em>. However, its impact on the pulmonary immune microenvironment and its role in modulating anti-tumour immune responses remains poorly characterized.</div><div>Here, we report that chronic exposure to diesel exhaust particles (DEPs), a major component of PM2.5, induces an immunosuppressive lung microenvironment that promotes tumour progression in a KRAS-driven lung adenocarcinoma model (<em>Kras<sup>LSL-G12D/+</sup>-Trp53<sup>lox/lox</sup></em> or KP mice). This environment is characterized by the emergence of PMN-MDSC (CD14<sup>pos</sup> PMNs) that exhibit NET formation and an immunosuppressive gene expression and functional profile. Additionally, we observed increased infiltration of regulatory T cells (Tregs), and upregulation of exhaustion/activation and immunosuppressive markers on T cells, factors that likely contribute to the increased tumour burden and enhanced tumour cell proliferation seen in DEP-exposed KP mice.</div><div>Our study reveals how chronic DEP exposure reshapes the lung microenvironment in ways that may impair the ability to mount effective anti-tumour immune responses. These findings highlight the need for stronger public and occupational health policies aimed at reducing air pollution and its associated disease burden.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101255"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145576960","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 : 2026-01-01Epub Date: 2025-11-13DOI: 10.1016/j.neo.2025.101253
Chiu-Lien Hung , Wen-Ning Hsu , Tsan-Chun Wang , Wan-Ru Chen , Yu-Ting Chen , Zong-Keng Kuo , Tsan-Lin Hu , Yu-Chin Lin , Hsun-Hao Yeh , Han-Chen Lin , Chia-Jung Yu , Chih-Wei Fu , Hao-Hsuan Liu , Hung-Chih Hsu , Po-Hung Lin , See-Tong Pang , Chih-Ho Lai , Ling-Yu Wang
Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer (CRPC), with AR splice variants like AR-V7 contributing to resistance against second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) provides a strategy to bypass ligand-binding domain (LBD)-mediated resistance. We developed ITRI-148, a CRBN-based AR-NTD degrader incorporating a rigid piperidine-alkyne linker optimized for oral pharmacokinetics. ITRI-148 efficiently degrades full-length AR, AR-V7, and clinically relevant mutants (L702H, H875Y). It facilitates the recruitment of active AR species to CRBN in the nucleus, promoting their polyubiquitination and proteasomal degradation. In CRPC and enzalutamide-resistant models, ITRI-148 robustly suppresses AR signaling and inhibits cell viability, outperforming enzalutamide. With long-term treatment, it achieves sustained AR suppression without inducing compensatory AR-V7 upregulation or PSA re-expression. In vivo, ITRI-148 demonstrates potent antitumor efficacy in both castrated and hormone-intact CRPC models, supported by favorable pharmacokinetic properties, stability and safety profiles. These findings position ITRI-148 as a promising next-generation AR-targeting agent capable of degrading resistant AR variants and providing durable inhibition of AR signaling in advanced prostate cancer.
{"title":"Oral bioavailable ITRI-148 degrades androgen receptor variants and overcomes antiandrogen resistance in advanced prostate cancer","authors":"Chiu-Lien Hung , Wen-Ning Hsu , Tsan-Chun Wang , Wan-Ru Chen , Yu-Ting Chen , Zong-Keng Kuo , Tsan-Lin Hu , Yu-Chin Lin , Hsun-Hao Yeh , Han-Chen Lin , Chia-Jung Yu , Chih-Wei Fu , Hao-Hsuan Liu , Hung-Chih Hsu , Po-Hung Lin , See-Tong Pang , Chih-Ho Lai , Ling-Yu Wang","doi":"10.1016/j.neo.2025.101253","DOIUrl":"10.1016/j.neo.2025.101253","url":null,"abstract":"<div><div>Androgen receptor (AR) signaling remains a key driver of castration-resistant prostate cancer (CRPC), with AR splice variants like AR-V7 contributing to resistance against second-generation antiandrogens. Targeting the AR N-terminal domain (NTD) provides a strategy to bypass ligand-binding domain (LBD)-mediated resistance. We developed ITRI-148, a CRBN-based AR-NTD degrader incorporating a rigid piperidine-alkyne linker optimized for oral pharmacokinetics. ITRI-148 efficiently degrades full-length AR, AR-V7, and clinically relevant mutants (L702H, H875Y). It facilitates the recruitment of active AR species to CRBN in the nucleus, promoting their polyubiquitination and proteasomal degradation. In CRPC and enzalutamide-resistant models, ITRI-148 robustly suppresses AR signaling and inhibits cell viability, outperforming enzalutamide. With long-term treatment, it achieves sustained AR suppression without inducing compensatory AR-V7 upregulation or PSA re-expression. In vivo, ITRI-148 demonstrates potent antitumor efficacy in both castrated and hormone-intact CRPC models, supported by favorable pharmacokinetic properties, stability and safety profiles. These findings position ITRI-148 as a promising next-generation AR-targeting agent capable of degrading resistant AR variants and providing durable inhibition of AR signaling in advanced prostate cancer.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101253"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145517985","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}
Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. Statement of significance: PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.
