Cancer Communications最新文献

{"title":"Immunosuppressive JAG2⁺ tumor-associated neutrophils hamper PD-1 blockade response in ovarian cancer by mediating the differentiation of effector regulatory T cells.","authors":"Chenyang Wang, Moran Yang, Yujing Zhong, Kankan Cao, Xueling Wang, Chen Zhang, Yiying Wang, Mengdi He, Jiaqi Lu, Guodong Zhang, Yan Huang, Haiou Liu","doi":"10.1002/cac2.70021","DOIUrl":"https://doi.org/10.1002/cac2.70021","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated neutrophils (TANs) play a critical role in modulating immune responses and exhibit significant heterogeneity. Our previous study demonstrated that jagged canonical Notch ligand 2 (JAG2)⁺ TANs were associated with an immunosuppressive microenvironment in high-grade serous ovarian cancer (HGSOC), but the underlying mechanism remains unclear. This study aimed to elucidate the role of JAG2⁺ TANs in tumor immunosuppressive microenvironment in HGSOC.</p><p><strong>Methods: </strong>HGSOC samples were collected, with 274 samples constituting two independent cohorts (training and validation cohorts) and an additional 30 samples utilized to establish patient-derived tumor organoids (PDTOs). We characterized the number and phenotype of JAG2⁺ TANs by multiplex immunohistochemistry, flow cytometry, and single-cell RNA sequencing (scRNA-seq). We investigated the biological functions of JAG2 in immune evasion using in vitro co-culture systems, flow cytometry, tumor-bearing mouse models, and PDTOs.</p><p><strong>Results: </strong>JAG2⁺ TANs expressed elevated levels of immunosuppressive molecules, including programmed cell death ligand 1 and CD14, and had independent prognostic value for the overall survival of patients with HGSOC. scRNA-seq analysis revealed that JAG2⁺ TANs exhibited a terminally mature phenotype. The infiltration of JAG2⁺ TANs was positively correlated with the abundance of effector regulatory T cells (eTregs). Interaction with JAG2⁺ TANs skewed CD4⁺ T cells towards an eTreg phenotype, a process that was suppressed by the Notch inhibitor LY3039478 and induced by recombinant Jagged2. Furthermore, we demonstrated that JAG2⁺ TANs enhanced Notch signaling activation, ultimately promoting recombination signal binding protein for immunoglobulin kappa J region (RBPJ)-induced differentiation of naïve CD4⁺ T cells into eTregs. Clinically, JAG2⁺ TANs could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of Notch signaling with LY3039478 or JAG2 neutralization antibodies enhanced the efficacy of programmed cell death protein 1 (PD-1) monoclonal antibodies (mAbs) in both xenograft and PDTO models.</p><p><strong>Conclusions: </strong>The emergence of JAG2⁺ TANs is crucial for the differentiation of eTregs, which triggers immune evasion and resistance to anti-PD-1 therapy. Inhibiting Notch signaling with LY3039478 or JAG2 neutralization antibodies may overcome this anti-PD-1 resistance in HGSOC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143691341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deletion of epithelial HKDC1 decelerates cellular proliferation and impairs mitochondrial function of tumorous epithelial cells thereby protecting from intestinal carcinogenesis.","authors":"Lea Järke, Saskia Weber-Stiehl, Kensuke Shima, Karlis Arturs Moors, Jerome Genth, Fenja Amrei Schuran, Lena Best, Markus Tschurtschenthaler, Burkhardt Flemer, Silke Lüschen, Christoph Röcken, Andreas Tholey, Christoph Kaleta, Jan Rupp, Philip Rosenstiel, Felix Sommer","doi":"10.1002/cac2.70022","DOIUrl":"https://doi.org/10.1002/cac2.70022","url":null,"abstract":"","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells","authors":"Ashley V. Makela,&nbsp;Anthony Tundo,&nbsp;Huiping Liu,&nbsp;Doug Schneider,&nbsp;Terry Hermiston,&nbsp;Pavlo Khodakivskyi,&nbsp;Elena Goun,&nbsp;Christopher H. Contag","doi":"10.1002/cac2.70018","DOIUrl":"10.1002/cac2.70018","url":null,"abstract":"&lt;p&gt;Despite advances in breast cancer therapy, effective targeting of cancer stem cells (CSCs) remains a challenge. CSCs, which have self-renewal, tumorigenic and metastatic properties, are often quiescent and located in hypoxic regions of tumors [&lt;span&gt;1&lt;/span&gt;], making them resistant to conventional chemo- and radiotherapies [&lt;span&gt;2&lt;/span&gt;]. These characteristics allow CSCs to survive, leading to relapse and metastasis. Studying CSCs under conditions similar to their hypoxic niche is essential for evaluating therapies that target these cells.