Pub Date : 2025-09-22DOI: 10.1016/j.neo.2025.101231
Natalie Le , Jingwei Chen , Paul G. Ekert , Lauren M. Brown , Neevika Manoharan
Paediatric high-grade gliomas (pHGGs) are aggressive and molecularly heterogenous paediatric brain tumours with extremely poor survival outcomes. Receptor tyrosine kinases (RTKs) are recurrently altered in a significant proportion of pHGGs and can be potentially targeted with tyrosine kinase inhibitors (TKIs). PDGFRA is the most frequently altered RTK in pHGG and as such, represents an attractive therapeutic target, yet patients harbouring PDGFRA aberrations have largely failed to respond to TKIs. This raises the question as to whether PDGFRA is the only oncogenic dependency in all cases of pHGG, or alternatively, if there are unrecognised mechanisms conferring TKI resistance. Here we explore the mechanisms by which specific PDGFRA alterations drive oncogenesis and potentially mediate therapeutic resistance, to ascertain whether PDGFRA is a clinically useful target or merely a distraction.
{"title":"PDGFRA in paediatric high-grade glioma – target or distraction?","authors":"Natalie Le , Jingwei Chen , Paul G. Ekert , Lauren M. Brown , Neevika Manoharan","doi":"10.1016/j.neo.2025.101231","DOIUrl":"10.1016/j.neo.2025.101231","url":null,"abstract":"<div><div>Paediatric high-grade gliomas (pHGGs) are aggressive and molecularly heterogenous paediatric brain tumours with extremely poor survival outcomes. Receptor tyrosine kinases (RTKs) are recurrently altered in a significant proportion of pHGGs and can be potentially targeted with tyrosine kinase inhibitors (TKIs). <em>PDGFRA</em> is the most frequently altered RTK in pHGG and as such, represents an attractive therapeutic target, yet patients harbouring <em>PDGFRA</em> aberrations have largely failed to respond to TKIs. This raises the question as to whether PDGFRA is the only oncogenic dependency in all cases of pHGG, or alternatively, if there are unrecognised mechanisms conferring TKI resistance. Here we explore the mechanisms by which specific PDGFRA alterations drive oncogenesis and potentially mediate therapeutic resistance, to ascertain whether PDGFRA is a clinically useful target or merely a distraction.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101231"},"PeriodicalIF":7.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145109552","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 : 2025-09-20DOI: 10.1016/j.neo.2025.101232
Doudou Jing , Binghong Chen , Ruqi Liang , Fei Li , Bin Zhao , Feifei Pu , Wei Wu
Osteosarcoma is a common malignant bone tumor, characterized by its high invasiveness and propensity for lung metastasis. Despite advances in treatment, clinical outcomes remain poor, and patient prognosis is still unsatisfactory. Therefore, the development of more effective therapies is urgently needed. Here, we demonstrate that differential expression of GBP1 significantly influences PD-L1 expression and mediates immune escape in osteosarcoma. Specifically, our results reveal that GBP1 regulates PD-L1 expression by activating CDK9 and promoting STAT3 phosphorylation. These findings suggest that targeting GBP1 may represent a promising therapeutic strategy for the treatment of osteosarcoma by impairing tumor immune evasion.
{"title":"GBP1-CDK9-STAT3 signaling axis promotes osteosarcoma PD-L1 expression and immune escape","authors":"Doudou Jing , Binghong Chen , Ruqi Liang , Fei Li , Bin Zhao , Feifei Pu , Wei Wu","doi":"10.1016/j.neo.2025.101232","DOIUrl":"10.1016/j.neo.2025.101232","url":null,"abstract":"<div><div>Osteosarcoma is a common malignant bone tumor, characterized by its high invasiveness and propensity for lung metastasis. Despite advances in treatment, clinical outcomes remain poor, and patient prognosis is still unsatisfactory. Therefore, the development of more effective therapies is urgently needed. Here, we demonstrate that differential expression of GBP1 significantly influences PD-L1 expression and mediates immune escape in osteosarcoma. Specifically, our results reveal that GBP1 regulates PD-L1 expression by activating CDK9 and promoting STAT3 phosphorylation. These findings suggest that targeting GBP1 may represent a promising therapeutic strategy for the treatment of osteosarcoma by impairing tumor immune evasion.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101232"},"PeriodicalIF":7.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096066","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 : 2025-09-20DOI: 10.1016/j.neo.2025.101227
Qingliu He , Haoran Li , Yukun Cong , Kang Chen , Lulin Cheng , Fang Lv , Pu Zhang , Yunjie Ju , Zehao Yu , Jinyu Chen , Chuxiong Wang , Yarong Song , Xuechao Li , Liang Chen , Yifei Xing
Background
The poor prognosis of metastatic prostate cancer (PCa) poses a major burden on both patients and the healthcare system. FAM111 trypsin-like peptidase B (FAM111B) is related to the development and progression of a wide array of cancers, but its role in PCa remains poorly understood.