{"title":"PDGFRα governs multiple cellular signals and plays a protective role in tumor progression","authors":"Masao Hayashi , Noriko Okuno , Le Thi Thu Trang , Ayaka Inami , Yosei Kato , Takeru Hamashima , Dang Son Tung , Yasuharu Watanabe , Rieko Kojima , Miwa Fujikawa , Akari Ejiri , Tomomi Kunisawa , Fumiko Itoh , Masashi Muramatsu , Tran Ngoc Dung , Dang Thanh Chung , Pham Van Thinh , Takeharu Minamitani , Tsutomu Yanagibashi , Toshihiko Fujimori , Seiji Yamamoto","doi":"10.1016/j.neo.2025.101248","DOIUrl":"10.1016/j.neo.2025.101248","url":null,"abstract":"<div><div>Extensive research has been done on the molecular mechanisms of tumor development and growth. However, multiple aspects remain elusive. We examined cellular signaling mechanisms involving platelet-derived growth factor (PDGF) and its receptor (PDGFR), using adult PDGFRα conditional knockout (α-KO) mice implanted with Lewis lung carcinoma (LLC) cells, which express PDGFRα. Unexpectedly, α-KO mice exhibited larger tumors and extensive lung metastasis compared to control mice. Mechanistically, under the activation of PDGF-BB-PDGFRα signal axis in LLC cells, transforming growth factor-α (TGF-α) induced accelerated tumor growth via epidermal growth factor receptor (EGFR) signal. Insufficient vascular development with lower pericyte coverage was also noted, leading to hypoxia and increased expression of transforming growth factor-β (TGF-β), which induced as a critical signaling molecule determining lung metastatic changes with the AKT1 activity. Our findings suggested that PDGFRα in interstitial cells may serve a protective role against tumor progression and selective inhibition of PDGFRα in tumor cells could offer a more targeted therapeutic approach for cancer patients. <strong>Statement of significance:</strong> PDGFRα in interstitial cells in tumors governs multiple cellular signals such as PDGF-BB, TGF-α, and TGF-β and plays a protective role in tumor progression.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101248"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145446179","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 : 2026-01-01Epub Date: 2025-11-28DOI: 10.1016/j.neo.2025.101258
Michael Sergeev , Melanie A. Meier , Petra Wohlleben , Laura Rupprecht , Mirka Kupraszewicz-Hutzler , Karl Hilgers , Andrea Hartner , Anna-Lena Voegele , Raja Atreya , Yannick Frey , Showmika Srirangan , Jutta Eichler , Caroline Confais , Benoît Hédan , Ulrich Jarry , Monilola A. Olayioye , Susanne Muehlich
Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) in vitro and in vivo in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.