&lt;/p&gt;&lt;p&gt;We show that CSCs can be targeted via binding to externalized phosphatidylserine (PS). PS, a negatively charged lipid, is typically confined to the inner leaflet of cell membranes [&lt;span&gt;3&lt;/span&gt;]. However, its externalization occurs on dying and diseased cells, and as we demonstrated, on stem cells [&lt;span&gt;4&lt;/span&gt;]. PS-targeting agents like Annexin V (AnnV) [&lt;span&gt;5&lt;/span&gt;] and the monoclonal antibody bavituxumab (Bavi) [&lt;span&gt;6&lt;/span&gt;] are under investigation for cancer therapy, but these are limited in their use as they remain surface bound and do not deliver payloads into cells. In contrast, we have found that a truncated protein S comprised of the PS-binding γ-carboxyglutamate (Gla) domain and four epidermal growth factor (EGF) domains (collectively referred to as GlaS), binds PS on the outer leaflet and is internalized after binding [&lt;span&gt;4&lt;/span&gt;] enabling delivery of payloads to the cytoplasm of cells with externalized PS, which would include CSC in the hypoxic regions of tumors.&lt;/p&gt;&lt;p&gt;We used patient derived models of human breast cancer which are enriched in CD44&lt;sup&gt;+&lt;/sup&gt;CD24&lt;sup&gt;−&lt;/sup&gt; CSCs (Supplementary Materials and Methods). Following isolation, the CSC were propogated in mice and engineered so they express bioluminescent and fluorescent reporters. Cells collected from the CSC enriched tumors [&lt;span&gt;7&lt;/span&gt;] were exposed to an oxygen level in culture that mimics the tumor microenvironment (TME) [&lt;span&gt;8, 9&lt;/span&gt;], 4% O&lt;sub&gt;2&lt;/sub&gt; (hypoxia), and compared to cells exposed to 7% O&lt;sub&gt;2&lt;/sub&gt; (physoxia) and 21% O&lt;sub&gt;2&lt;/sub&gt; (hyperoxia, typical cell culture). The percentage of CD44&lt;sup&gt;+&lt;/sup&gt; cells did not show significant differences at different oxygen levels (F&lt;sub&gt;2,36&lt;/sub&gt; = 1.32, &lt;i&gt;P&lt;/i&gt; = 0.28, Figure 1A-B, Supplemental Figure S1A). However, the percentage of CD44&lt;sup&gt;+&lt;/sup&gt;GlaS&lt;sup&gt;+&lt;/sup&gt; cells (indicating GlaS binding) varied significantly (F&lt;sub&gt;2,36&lt;/sub&gt; = 27.69, &lt;i&gt;P&lt;/i&gt; &lt; 0.001, Figure 1C-D, Supplemental Figure S1B). Hypoxic conditions showed increased GlaS binding, with 61% of cells being CD44&lt;sup&gt;+&lt;/sup&gt;GlaS&lt;sup&gt;+&lt;/sup&gt; under hypoxic conditions, compared to 47% in physoxia (&lt;i&gt;P&lt;/i&gt; = 0.01) and 28% in hyperoxia (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). There were no significant differences in GlaS binding in CD44&lt;sup&gt;−&lt;/sup&gt; cells (&lt;i&gt;P&lt;/i&gt; = 0.054), suggesting that oxygen dependent binding is specific to CD44&lt;sup&gt;+&lt;/sup&gt; cells (Figure 1E-F). These findings were also validate","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"714-718"},"PeriodicalIF":20.1,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70018","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143662565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Whole-genome CRISPR-Cas9 knockout screens identify SHOC2 as a genetic dependency in NRAS-mutant melanoma","authors":"Andrea Y. Gu,&nbsp;Tet Woo Lee,&nbsp;Aziza Khan,&nbsp;Xuenan Zhang,&nbsp;Francis W. Hunter,&nbsp;Dean C. Singleton,&nbsp;Stephen M. F. Jamieson","doi":"10.1002/cac2.70013","DOIUrl":"10.1002/cac2.70013","url":null,"abstract":"&lt;p&gt;Mutations in the oncogene &lt;i&gt;NRAS&lt;/i&gt; that induce constitutive RAS-GTPase activity lead to unchecked cell proliferation and migration through downstream activation of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signalling pathways [&lt;span&gt;1&lt;/span&gt;]. These mutations occur in approximately 20% of melanomas and very rarely coexist with &lt;i&gt;BRAF&lt;/i&gt; V600 mutations. &lt;i&gt;NRAS&lt;/i&gt;-mutant melanoma is associated with poor survival [&lt;span&gt;2&lt;/span&gt;] and represents an unmet clinical need, with no effective therapies available following immunotherapy failure.