Cancer Communications最新文献

{"title":"N6-methyladenosine-regulated exosome biogenesis orchestrates an immunosuppressive pre-metastatic niche in gastric cancer peritoneal metastasis","authors":"Song Li,&nbsp;Jianyuan Zhou,&nbsp;Shuang Wang,&nbsp;Qian Yang,&nbsp;Shulun Nie,&nbsp;Chunwang Ji,&nbsp;Xue Zhang,&nbsp;Shuhan Li,&nbsp;Xuanyu Zhou,&nbsp;Jiahui Chu,&nbsp;Xuehui Wu,&nbsp;Jianqiao Jiao,&nbsp;Ruitao Xu,&nbsp;Qian Xu,&nbsp;Miao Huang,&nbsp;Qiushi Wang,&nbsp;Liliang Dou,&nbsp;Qinqin Hu,&nbsp;Fan Jiang,&nbsp;Xin Dai,&nbsp;Zhaodi Nan,&nbsp;Xinyu Song,&nbsp;Di Zhang,&nbsp;Lian Liu","doi":"10.1002/cac2.70034","DOIUrl":"10.1002/cac2.70034","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre-metastatic niche (PMN), and its relationship with <i>N</i>⁶-methyladenosine (m⁶A) modification remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase-like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m⁶A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA-immunoprecipitation, dual-luciferase assays, and point mutations in the ras-related protein Rab-27A (<i>RAB27A</i>) in cells. Macrophage and T-cell functions were assessed using enzyme-linked immunosorbent assay, flow cytometry, and cytotoxicity assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>METTL3 overexpression in gastric cancer cells enhanced <i>RAB27A</i> translation by methylating its mRNA A502 base, facilitated by its m⁶A “reader” YTH <i>N</i>⁶-methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA-17-92 cluster was enriched in METTL3-overexpressed cell-derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto-oncogene, non-receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)-10 and tumor necrosis factor (TNF) and reducing the levels of IL-1 and IL-6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study identified an intricate m⁶A-regulated mechanism of peritoneal PMN development that is mediated by exosome-promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"941-965"},"PeriodicalIF":24.9,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70034","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076207","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":"Extranodal diffuse large B-cell lymphoma: Clinical and molecular insights with survival outcomes from the multicenter EXPECT study","authors":"Si-Yuan Chen,&nbsp;Peng-Peng Xu,&nbsp;Ru Feng,&nbsp;Guo-Hui Cui,&nbsp;Li Wang,&nbsp;Shu Cheng,&nbsp;Rong-Ji Mu,&nbsp;Hui-Lai Zhang,&nbsp;Xiao-Lei Wei,&nbsp;Yong-Ping Song,&nbsp;Kai-Yang Ding,&nbsp;Li-Hua Dong,&nbsp;Zun-Min Zhu,&nbsp;Shen-Miao Yang,&nbsp;Xin Wang,&nbsp;Ting-Bo Liu,&nbsp;Jian-Da Hu,&nbsp;Xiao-Yun Zheng,&nbsp;Ou Bai,&nbsp;Jing-Yan Xu,&nbsp;Liang Huang,&nbsp;Wei Sang,&nbsp;Ke-Qian Shi,&nbsp;Fan Zhou,&nbsp;Fei Li,&nbsp;Ai-Bin Liang,&nbsp;Hui Zhou,&nbsp;Si-Guo Hao,&nbsp;Hong-Hui Huang,&nbsp;Bin Xu,&nbsp;Wen-Bin Qian,&nbsp;Cai-Xia Li,&nbsp;Zhi-Ming Li,&nbsp;Chong-Yang Wu,&nbsp;Xiao-Bo Wang,&nbsp;Wen-Yu Shi,&nbsp;Shu-Ye Wang,&nbsp;Yu-Yang Tian,&nbsp;Xi Zhang,&nbsp;Ke-Shu Zhou,&nbsp;Li-Juan Cui,&nbsp;Hui Liu,&nbsp;Huo Tan,&nbsp;Qing Leng,&nbsp;Dong-Lu Zhao,&nbsp;Ting Niu,&nbsp;Wei-Li Zhao","doi":"10.1002/cac2.70033","DOIUrl":"10.1002/cac2.70033","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of aggressive non-Hodgkin's lymphoma with distinct clinical and molecular heterogeneity. DLBCL that arises in extranodal organs is particularly linked to poor prognosis. This study aimed to determine the clinical and molecular characteristics of extranodal involvement (ENI) in DLBCL and assess the actual survival status of the patients.