{"title":"Filamin a binds deleted in liver cancer 1 (DLC1) to promote its tumor suppressor activity and inhibit the SRF coactivator MRTF-A","authors":"Michael Sergeev , Melanie A. Meier , Petra Wohlleben , Laura Rupprecht , Mirka Kupraszewicz-Hutzler , Karl Hilgers , Andrea Hartner , Anna-Lena Voegele , Raja Atreya , Yannick Frey , Showmika Srirangan , Jutta Eichler , Caroline Confais , Benoît Hédan , Ulrich Jarry , Monilola A. Olayioye , Susanne Muehlich","doi":"10.1016/j.neo.2025.101258","DOIUrl":"10.1016/j.neo.2025.101258","url":null,"abstract":"<div><div>Filamin A (FLNA) is an actin binding protein that organizes the cytoskeleton and controls many fundamental biological processes, such as cell migration and adhesion. The interaction between FLNA and the Myocardin-related transcription factor A (MRTF-A) promotes the activity of serum response factor (SRF) and cell migration. MRTF-A and SRF play an important role for tumor growth and senescence of hepatocellular carcinoma (HCC). Here, we identified a novel interaction between FLNA and the tumor suppressor Deleted in Liver Cancer 1 (DLC1) <em>in vitro</em> and <em>in vivo</em> in organoids and mapped the regions of interaction between DLC1 and FLNA. Association with FLNA enhanced DLC1 RhoGAP function, impaired SRF transcriptional activity, and induced cellular senescence. We found a novel molecular switch between the DLC1-FLNA and the MRTF-A-FLNA complexes that is mediated by FLNA phosphorylation at serine 2152. We generated DLC1 binding peptides that dissociate the MRTF-A-FLNA complex and favor the novel DLC1-FLNA complex by preventing actin polymerization and FLNA phosphorylation at serine 2152. Since FLNA phosphorylation at serine 2152 was increased in mouse xenografts, reinforcing the DLC1-FLNA complex by targeting FLNA phosphorylation at serine 2152 represents a promising therapeutic approach for HCC treatment.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"71 ","pages":"Article 101258"},"PeriodicalIF":7.7,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145620907","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 : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-10-27DOI: 10.1016/j.neo.2025.101243
Rachele Niccolai , Camiel Göbel , Klevis Ndoj , Maaike Kreft , Hendrik J. Kuiken , Cor Lieftink , Ben Morris , Sietse D. Yska , Sebastian Hendrix , Bram van den Broek , Vincent Pappalardo , Marie José Kersten , Roderick L. Beijersbergen , Noam Zelcer , Fred van Leeuwen , Heinz Jacobs
The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.
{"title":"Cholesterol biosynthesis as a drug-induced vulnerability in diffuse large B cell lymphoma insensitive to EZH2 inhibition","authors":"Rachele Niccolai , Camiel Göbel , Klevis Ndoj , Maaike Kreft , Hendrik J. Kuiken , Cor Lieftink , Ben Morris , Sietse D. Yska , Sebastian Hendrix , Bram van den Broek , Vincent Pappalardo , Marie José Kersten , Roderick L. Beijersbergen , Noam Zelcer , Fred van Leeuwen , Heinz Jacobs","doi":"10.1016/j.neo.2025.101243","DOIUrl":"10.1016/j.neo.2025.101243","url":null,"abstract":"<div><div>The methyltransferase EZH2 is a critical epigenetic writer in Germinal Center B cell-like Diffuse Large B Cell Lymphoma (GCB-DLBCL). Clinically and experimentally, GCB-DLBCLs are either sensitive or insensitive to EZH2 inhibition. We hypothesized that EZH2 inhibitor (EZH2i) exposure of the insensitive subset may unfold epi‑drug induced, therapeutically exploitable dependencies. An EZH2i-anchored CRISPR-Cas9 drop-out screen identified the cholesterol biosynthesis pathway as an essential co-target in sensitizing EZH2i-insensitive GCB-DLBCLs. Mechanistic investigations into this metabolic dependency revealed that the loss of EZH2 activity impairs the exogenous cholesterol uptake due to reduced surface expression of the low-density lipoprotein (LDL) receptor, which accumulated in the lysosomal compartment. The reduced LDL uptake failed to upregulate SREBP2-mediated cholesterol biosynthesis as a compensatory response, rendering cells sensitive to cholesterol biosynthesis inhibition. In support of this, inhibition of EZH2 of cholesterol biosynthesis-deficient GCB-DLBCL xenograft increased tumor survival. Together, our findings identified the cholesterol biosynthesis pathway as a targetable vulnerability specific to EZH2i-insensitive GCB-DLBCL. These data support future translational studies to determine how clinically approved cholesterol inhibitors can be used to improve treatment outcomes for DLBCL patients non-responsive to EZH2 inhibition.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101243"},"PeriodicalIF":7.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394489","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":"2025-12-01","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}
Pub Date : 2025-12-01Epub 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":"2025-12-01","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 : 2025-12-01Epub Date: 2025-10-29DOI: 10.1016/j.neo.2025.101244
Jose L. Mondaza-Hernandez , David S. Moura , Yi Li , Jesus L. Marti , Paulino Gomez-Puertas , John T. Nguyen , Shuguang Wei , Bruce A. Posner , Clark A. Meyer , Leonidas Bleris , Javier Martin-Broto , Heather N. Hayenga
Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses with an average survival of two years. We constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, and we used these cells as models of SFT. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to high levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.