&lt;/p&gt;&lt;p&gt;Identification of contextual essential genes that exert stronger fitness effects on &lt;i&gt;NRAS&lt;/i&gt;-mutant melanoma cells presents an opportunity for the discovery of targeted therapies. In this study, we employed CRISPR-Cas9-mediated whole-genome dropout screens to identify genetic dependencies in &lt;i&gt;NRAS&lt;/i&gt;-mutant melanoma. Typically, melanoma cell lines are cultured under ambient (∼20%) O&lt;sub&gt;2&lt;/sub&gt; conditions, despite O&lt;sub&gt;2&lt;/sub&gt; concentrations of &lt; 8% at the epidermal-dermal junction where melanocytes reside, resulting in adaptations in gene and protein expression [&lt;span&gt;3&lt;/span&gt;]. Therefore, for our screens, we used a panel of early-passage New Zealand Melanoma (NZM) cell lines that were established and cultured under physiological (5%) O&lt;sub&gt;2&lt;/sub&gt; conditions [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Six &lt;i&gt;NRAS&lt;/i&gt;-mutant and seven &lt;i&gt;NRAS&lt;/i&gt;-wildtype (five &lt;i&gt;BRAF&lt;/i&gt;-mutant, two &lt;i&gt;BRAF&lt;/i&gt;/&lt;i&gt;NRAS&lt;/i&gt;/&lt;i&gt;NF1&lt;/i&gt;-wildtype) NZM cell lines (Supplementary Table S1) were transduced in multiple replicates with the Brunello single guide RNA (sgRNA) library at a multiplicity of infection of approximately 0.3 and screened at 5% O&lt;sub&gt;2&lt;/sub&gt; for up to 35 days (Supplementary Methods and Materials). All NZM lines were cultured for transduction at fewer than 10 passages from derivation. The representation of the sgRNA libraries was assessed to evaluate transducibility, with any cell lines exhibiting poor sgRNA representation (&lt; 80% of sgRNAs detected with ≥1 count) excluded from further analyses (Supplementary Table S2). Moderate to high representation was observed in nine of the 13 NZM cell lines, whereas four cell lines were excluded due to &lt; 80% of sgRNAs being detected (Figure 1A). Reduced sgRNA representation was accompanied by dropout of non-targeting control (NTC) sgRNAs (Figure 1A), greater read count inequality (Supplementary Figure S1, Supplementary Table S2) and reduced correlation with the Brunello library plasmids and between individual cell line replicates (Supplementary Figure S2), suggesting stochastic evolution rather than knockout-induced fitness effects.&lt;/p&gt;&lt;p&gt;We used BAGEL2 to estimate gene essentiality relative to reference sets of common essential and nonessential genes. Typically, tissue-agnostic gene sets are used for this purpose [&lt;span&gt;5&lt;/span&gt;], but we established a combined essential gene set incorporating both tissue-agnostic and melanoma-sp","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"709-713"},"PeriodicalIF":20.1,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70013","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143646894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive DSRCT multi-omics analyses unveil CACNA2D2 as a diagnostic hallmark and super-enhancer-driven EWSR1::WT1 signature gene","authors":"Florian Henning Geyer,&nbsp;Alina Ritter,&nbsp;Seneca Kinn-Gurzo,&nbsp;Tobias Faehling,&nbsp;Jing Li,&nbsp;Armin Jarosch,&nbsp;Carine Ngo,&nbsp;Endrit Vinca,&nbsp;Karim Aljakouch,&nbsp;Azhar Orynbek,&nbsp;Shunya Ohmura,&nbsp;Thomas Kirchner,&nbsp;Roland Imle,&nbsp;Laura Romero-Pérez,&nbsp;Juan Díaz-Martín,&nbsp;Stefanie Bertram,&nbsp;Enrique de Álava,&nbsp;Clémence Henon,&nbsp;Sophie Postel-Vilnay,&nbsp;Ana Banito,&nbsp;Martin Sill,&nbsp;Yvonne Versleijen-Jonkers,&nbsp;Benjamin Friedrich Berthold Mayer,&nbsp;Martin Ebinger,&nbsp;Monika Sparber-Sauer,&nbsp;Sabine Stegmaier,&nbsp;Daniel Baumhoer,&nbsp;Wolfgang Hartmann,&nbsp;Jeroen Krijgsveld,&nbsp;David Horst,&nbsp;Olivier Delattre,&nbsp;Patrick Joseph Grohar,&nbsp;Thomas Georg Phillip Grünewald,&nbsp;Florencia Cidre-Aranaz","doi":"10.1002/cac2.70015","DOIUrl":"10.1002/cac2.70015","url":null,"abstract":"&lt;p&gt;Desmoplastic small round cell tumor (DSRCT) is an aggressive cancer that predominantly affects adolescents and young adults, typically developing at sites lined by mesothelium [&lt;span&gt;1, 2&lt;/span&gt;]. DSRCT is genetically defined by a chromosomal translocation that fuses the N-terminus of EWS RNA binding protein 1 (&lt;i&gt;EWSR1&lt;/i&gt;) to the C-terminus of Wilms tumor protein (&lt;i&gt;WT1)&lt;/i&gt;, forming EWSR1::WT1 [&lt;span&gt;3&lt;/span&gt;]. This fusion encodes a potent transcription factor and is the only known driver of oncogenic transformation in DSRCT [&lt;span&gt;4&lt;/span&gt;]. The lack of a comprehensive understanding of DSRCT biology parallels its dismal survival rate (5%-20%) [&lt;span&gt;1&lt;/span&gt;]. These challenges are exacerbated by the absence of clinical trials, the limited systematic collection and analysis of DSRCT biomaterial [&lt;span&gt;1&lt;/span&gt;], and the notable lack of specific diagnostic markers, necessitating resource-intensive molecular testing for an accurate diagnosis.