Methods
Primary cells were extracted from subcutaneous and pulmonary metastatic tumors and were used to verify differences in metastatic potential through wound healing assay, Transwell assay, soft agar colony formation assay, and in vivo pulmonary metastasis reformation assays. The key differentially expressed gene FAM111B related to metastatic prostate cancer (mPCa) was identified through transcriptomic combination analysis, proteomic analysis, quantitative real-time fluorescent polymerase chain reaction and western blot assays. The effect of FAM111B on the glycolytic capacity of PCa cells with high metastatic potential was analyzed by gene enrichment analysis, glucose uptake, lactate and ATP content measurement assays, including glycolytic stress test.
Results
FAM111B was highly expressed in metastatic PCa cells and associated with adverse clinical features, which upregulated LDHA to enhance glycolysis. Mechanistically, the expression of P27 was inhibited by a hydrolytic triad coded by the functional coding region of FAM111B, which activated Cyclin-CDKs/RB/E2F1 classical signaling pathway to promote the transcription and protein expression of LDHA.
Conclusions
The high expression of FAM111B is associated with adverse clinical features of PCa. FAM111B protein binds to and hydrolyzes P27 protein, which activates Cyclin-CDKs/RB/E2F1 signaling pathway to increase LDHA expression, thereby enhancing the glycolytic ability and ultimately promoting the metastasis of PCa and may potentially serve as new targets for the treatment of metastatic PCa.
{"title":"FAM111B enhances glycolysis and promotes metastasis of prostate cancer by upregulating LDHA","authors":"Qingliu He , Haoran Li , Yukun Cong , Kang Chen , Lulin Cheng , Fang Lv , Pu Zhang , Yunjie Ju , Zehao Yu , Jinyu Chen , Chuxiong Wang , Yarong Song , Xuechao Li , Liang Chen , Yifei Xing","doi":"10.1016/j.neo.2025.101227","DOIUrl":"10.1016/j.neo.2025.101227","url":null,"abstract":"<div><h3>Background</h3><div>The poor prognosis of metastatic prostate cancer (PCa) poses a major burden on both patients and the healthcare system. FAM111 trypsin-like peptidase B (FAM111B) is related to the development and progression of a wide array of cancers, but its role in PCa remains poorly understood.</div></div><div><h3>Methods</h3><div>Primary cells were extracted from subcutaneous and pulmonary metastatic tumors and were used to verify differences in metastatic potential through wound healing assay, Transwell assay, soft agar colony formation assay, and in vivo pulmonary metastasis reformation assays. The key differentially expressed gene FAM111B related to metastatic prostate cancer (mPCa) was identified through transcriptomic combination analysis, proteomic analysis, quantitative real-time fluorescent polymerase chain reaction and western blot assays. The effect of FAM111B on the glycolytic capacity of PCa cells with high metastatic potential was analyzed by gene enrichment analysis, glucose uptake, lactate and ATP content measurement assays, including glycolytic stress test.</div></div><div><h3>Results</h3><div>FAM111B was highly expressed in metastatic PCa cells and associated with adverse clinical features, which upregulated LDHA to enhance glycolysis. Mechanistically, the expression of P27 was inhibited by a hydrolytic triad coded by the functional coding region of FAM111B, which activated Cyclin-CDKs/RB/E2F1 classical signaling pathway to promote the transcription and protein expression of LDHA.</div></div><div><h3>Conclusions</h3><div>The high expression of FAM111B is associated with adverse clinical features of PCa. FAM111B protein binds to and hydrolyzes P27 protein, which activates Cyclin-CDKs/RB/E2F1 signaling pathway to increase LDHA expression, thereby enhancing the glycolytic ability and ultimately promoting the metastasis of PCa and may potentially serve as new targets for the treatment of metastatic PCa.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101227"},"PeriodicalIF":7.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096064","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 : 2025-09-20DOI: 10.1016/j.neo.2025.101230
Greg Shelley , Allison May , Tyler Robinson , Jinlu Dai , Sethu Pitchiaya , Evan T. Keller