癌症，特别是融合癌蛋白（FO）驱动的血液学癌症和肉瘤，通常由少量关键突变发展而来。孤立性纤维瘤（SFT）是一种罕见的由NAB2-STAT6混淆基因驱动的间质肿瘤。目前，SFT的治疗选择仍然有限，抗血管生成药物只能提供部分反应，平均生存期为两年。我们使用CRISPR （Clustered Regularly Interspaced Short Palindromic Repeats）技术构建了含有特定NAB2-STAT6融合转录本的SFT细胞模型，并将这些细胞用作SFT模型。高通量药物筛选表明，BET抑制剂Mivebresib可以不同程度地减少SFT细胞模型的增殖。随后，BET抑制剂Mivebresib和BMS-986158在SFT患者来源的异种移植（PDX）动物模型中有效地降低了肿瘤生长。此外，我们的数据显示，NAB2-STAT6融合可能导致SFTs中高水平的DNA损伤。因此，将BET抑制剂与PARP（聚（adp -核糖）聚合酶）抑制剂或ATR抑制剂联合使用可显著增强SFT细胞的抗增殖作用。综上所述，本研究确定BET抑制剂Mivebresib和BMS-986158是有前景的抗sft药物。
{"title":"Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS)","authors":"Jose L. Mondaza-Hernandez , David S. Moura , Yi Li , Jesus L. Marti , Paulino Gomez-Puertas , John T. Nguyen , Shuguang Wei , Bruce A. Posner , Clark A. Meyer , Leonidas Bleris , Javier Martin-Broto , Heather N. Hayenga","doi":"10.1016/j.neo.2025.101244","DOIUrl":"10.1016/j.neo.2025.101244","url":null,"abstract":"<div><div>Cancers, especially fusion oncoprotein (FO)-driven hematological cancers and sarcomas, often develop from a low number of key mutations. Solitary Fibrous Tumor (SFT) is a rare mesenchymal tumor driven by the NAB2-STAT6 oncofusion gene. Currently, the treatment options for SFT remain limited, with anti-angiogenic drugs providing only partial responses with an average survival of two years. We constructed SFT cell models harboring specific NAB2-STAT6 fusion transcripts using the CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, and we used these cells as models of SFT. High-throughput drug screens demonstrated that the BET inhibitor Mivebresib can differentially reduce proliferation in SFT cell models. Subsequently, BET inhibitors Mivebresib and BMS-986158 efficiently reduced tumor growth in an SFT patient-derived xenograft (PDX) animal model. Furthermore, our data showed that NAB2-STAT6 fusions may lead to high levels of DNA damage in SFTs. Consequently, combining BET inhibitors with PARP (Poly (ADP-ribose) polymerase) inhibitors or with ATR inhibitors significantly enhanced anti-proliferative effects in SFT cells. Taken together, this study establishes BET inhibitors Mivebresib and BMS-986158 as promising anti-SFT agents.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101244"},"PeriodicalIF":7.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410705","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 : 2025-12-01Epub Date: 2025-10-27DOI: 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.
{"title":"EGFL6 is a novel HER3 ligand, inducing HER3/integrin heterodimers to induce pERK centrosomal deposition and therapeutic resistance","authors":"Shoumei Bai , Navneet Gupta , Victoria Liu , Adetunji Fayomi , Stacy McGonigal , Ronald J. Buckanovich","doi":"10.1016/j.neo.2025.101246","DOIUrl":"10.1016/j.neo.2025.101246","url":null,"abstract":"<div><div>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 <em>in vitro</em>. 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 <em>in vitro</em> and significant restricted tumor growth <em>in vivo</em>. 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.</div></div><div><h3>Significance</h3><div>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.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"70 ","pages":"Article 101246"},"PeriodicalIF":7.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145394454","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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