&lt;/p&gt;&lt;p&gt;Here we first focused on identifying promising candidates for validation as single, fast, and reliable diagnostic DSRCT markers. For this, we performed differential gene expression (DEG) analysis on datasets comprising patient samples from 32 DSRCT and 20 morphological mimics, identifying 23 genes overexpressed in DSRCT (log&lt;sub&gt;2&lt;/sub&gt; fold change (log&lt;sub&gt;2&lt;/sub&gt;FC) &gt; 2.5; adjusted &lt;i&gt;P&lt;/i&gt;-value (&lt;i&gt;Padj)&lt;/i&gt; &lt; 0.01; Figure 1A, Supplementary Figure S1A). Secondly, we analyzed EWSR1::WT1 binding sites derived from chromatin immunoprecipitation followed by sequencing (ChIP-seq) data [&lt;span&gt;5&lt;/span&gt;] obtained from the JN-DSRCT-1 cell line, identifying 2,065 genomic loci likely regulated by EWSR1::WT1 (Figure 1A). Third, we established JN-DSRCT-1 and SK-DSRCT2 cell lines expressing doxycycline (DOX)-inducible short hairpin RNA (shRNA)-mediated EWSR1::WT1 knockdown (KD) (Supplementary Figure S1B). Differential protein expression (DEP) analysis of these cells identified 104 proteins consistently regulated across both cell lines (log&lt;sub&gt;2&lt;/sub&gt;FC &gt; 1.0 and &lt;i&gt;Padj&lt;/i&gt; &lt; 0.01; Figure 1A, Supplementary Table S1). The intersection of these analyses revealed calcium voltage-gated channel auxiliary subunit alpha2delta 2 (CACNA2D2) and IQ motif containing G (IQCG) as potential DSRCT biomarkers (Figure 1A). &lt;i&gt;CACNA2D2&lt;/i&gt; was selected for validation due to its significantly higher expression in DSRCTs compared to &lt;i&gt;IQCG&lt;/i&gt; (&lt;i&gt;P&lt;/i&gt; &lt; 0.001; Figure 1A). Indeed, DSRCT exhibited the highest expression of &lt;i&gt;CACNA2D2&lt;/i&gt; among all studied morphological mimics and normal tissues (&lt;i&gt;P &lt;&lt;/i&gt; 0.001; Supplementary Figures S1C-D). Further ChIP-seq data and motif analyses of EWSR1::WT1 binding coordinates and histone marks in JN-DSRCT-1 and four DSRCT patient samples [&lt;span&gt;5, 6&lt;/span&gt;] suggested a direct regulatory role of EWSR1::WT1 through an enhancer interaction at the &lt;i&gt;CACNA2D2&lt;/i&gt; locus (Figure 1B). Notably, KD of EWSR1::WT1 in JN-DSRCT-1 resulted in a loss of the EWSR1::WT1 signal and H","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"702-708"},"PeriodicalIF":20.1,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70015","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143633515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Blocking ITGA5 potentiates the efficacy of anti-PD-1 therapy on glioblastoma by remodeling tumor-associated macrophages","authors":"Rongrong Zhao,&nbsp;Ziwen Pan,&nbsp;Jiawei Qiu,&nbsp;Boyan Li,&nbsp;Yanhua Qi,&nbsp;Zijie Gao,&nbsp;Wei Qiu,&nbsp;Weijie Tang,&nbsp;Xiaofan Guo,&nbsp;Lin Deng,&nbsp;Gang Li,&nbsp;Hao Xue","doi":"10.1002/cac2.70016","DOIUrl":"10.1002/cac2.70016","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Glioblastoma (GBM) is largely refractory to antibodies against programmed cell death 1 (anti-PD-1) therapy. Fully understanding the cellular heterogeneity and immune adaptations in response to anti-PD-1 therapy is necessary to design more effective immunotherapies for GBM. This study aimed to dissect the molecular mechanisms of specific immunosuppressive subpopulations to drive anti-PD-1 resistance in GBM.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We systematically analysed single-cell RNA sequencing and spatial transcriptomics data from GBM tissues receiving anti-PD-1 therapy to characterize the microenvironment alterations. The biological functions of a novel circular RNA (circRNA) were validated both in vitro and in vivo. Mechanically, co-immunoprecipitation, RNA immunoprecipitation and pull-down assays were conducted.