Neoplasia最新文献

{"title":"Metabolic and imaging phenotypes associated with RB1 and TP53 loss in prostate cancer","authors":"Fahim Ahmad ,&nbsp;Margaret White ,&nbsp;Kazutoshi Yamamoto ,&nbsp;Daniel R. Crooks ,&nbsp;Supreet Agarwal ,&nbsp;Ye Yang ,&nbsp;Brian Capaldo ,&nbsp;Sonam Raj ,&nbsp;Aian Neil Alilin ,&nbsp;Anita Ton ,&nbsp;Stephen Adler ,&nbsp;Jurgen Seidel ,&nbsp;Colleen Olkowski ,&nbsp;Murali Krishna Cherukuri ,&nbsp;Peter L Choyke ,&nbsp;Kathleen Kelly ,&nbsp;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}

{"title":"Ovulation releases G-CSF to induce peritoneal neutrophil influx and netosis, facilitating peritoneal seeding of high-grade serous carcinoma","authors":"Tang-Yuan Chu ,&nbsp;Pao-Chu Chen ,&nbsp;Aye Aye Khine ,&nbsp;Ying-Hsi Chen ,&nbsp;Sung-Chao Chu ,&nbsp;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}

{"title":"PD-L1(+) tumor-associated macrophages induce CD8(+) T Cell exhaustion in hepatocellular carcinoma","authors":"Takuto Nosaka ,&nbsp;Masahiro Ohtani ,&nbsp;Junki Yamashita ,&nbsp;Yosuke Murata ,&nbsp;Yu Akazawa ,&nbsp;Tomoko Tanaka ,&nbsp;Kazuto Takahashi ,&nbsp;Tatsushi Naito ,&nbsp;Yoshiaki Imamura ,&nbsp;Kenji Koneri ,&nbsp;Takanori Goi ,&nbsp;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}

{"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 ,&nbsp;Sinae An ,&nbsp;Junghyun Lim ,&nbsp;Young-Hee Kim ,&nbsp;Ahyeon Shim ,&nbsp;Taewoo Han ,&nbsp;Hawsan Kim ,&nbsp;Sue-Jee Park ,&nbsp;Yeong Jin Kim ,&nbsp;Kyung-Sub Moon ,&nbsp;In-Young Kim ,&nbsp;Shin Jung ,&nbsp;Chul Won Lee ,&nbsp;Kyung-Hwa Lee ,&nbsp;Ae Kyung Park ,&nbsp;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}

{"title":"PDGFRA in paediatric high-grade glioma – target or distraction?","authors":"Natalie Le ,&nbsp;Jingwei Chen ,&nbsp;Paul G. Ekert ,&nbsp;Lauren M. Brown ,&nbsp;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}

{"title":"GBP1-CDK9-STAT3 signaling axis promotes osteosarcoma PD-L1 expression and immune escape","authors":"Doudou Jing ,&nbsp;Binghong Chen ,&nbsp;Ruqi Liang ,&nbsp;Fei Li ,&nbsp;Bin Zhao ,&nbsp;Feifei Pu ,&nbsp;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}

{"title":"FAM111B enhances glycolysis and promotes metastasis of prostate cancer by upregulating LDHA","authors":"Qingliu He ,&nbsp;Haoran Li ,&nbsp;Yukun Cong ,&nbsp;Kang Chen ,&nbsp;Lulin Cheng ,&nbsp;Fang Lv ,&nbsp;Pu Zhang ,&nbsp;Yunjie Ju ,&nbsp;Zehao Yu ,&nbsp;Jinyu Chen ,&nbsp;Chuxiong Wang ,&nbsp;Yarong Song ,&nbsp;Xuechao Li ,&nbsp;Liang Chen ,&nbsp;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}

{"title":"A spatiotemporal atlas of orchiectomy-induced androgen deprivation-mediated modulation of cellular composition and gene expression in the mouse prostate","authors":"Greg Shelley ,&nbsp;Allison May ,&nbsp;Tyler Robinson ,&nbsp;Jinlu Dai ,&nbsp;Sethu Pitchiaya ,&nbsp;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}

{"title":"Proteomic analysis uncovers biological diversity in molecularly defined endometrial carcinomas","authors":"Dawn R. Cochrane ,&nbsp;Gian Luca Negri ,&nbsp;Jutta Huvila ,&nbsp;Forouh Kalantari ,&nbsp;David A. Farnell ,&nbsp;Nissreen Mohammad ,&nbsp;Emily Thompson ,&nbsp;Winnie Yang ,&nbsp;Amy Lum ,&nbsp;Sandra E. Spencer ,&nbsp;Ryan Riley ,&nbsp;Amy Jamieson ,&nbsp;Samuel Leung ,&nbsp;Derek Chiu ,&nbsp;Christine Chow ,&nbsp;Jamie L.P. Lim ,&nbsp;Martin Köbel ,&nbsp;Stefan Kommoss ,&nbsp;Friedrich Kommoss ,&nbsp;Blake Gilks ,&nbsp;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}

{"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 ,&nbsp;Haoyu Zhang ,&nbsp;Xueying Wang ,&nbsp;Jiaqi Tan ,&nbsp;Minghao Wang ,&nbsp;Yuhan Chen ,&nbsp;Imadoudini Hassimi Safia ,&nbsp;Gangcai Zhu ,&nbsp;Xin Zhang ,&nbsp;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}