Androgen deprivation therapy (ADT) remains a cornerstone in the treatment of prostate cancer (PCa), yet most tumors eventually develop resistance. Murine models are widely used to study PCa progression and ADT response, but a detailed understanding of the prostate’s biological response to androgen deprivation in these models is lacking. Here, we present a spatiotemporal analysis of cellular and transcriptional dynamics in the mouse prostate following orchiectomy (ORX)-induced androgen deprivation with a focus on non-epithelial components. We observed progressive involution across all prostate lobes (dorsal, ventral, lateral, and anterior) and distinct lobe-specific temporal gene expression changes post-ORX. Immune cell infiltration markedly increased over time, highlighting a shift in the prostate’s cellular landscape. Single-cell RNA sequencing uncovered a previously undescribed fibroblast subtype—termed ORX-induced fibroblast (OIF)—characterized by high expression of Wnt2, Rorb, and Wif1, with distinct spatial localization. Pathway analysis revealed upregulation of amide and peptide binding functions, alongside suppression of peptidase and endopeptidase activity. Furthermore, dynamic changes in ligand–receptor interactions across lobes underscored the evolving intercellular communication in the post-ORX prostate. By integrating spatial transcriptomics with single-cell profiling, our study generates a high-resolution atlas of the murine prostate’s response to androgen deprivation. These findings provide a foundational resource for interpreting ADT responses in preclinical models of PCa.
{"title":"A spatiotemporal atlas of orchiectomy-induced androgen deprivation-mediated modulation of cellular composition and gene expression in the mouse prostate","authors":"Greg Shelley , Allison May , Tyler Robinson , Jinlu Dai , Sethu Pitchiaya , Evan T. Keller","doi":"10.1016/j.neo.2025.101230","DOIUrl":"10.1016/j.neo.2025.101230","url":null,"abstract":"<div><div>Androgen deprivation therapy (ADT) remains a cornerstone in the treatment of prostate cancer (PCa), yet most tumors eventually develop resistance. Murine models are widely used to study PCa progression and ADT response, but a detailed understanding of the prostate’s biological response to androgen deprivation in these models is lacking. Here, we present a spatiotemporal analysis of cellular and transcriptional dynamics in the mouse prostate following orchiectomy (ORX)-induced androgen deprivation with a focus on non-epithelial components. We observed progressive involution across all prostate lobes (dorsal, ventral, lateral, and anterior) and distinct lobe-specific temporal gene expression changes post-ORX. Immune cell infiltration markedly increased over time, highlighting a shift in the prostate’s cellular landscape. Single-cell RNA sequencing uncovered a previously undescribed fibroblast subtype—termed ORX-induced fibroblast (OIF)—characterized by high expression of Wnt2, Rorb, and Wif1, with distinct spatial localization. Pathway analysis revealed upregulation of amide and peptide binding functions, alongside suppression of peptidase and endopeptidase activity. Furthermore, dynamic changes in ligand–receptor interactions across lobes underscored the evolving intercellular communication in the post-ORX prostate. By integrating spatial transcriptomics with single-cell profiling, our study generates a high-resolution atlas of the murine prostate’s response to androgen deprivation. These findings provide a foundational resource for interpreting ADT responses in preclinical models of PCa.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101230"},"PeriodicalIF":7.7,"publicationDate":"2025-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145096065","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 : 2025-09-17DOI: 10.1016/j.neo.2025.101229
Dawn R. Cochrane , Gian Luca Negri , Jutta Huvila , Forouh Kalantari , David A. Farnell , Nissreen Mohammad , Emily Thompson , Winnie Yang , Amy Lum , Sandra E. Spencer , Ryan Riley , Amy Jamieson , Samuel Leung , Derek Chiu , Christine Chow , Jamie L.P. Lim , Martin Köbel , Stefan Kommoss , Friedrich Kommoss , Blake Gilks , Jessica N. McAlpine
While endometrial cancer has an overall favorable prognosis, some patients have poor outcomes and may benefit from further refinements of the current classification systems. Molecular classification stratifies endometrial cancer patients into four prognostic subtypes: POLEmut, MMRd (mismatch repair deficient), p53abn, and NSMP (no specific molecular profile), where patients with POLEmut have the best prognosis and p53abn has the worst prognosis. We used proteomic profiling to assess if additional prognostic or predictive information could be identified across or within molecular subtypes. Global proteome profiling of formalin fixed, paraffin embedded samples, that had clinicopathologic and outcome data, was performed on 184 endometrial cancers encompassing all