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)&lt;sup&gt;+&lt;/sup&gt; myeloid-derived macrophages (SPP1&lt;sup&gt;+&lt;/sup&gt; MDMs), a unique subpopulation of MDMs with complex functions, preferentially accumulated in non-responders to anti-PD-1 therapy, indicating that MES-GBM cells and SPP1&lt;sup&gt;+&lt;/sup&gt; MDMs were the main anti-PD-1-resistant cell subpopulations. Functionally, we determined that circular RNA succinate dehydrogenase complex assembly factor 2 (circSDHAF2), which was positively associated with the abundance of these two anti-PD-1-resistant cell subpopulations, facilitated the formation of a regional MES-GBM and SPP1&lt;sup&gt;+&lt;/sup&gt; MDM cell interaction loop, resulting in a spatially specific adaptive immunosuppressive microenvironment. Mechanically, we found that circSDHAF2 promoted MES-GBM cell formation by stabilizing the integrin alpha 5 (ITGA5) protein through N-glycosylation. Meanwhile, the N-glycosylation of the ITGA5 protein facilitated its translocation into exosomes and subsequent delivery to MDMs to induce the formation of SPP1&lt;sup&gt;+&lt;/sup&gt; MDMs, which in turn maintained the MES-GBM cell status and induced T-cell dysfunction via the SPP1-ITGA5 pathway, ultimately promoting GBM immune escape. Importantly, our findings demonstrated that antibody-mediated ITGA5 blockade enhanced anti-PD-1-mediated antitumor immunity.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;This work elucidated the potential tissue adaptation mechanism of intratumoral dynamic interactions between MES-GBM cells, MDMs and T cells in anti-PD-1 non-responders and identified the therapeutic potential of target","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"677-701"},"PeriodicalIF":20.1,"publicationDate":"2025-03-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70016","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143623806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rare germline ATM variants predispose to secondary cancer in chronic lymphocytic leukaemia patients","authors":"Anna Petrackova,&nbsp;Jirina Manakova,&nbsp;Romana Nesnadna,&nbsp;Zuzana Kubova,&nbsp;Tomas Papajik,&nbsp;Eva Kriegova","doi":"10.1002/cac2.70010","DOIUrl":"10.1002/cac2.70010","url":null,"abstract":"&lt;p&gt;Chronic lymphocytic leukaemia (CLL) has one of the strongest familial risks of all cancers, as evidenced by the eight-fold increased risk seen in relatives of CLL patients, yet much of the heritable risk remains unexplained [&lt;span&gt;1&lt;/span&gt;]. Patients with CLL also have a high rate of secondary cancer, i.e., the development of second primary malignancy, compared to the general population, which may be explained by immune dysregulation due to CLL and/or its treatment, but also by environmental and genetic risk factors [&lt;span&gt;2&lt;/span&gt;]. The development of second cancer in patients with CLL contributes to higher morbidity in these patients [&lt;span&gt;2&lt;/span&gt;]. As the population of long-term CLL survivors expands due to novel agents used in therapy, the identification of patients with risk of developing the second cancer may help to improve longevity of CLL patients.&lt;/p&gt;&lt;p&gt;In this monocentric study, we aimed to assess whether patients with CLL carrying rare germline variants in &lt;i&gt;ATM&lt;/i&gt; have a higher risk of familial CLL or a higher risk of cancer in first-degree relatives than patients without these variants. Next, we aimed to assess whether patients carrying rare &lt;i&gt;ATM&lt;/i&gt; variants develop secondary cancer or develop CLL at an earlier age than patients without these variants, and whether these variants influence the time to first treatment (TTFT) and overall survival (OS) in patients with CLL. In this large cohort, we also sought to confirm our previous observation that rare variants in &lt;i&gt;ATM&lt;/i&gt; are associated with the development of IGHV-unmutated CLL [&lt;span&gt;3&lt;/span&gt;], which has a worse prognosis compared to IGHV-mutated disease.&lt;/p&gt;&lt;p&gt;A total of 629 patients with CLL were included in the study with a median follow-up of 6 years (range, 0.08-37.80; Supplementary Materials and Methods, Supplementary Table S1). Ten (1.6%) of these patients carried rare pathogenic (P) or likely pathogenic (LP) variants in &lt;i&gt;ATM&lt;/i&gt; and 18 (2.9%) carried rare variant of uncertain significance (VUS) in &lt;i&gt;ATM&lt;/i&gt;, all heterozygous (Supplementary Table S2, Figure 1). Patients harbouring P/LP &lt;i&gt;ATM&lt;/i&gt; variants had a higher risk of secondary cancer (50.0% of patients; relative risk [RR], 2.88; 95% confidence interval [CI], 1.51-5.47; &lt;i&gt;P&lt;/i&gt; = 0.001) than those without these variants (17.0%). Similarly, patients harbouring rare VUSes in &lt;i&gt;ATM&lt;/i&gt; had a higher risk of secondary cancer (46.0% of patients; RR, 2.56; 95% CI, 1.48-4.41; &lt;i&gt;P&lt;/i&gt; = 0.001) than those without these variants (17.0%). Half (7/14) of patients who carried these germline &lt;i&gt;ATM&lt;/i&gt; variants and had secondary cancer were first diagnosed with CLL, while the other half (5/9) were first diagnosed with another malignancy. Secondary cancers were always of a different type, with the exception of prostate cancer, which occurred in 2 patients.&lt;/p&gt;&lt;p&gt;Regarding age at diagnosis of first malignancy in patients with secondary cancer, there was no significant difference between patients carrying rare P/LP ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"669-672"},"PeriodicalIF":20.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70010","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143603972","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reflections and insights into the evolution of restrictive eligibility criteria for cancer clinical trials in China and beyond","authors":"Huiyao Huang,&nbsp;Huilei Miao,&nbsp;Jinling Tang,&nbsp;Ning Li","doi":"10.1002/cac2.70007","DOIUrl":"10.1002/cac2.70007","url":null,"abstract":"&lt;p&gt;Trial eligibility criteria, which define an appropriate evaluable population through inclusion and exclusion criteria, are fundamental for reliable evidence and should be tailored to the question that the trial sets out to answer [&lt;span&gt;1&lt;/span&gt;]. However, exclusion criteria for cancer trials have become increasingly restrictive over the years, with the median number increased from 21 in 1986 to 46 in 2016 [&lt;span&gt;2, 3&lt;/span&gt;]. These restrictive exclusion criteria have created substantial barriers to patient access to novel therapies, hindered trial recruitment and limited the generalizability of trial results, presenting not only practical and scientific problem, but also raises important issues of equity that affect everyone [&lt;span&gt;4&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;While this longstanding issue has garnered widespread attention in the United States (US), research on the severity of restrictive criteria and efforts to modernize them in China remain scarce [&lt;span&gt;5&lt;/span&gt;]. Our limited study revealed that the restriction rate for older patients aged over 75 years in cancer trials in China was 56.5%, which is more than 10 times higher than that of the US [&lt;span&gt;5&lt;/span&gt;]. Meanwhile, significant shifts in patterns of exclusion criteria, such as brain metastases from conditionally excluded to not excluded, have been observed in the US since a joint recommendation on broadening cancer eligibility criteria was made in 2017 [&lt;span&gt;6&lt;/span&gt;]. The above observations inspire us to understand the potential drivers behind the evolution of overly restrictive exclusion criteria, and provide insights into best practice towards modernizing eligibility criteria in China and beyond.&lt;/p&gt;&lt;p&gt;Regarding to the evolution of overly restrictive eligibility criteria, several fundamental factors should be emphasized. The fundamental consideration about who should be recruited is the future application of the results. Logically, those eligible for a trial should be those who are deemed beneficial from using the treatment in the future. However, when the approved indications are not impacted, sponsors and researchers tend to exclude weaker patients and recruit healthier ones due to excessive concerns about vulnerable populations and drug risk-benefit profiles. This tendency is evident in the fact that most cancer trials in the US enroll healthier patients, such as those with no brain metastases (77.4%), better performance status (PS) (65%) [&lt;span&gt;7&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Exclusion criteria are often applied in series, meaning that participants meeting any one of the criteria are eliminated. However, many common criteria, when used alone may not represent manifestations of the underlying malignancy or the potential risk-benefit profiles. For instance, if a therapy does not undergo hepatic metabolism and is not expected to cause hepatic toxicity, strict hepatic function eligibility criteria may not be necessary, or there should be very broad entry criteria. Therefore, it is essential to consider the","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"673-676"},"PeriodicalIF":20.