four molecular subtypes, including replicate samples of the same tumor, and both biopsy and final hysterectomy specimens. To ensure representation of each subtype, we profiled an approximately equal distribution in the 148 unique tumors; 34 (23%) POLEmut, 40 (27%) MMRd, 35 (24%) p53abn and 39 (26%) NSMP, rather than the population-based distributions. There was high reproducibility in the proteomic profiles of intra-tumor replicate samples, and between matched biopsy and hysterectomy tumor samples. Consensus clustering identified four clusters with different prognosis, named ‘Adhesion’, ‘Immune’, ‘Proliferation’, and ‘Metabolic’ based on the functional characteristics of the enriched proteins. We associated protein expression features with common mutations, molecular subtype, and outcomes. These results demonstrate the biologic diversity within endometrial cancers, both between and within molecular subtypes, and provide candidate features for functional and clinical investigation.
{"title":"Proteomic analysis uncovers biological diversity in molecularly defined endometrial carcinomas","authors":"Dawn R. Cochrane , Gian Luca Negri , Jutta Huvila , Forouh Kalantari , David A. Farnell , Nissreen Mohammad , Emily Thompson , Winnie Yang , Amy Lum , Sandra E. Spencer , Ryan Riley , Amy Jamieson , Samuel Leung , Derek Chiu , Christine Chow , Jamie L.P. Lim , Martin Köbel , Stefan Kommoss , Friedrich Kommoss , Blake Gilks , Jessica N. McAlpine","doi":"10.1016/j.neo.2025.101229","DOIUrl":"10.1016/j.neo.2025.101229","url":null,"abstract":"<div><div>While endometrial cancer has an overall favorable prognosis, some patients have poor outcomes and may benefit from further refinements of the current classification systems. Molecular classification stratifies endometrial cancer patients into four prognostic subtypes: <em>POLE</em>mut, MMRd (mismatch repair deficient), p53abn, and NSMP (no specific molecular profile), where patients with <em>POLE</em>mut have the best prognosis and p53abn has the worst prognosis. We used proteomic profiling to assess if additional prognostic or predictive information could be identified across or within molecular subtypes. Global proteome profiling of formalin fixed, paraffin embedded samples, that had clinicopathologic and outcome data, was performed on 184 endometrial cancers encompassing all four molecular subtypes, including replicate samples of the same tumor, and both biopsy and final hysterectomy specimens. To ensure representation of each subtype, we profiled an approximately equal distribution in the 148 unique tumors; 34 (23%) <em>POLE</em>mut, 40 (27%) MMRd, 35 (24%) p53abn and 39 (26%) NSMP, rather than the population-based distributions. There was high reproducibility in the proteomic profiles of intra-tumor replicate samples, and between matched biopsy and hysterectomy tumor samples. Consensus clustering identified four clusters with different prognosis, named ‘Adhesion’, ‘Immune’, ‘Proliferation’, and ‘Metabolic’ based on the functional characteristics of the enriched proteins. We associated protein expression features with common mutations, molecular subtype, and outcomes. These results demonstrate the biologic diversity within endometrial cancers, both between and within molecular subtypes, and provide candidate features for functional and clinical investigation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101229"},"PeriodicalIF":7.7,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145087803","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 : 2025-09-16DOI: 10.1016/j.neo.2025.101228
Yaodong Ding , Haoyu Zhang , Xueying Wang , Jiaqi Tan , Minghao Wang , Yuhan Chen , Imadoudini Hassimi Safia , Gangcai Zhu , Xin Zhang , Yong Liu
Cathepsin L (CTSL) is expressed in head and neck squamous cell carcinoma (HNSCC), yet its role in immune escape is unclear. Here we show that CTSL directly binds PDK1, blocks its ubiquitin and restrains NEDD4L-mediated ubiquitination, thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 on tumor cells. This establishes a non-proteolytic scaffolding function, and suppresses tumor growth in xenograft and immunocompetent mouse models; these effects synergize with anti-PD-1 therapy. Clinically, high CTSL expression correlates with increased PD-L1, scarce CD8+ T-cell infiltration, and poor prognosis in multiple HNSCC cohorts. Collectively, our data identify CTSL as a key driver of PD-L1-dependent immune evasion through the CTSL–PDK1–AKT axis and highlight CTSL inhibition as a promising therapeutic strategy and predictive biomarker for PD-1/PD-L1 blockade in HNSCC.