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143613073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dlk1 is a novel adrenocortical stem/progenitor cell marker that predicts malignancy in adrenocortical carcinoma","authors":"Katia Mariniello,&nbsp;James F. H. Pittaway,&nbsp;Barbara Altieri,&nbsp;Kleiton Silva Borges,&nbsp;Irene Hadjidemetriou,&nbsp;Claudio Ribeiro,&nbsp;Gerard Ruiz-Babot,&nbsp;David S. Tourigny,&nbsp;Jiang A. Lim,&nbsp;Julie Foster,&nbsp;Julie Cleaver,&nbsp;Jane Sosabowski,&nbsp;Nafis Rahman,&nbsp;Milena Doroszko,&nbsp;Constanze Hantel,&nbsp;Sandra Sigala,&nbsp;Andrea Abate,&nbsp;Mariangela Tamburello,&nbsp;Katja Kiseljak-Vassiliades,&nbsp;Margaret Wierman,&nbsp;Charlotte Hall,&nbsp;Laila Parvanta,&nbsp;Tarek E. Abdel-Aziz,&nbsp;Teng-Teng Chung,&nbsp;Aimee Di Marco,&nbsp;Fausto Palazzo,&nbsp;Celso E. Gomez-Sanchez,&nbsp;David R. Taylor,&nbsp;Oliver Rayner,&nbsp;Cristina L. Ronchi,&nbsp;Carles Gaston-Massuet,&nbsp;Silviu Sbiera,&nbsp;William M. Drake,&nbsp;Emanuel Rognoni,&nbsp;Matthias Kroiss,&nbsp;David T. Breault,&nbsp;Martin Fassnacht,&nbsp;Leonardo Guasti","doi":"10.1002/cac2.70012","DOIUrl":"10.1002/cac2.70012","url":null,"abstract":"&lt;p&gt;Adrenocortical carcinoma (ACC) is a rare malignancy with no widely available biomarkers and commonly presents at later stages with a bleak prognosis [&lt;span&gt;1&lt;/span&gt;]. Dysregulation of signaling pathways involved in the organogenesis and homeostasis of the adrenal cortex is implicated in its pathogenesis [&lt;span&gt;2&lt;/span&gt;]. The paternally expressed, cleavable protein delta-like non-canonical Notch ligand 1 (DLK1) is expressed in rat adrenocortical progenitor cells [&lt;span&gt;3&lt;/span&gt;] and in clusters of relatively undifferentiated cells in the human adrenal gland [&lt;span&gt;4&lt;/span&gt;]. Its expression is rare in most adult human tissues but has been reported across various cancers, often associated with worse survival [&lt;span&gt;5&lt;/span&gt;]. Here we define the role of DLK1 in adrenocortical development, self-renewal, and the development and progression of ACC.&lt;/p&gt;&lt;p&gt;Dlk1&lt;sup&gt;+&lt;/sup&gt; cells were present in both the capsule and cortex during embryonic development but became restricted to the capsule postnatally in both male and female mice (Supplementary Figure S1), with minimal overlap in expression with Axin-2 (Wnt-active) cells, their early descendants, and platelet-derived growth factor receptor alpha (PDGFRα), a marker of mesenchymal stem/fibroblastic cells (Supplementary Figure S2). Dlk1 cells were rarely positive for Ki-67, whereas &lt;i&gt;Gli1&lt;/i&gt; expression in the capsule, unlike Dlk1, remained high during development and throughout postnatal life (Supplementary Figure S3). Genetic lineage tracing using inducible &lt;i&gt;Dlk1&lt;sup&gt;CreERT2/+&lt;/sup&gt;&lt;/i&gt;; &lt;i&gt;Rosa&lt;sup&gt;tdTomato/+&lt;/sup&gt;&lt;/i&gt; mice showed that Dlk1&lt;sup&gt;+&lt;/sup&gt; cells functioned as adrenocortical stem cells during development (Figure 1A-F), but were largely dormant postnatally and inactive during postnatal adrenocortical remodeling (Supplementary Figure S4).&lt;/p&gt;&lt;p&gt;Capsular-like cells are pathognomonic of subcapsular hyperplasia (SH), a histological hallmark in mouse adrenals that occurs spontaneously in aged females and in certain strains/transgenic models after gonadectomy (GDX) [&lt;span&gt;6&lt;/span&gt;]. SH foci are thought to represent a morphological continuum progressing toward adrenocortical tumors. Dlk1 was not expressed in SH or in subsequent tumors in two GDX mouse models (Supplementary Figure S5). Moreover, spontaneous SH foci in aged mice were neither enriched in nor derived from Dlk1-expressing cells (Supplementary Figure S6), supporting the hypothesis that SH results from a de-differentiation event [&lt;span&gt;7&lt;/span&gt;]. Interestingly, Dlk1 was re-expressed in an autochthonous mouse model of ACC, in which concomitant inactivation of &lt;i&gt;Trp53&lt;/i&gt; and activation of &lt;i&gt;Ctnnb1&lt;/i&gt;, driven by the aldosterone synthase promoter (&lt;i&gt;BPCre&lt;/i&gt;) [&lt;span&gt;8&lt;/span&gt;], leads to ACC formation with high penetrance. In 23 tumor samples from 17 mice (9 female), Dlk1 expression was low or absent in benign and pre-malignant tumors, moderate in localized ACC, and higher in metastatic disease, both in the primary tumors and in lung meta","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"663-668"},"PeriodicalIF":20.1,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70012","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143540150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low household income and income volatility increase risk of lung cancer: A nationwide retrospective cohort study","authors":"Chiwook Chung,&nbsp;Dong Wook Shin,&nbsp;Kyu Na Lee,&nbsp;Sei Won Lee,&nbsp;Kyungdo Han","doi":"10.1002/cac2.70011","DOIUrl":"10.1002/cac2.70011","url":null,"abstract":"&lt;p&gt;Low socioeconomic conditions, including low education, low income, manual or unskilled work, and unemployment, have been associated with increased lung cancer risks [&lt;span&gt;1, 2&lt;/span&gt;]. Although some studies have identified low household status as a risk factor for lung cancer, they had some limitations in terms of their study design, including limited covariates in multivariate models, and cross-sectional assessment of income status, thereby failing to describe the association between income status change over time and lung cancer [&lt;span&gt;1, 2&lt;/span&gt;]. Therefore, we investigated the association between longitudinal low household income status and lung cancer in the South Korean general population. We collected information on income status for 5 years to determine the change in household income status and income volatility. We also designed multivariate regression models with covariates including demographics, lifestyle behaviors, and comorbidities. Consequently, this study investigated the relationship between economic vulnerability, such as income volatility, and lung cancer risk.&lt;/p&gt;&lt;p&gt;We sampled 40% (4,910,068) of individuals who underwent a national health examination in 2012 (the index year). Among them, we included 3,816,680 individuals aged 30-65 years (economically active population). Thereafter, we excluded individuals with insufficient income information, identified with any cancer (any insurance claim with the International Classification of Diseases 10th Revision [ICD-10] codes for cancer [C00-97] and the critical illness registration code for cancer [V193]) before their health examination (all cancer wash-out), with insufficient medical records, and identified with any cancer within 1 year after the index date (1-year lag period, to exclude over-detection of cancer after the health examination). Finally, the remaining 3,361,091 eligible individuals started follow-up 1 year after the index date, until December 2022. The follow-up was terminated upon lung cancer development, death, or censor.&lt;/p&gt;&lt;p&gt;Lung cancer was identified using the ICD-10 code (C33 and C34) and matched with the critical illness registration program code (V193). The household income level was estimated based on subscribers’ monthly national health insurance premium, which is a proxy for household income. We categorized household income into quartiles (Q1 = lowest and Q4 = highest). Individuals receiving medical aid benefits (public assistance, the lowest 3% income) were assessed as a separate income category. To evaluate the temporal changes in household income status, we evaluated (1) cumulative number of years receiving medical aid (sustained low-income status) and (2) income volatility, defined as the intraindividual standard deviation (SD) of the percentage change in income (Q1 = the lowest and Q4 = the highest, Supplementary Figure S1), predicts income uncertainty and may limit health behaviors.&lt;/p&gt;&lt;p&gt;Covariates were collected from the health examination and ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 6","pages":"654-657"},"PeriodicalIF":20.1,"publicationDate":"2025-02-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}