{"title":"Targeting lysosomal protease CTSL promotes anti-tumor immunity and sensitizes HNSCC to PD-1 blockade by stabilizing PDK1 and activating Akt–PD-L1 axis","authors":"Yaodong Ding , Haoyu Zhang , Xueying Wang , Jiaqi Tan , Minghao Wang , Yuhan Chen , Imadoudini Hassimi Safia , Gangcai Zhu , Xin Zhang , Yong Liu","doi":"10.1016/j.neo.2025.101228","DOIUrl":"10.1016/j.neo.2025.101228","url":null,"abstract":"<div><div>Cathepsin L (CTSL) is expressed in head and neck squamous cell carcinoma (HNSCC), yet its role in immune escape is unclear. Here we show that CTSL directly binds PDK1, blocks its ubiquitin and restrains NEDD4L-mediated ubiquitination, thereby stabilizing PDK1, sustaining AKT phosphorylation, and increasing PD-L1 on tumor cells. This establishes a non-proteolytic scaffolding function, and suppresses tumor growth in xenograft and immunocompetent mouse models; these effects synergize with anti-PD-1 therapy. Clinically, high CTSL expression correlates with increased PD-L1, scarce CD8+ <em>T</em>-cell infiltration, and poor prognosis in multiple HNSCC cohorts. Collectively, our data identify CTSL as a key driver of PD-L1-dependent immune evasion through the CTSL–PDK1–AKT axis and highlight CTSL inhibition as a promising therapeutic strategy and predictive biomarker for PD-1/PD-L1 blockade in HNSCC.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101228"},"PeriodicalIF":7.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082125","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 : 2025-09-06DOI: 10.1016/j.neo.2025.101226
Mohamed Kamal , Stephanie N. Shishido , Jeremy Mason , Krina Patel , Elisabet E. Manasanch , Robert Z. Orlowski , Peter Kuhn
{"title":"Corrigendum to “Single-cell proteomic analysis reveals Multiple Myeloma heterogeneity and the dynamics of the tumor immune microenvironment in precursor and advanced states” [Neoplasia 66 (2025) 1101189]","authors":"Mohamed Kamal , Stephanie N. Shishido , Jeremy Mason , Krina Patel , Elisabet E. Manasanch , Robert Z. Orlowski , Peter Kuhn","doi":"10.1016/j.neo.2025.101226","DOIUrl":"10.1016/j.neo.2025.101226","url":null,"abstract":"","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101226"},"PeriodicalIF":7.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145004604","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 : 2025-09-02DOI: 10.1016/j.neo.2025.101224
E. Massy , C.B. Confavreux , M. Point , E. Bonnelye , P. Clézardin
Bone metastases are frequent complications of many solid tumors, leading to painful skeletal morbidities and increasing mortality for patients with advanced cancer. Once in bone, cancer cells deregulate bone homeostasis, altering the functions of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells, which results in skeletal deconstruction. Aside from bone cells, cancer cells in the bone marrow interact with other cell populations, including immune cells that also play an integral part in the regulation of bone homeostasis. In this respect, immune checkpoint inhibitors (ICIs) have become a standard of care in immunotherapy for the treatment of patients with advanced cancer. Strikingly, however, those with bone metastases have a shorter survival when treated with ICIs than ICI-treated cancer patients without bone metastases. In this Review, after presenting the immune cells involved in bone metastasis, we review preclinical and clinical findings assessing ICI efficacy both in bone and extraosseous metastases, and we discuss the clinical utility of using bone-targeted agents —including denosumab and bisphosphonates— to improve anti-tumoral efficacy of ICI treatments in patients with cancer and bone metastases.
{"title":"Contribution of the immune bone marrow microenvironment to tumor growth and bone deconstruction: implications for improving immunotherapeutic strategies in bone metastasis","authors":"E. Massy , C.B. Confavreux , M. Point , E. Bonnelye , P. Clézardin","doi":"10.1016/j.neo.2025.101224","DOIUrl":"10.1016/j.neo.2025.101224","url":null,"abstract":"<div><div>Bone metastases are frequent complications of many solid tumors, leading to painful skeletal morbidities and increasing mortality for patients with advanced cancer. Once in bone, cancer cells deregulate bone homeostasis, altering the functions of bone-forming (osteoblasts) and bone-resorbing (osteoclasts) cells, which results in skeletal deconstruction. Aside from bone cells, cancer cells in the bone marrow interact with other cell populations, including immune cells that also play an integral part in the regulation of bone homeostasis. In this respect, immune checkpoint inhibitors (ICIs) have become a standard of care in immunotherapy for the treatment of patients with advanced cancer. Strikingly, however, those with bone metastases have a shorter survival when treated with ICIs than ICI-treated cancer patients without bone metastases. In this Review, after presenting the immune cells involved in bone metastasis, we review preclinical and clinical findings assessing ICI efficacy both in bone and extraosseous metastases, and we discuss the clinical utility of using bone-targeted agents —including denosumab and bisphosphonates— to improve anti-tumoral efficacy of ICI treatments in patients with cancer and bone metastases.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101224"},"PeriodicalIF":7.7,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144933442","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 : 2025-08-28DOI: 10.1016/j.neo.2025.101222
Adi S. Yehezkel , Eyal Yehezkel , Nathalie Abudi , Rinat Abramovitch
Background & Aims
The liver is the most common site for distant metastasis. Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide and significantly increases the risk of liver metastasis in colorectal cancer (CRC) patients. We aimed to elucidate hepatic immune cells alterations in response to the metabolic stress in MAFLD and their influence on the early stages of CRC liver metastasis (CRLM).
Methods
High-fat diet (HFD) and Western diet (WD), were used to create MAFLD and MASH respectively. MC38 cancer cells were injected intrasplenically to create CRLM model. Single-cell RNA sequencing (scRNA-seq), RT-PCR and immunohistology were used to study hepatic immune-cell composition, phenotypes, and localization.
Results
Both diets significantly increased CRLM establishment, while only WD altered hepatic inflammation. The WD-promotes IL-10 and TGF-β1 elevation, an anti-inflammatory cytokines, inhibiting cytotoxic CD8+ T cells and NK cells and supporting an immunosuppressive environment. Although MASH led to an increased presence of hepatic CD8+ and NK cells, their infiltration into metastatic foci was reduced and was associated with a decrease in expression of cytotoxic markers. In our murine model of MASH, CD8+ T-cell depletion reduced the number of CRLM foci, which was accompanied by a decrease in IFN-γ-associated cytokines and a significant increase in the infiltration of granzyme-B expressing NK cells, ultimately enhancing cytotoxic killing ability.
Conclusions
This research underscores the crucial influence of diet-induced immune changes on CRLM establishment and progression. It illustrates that the co-localization of immune cells within liver metastases significantly affects their functionality, highlighting potential therapeutic strategies to balance immune exhaustion and activation.
{"title":"Steatohepatitis alters lymphocytes cytotoxicity and localization, accelerating colorectal liver metastases","authors":"Adi S. Yehezkel , Eyal Yehezkel , Nathalie Abudi , Rinat Abramovitch","doi":"10.1016/j.neo.2025.101222","DOIUrl":"10.1016/j.neo.2025.101222","url":null,"abstract":"<div><h3>Background & Aims</h3><div>The liver is the most common site for distant metastasis. Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most common liver disease worldwide and significantly increases the risk of liver metastasis in colorectal cancer (CRC) patients. We aimed to elucidate hepatic immune cells alterations in response to the metabolic stress in MAFLD and their influence on the early stages of CRC liver metastasis (CRLM).</div></div><div><h3>Methods</h3><div>High-fat diet (HFD) and Western diet (WD), were used to create MAFLD and MASH respectively. MC38 cancer cells were injected intrasplenically to create CRLM model. Single-cell RNA sequencing (scRNA-seq), RT-PCR and immunohistology were used to study hepatic immune-cell composition, phenotypes, and localization.</div></div><div><h3>Results</h3><div>Both diets significantly increased CRLM establishment, while only WD altered hepatic inflammation. The WD-promotes IL-10 and TGF-β1 elevation, an anti-inflammatory cytokines, inhibiting cytotoxic CD8<sup>+</sup> T cells and NK cells and supporting an immunosuppressive environment. Although MASH led to an increased presence of hepatic CD8<sup>+</sup> and NK cells, their infiltration into metastatic foci was reduced and was associated with a decrease in expression of cytotoxic markers. In our murine model of MASH, CD8<sup>+</sup> T-cell depletion reduced the number of CRLM foci, which was accompanied by a decrease in IFN-γ-associated cytokines and a significant increase in the infiltration of granzyme-B expressing NK cells, ultimately enhancing cytotoxic killing ability.</div></div><div><h3>Conclusions</h3><div>This research underscores the crucial influence of diet-induced immune changes on CRLM establishment and progression. It illustrates that the co-localization of immune cells within liver metastases significantly affects their functionality, highlighting potential therapeutic strategies to balance immune exhaustion and activation.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"69 ","pages":"Article 101222"},"PeriodicalIF":7.7,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144907856","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 : 2025-08-23DOI: 10.1016/j.neo.2025.101223
Jiang Zhou , Xinxin Chai , Yi Zhu , Zhi Huang , Tingting Lin , Zhen Hu , Guangdi Chen , Chi Luo , Rutao Cui , Jinghao Sheng
The BRAFV600E pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAFV600E-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAFV600E downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAFV600E-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAFV600E inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAFV600E inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.
{"title":"A methyl-to-acetyl switch in H3K27 drives metabolic reprogramming and resistance to BRAFV600E inhibition in melanoma","authors":"Jiang Zhou , Xinxin Chai , Yi Zhu , Zhi Huang , Tingting Lin , Zhen Hu , Guangdi Chen , Chi Luo , Rutao Cui , Jinghao Sheng","doi":"10.1016/j.neo.2025.101223","DOIUrl":"10.1016/j.neo.2025.101223","url":null,"abstract":"<div><div>The BRAF<sup>V600E</sup> pathway and epigenetic machinery are central to melanoma pathogenesis. However, how these processes intersect and their potential for synthetic lethality remains unclear. Here, we identified a BRAF<sup>V600E</sup>-driven epigenetic mechanism in melanoma that involves a H3K27 methylation-to-acetylation switch, facilitating metabolic adaptation to targeted therapies. Inhibition of BRAF<sup>V600E</sup> downregulates the methyltransferase EZH2, leading to KDM6A-mediated removal of H3K27me3 and a subsequent increase in H3K27 acetylation (H3K27ac). This H3K27 methyl-to-acetyl conversion shifts chromatin from a repressive to an active state, thereby promoting gene transcription through the acetylation reader BRD4. Specifically, the KDM6A-H3K27ac-BRD4 axis upregulates PGC1α, a master regulator of mitochondrial metabolism, enabling melanoma cells to sustain oxidative metabolism and survive BRAF<sup>V600E</sup>-targeted therapies. Blocking this H3K27 methyl-to-acetyl switch disrupted metabolic adaptation and sensitized melanoma cells to BRAF<sup>V600E</sup> inhibition. In conclusion, we revealed an epigenetic and metabolic reprogramming mechanism that enables melanoma to survive the treatment with BRAF<sup>V600E</sup> inhibitors, presenting druggable targets within the H3K27 modification pathway that could enhance the efficacy of BRAF-targeted therapies in melanoma patients.</div></div>","PeriodicalId":18917,"journal":{"name":"Neoplasia","volume":"68 ","pages":"Article 101223"},"PeriodicalIF":7.7,"publicationDate":"2025-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144892261","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号