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this population-based cohort study, we investigated the clinical features of 5,023 patients newly diagnosed with DLBCL. Their clinical conditions, eligibility criteria, and sociodemographic details were recorded and analyzed. Gene panel sequencing was performed on 1,050 patients to discern molecular patterns according to ENI.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The 2-year overall survival (OS) rate was 76.2% [95% confidence interval (CI), 74.0%-78.2%], and the 5-year OS rate was 67.9% (95% CI, 65.2%-70.4%). The primary treatment was immunochemotherapy with rituximab. Specific lymphoma involvement sites, especially the bones, bone marrow, and central nervous system, were identified as independent adverse prognostic factors. A high prevalence of non-germinal center B-cell (non-GCB) phenotype and myeloid differentiation primary response 88 (<i>MYD88</i>)/<i>CD79B</i> mutations were noted in lymphomas affecting the breasts, skin, uterus, and immune-privileged sites. Conversely, the thyroid and gastrointestinal tract showed a low occurrence of non-GCB phenotype. Remarkably, patients with multiple ENIs exhibited a high frequency of <i>MYD88</i>, tet methylcytosine dioxygenase 2 (<i>TET2</i>), CREB binding protein (<i>CREBBP</i>) mutations, increased <i>MYD88^L265P</i> and <i>CD79B</i> mutation (MCD)-like subtypes, and poor prognosis. Genetic subtype-guided immunochemotherapy showed good efficacy in subgroup analyses after propensity score matching with 5-year OS and progression-free survival rates of 85.0% (95% CI, 80.6%-89.5%) and 72.1% (95% CI, 67.3%-76.7%).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>In the rituximab era, this large-scale retrospective analysis from Asia confirmed the poor prognosis of DLBCL with multiple ENIs and underscored the efficacy of genetic subtype-guided immunochemotherapy in treating extranodal DLBCL.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"919-935"},"PeriodicalIF":24.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70033","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954187","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":"Ascites of patients with solid tumors shows distinct inflammatory patterns","authors":"Julia M. Berger,&nbsp;Martin Korpan,&nbsp;Carina Zierfuss,&nbsp;Katharina Syböck,&nbsp;Erwin Tomasich,&nbsp;Andreas Kienzle,&nbsp;Maria Koenig,&nbsp;Markus Kleinberger,&nbsp;Lynn Gottmann,&nbsp;Birgit Fendl,&nbsp;Cihan Ay,&nbsp;Johannes Pammer,&nbsp;Catharina Müller,&nbsp;Rudolf Oehler,&nbsp;Lorenz Balcar,&nbsp;Thomas Reiberger,&nbsp;Elisabeth S. Bergen,&nbsp;Barbara Niederdorfer,&nbsp;Matthias Preusser,&nbsp;Anna S. Berghoff","doi":"10.1002/cac2.70031","DOIUrl":"10.1002/cac2.70031","url":null,"abstract":"<p>Ascites formation in solid tumor patients is associated with an increased risk of death [<span>1, 2</span>]. The lack of pathophysiological insight limited the development of targeted treatment so far. With advances in immune modulating therapies, the inflammatory component of ascites moved into focus. Experimental approaches targeting immunologic dysregulation have shown only limited success [<span>3, 4</span>]. Therefore, we investigated inflammatory processes of ascites, taking the presence of tumor cells into account, while focusing on gastrointestinal tract malignancies due to their underrepresentation in literature.</p><p>A total of 63 patients were included in this study. Among these patients, 55 (87.3%) underwent paracentesis for ascites caused by advanced solid tumors, of which 30/63 (47.6%) patients had negative tumor cell cytology (paramalignant ascites) and 25/63 (39.7%) had positive tumor cell cytology (malignant ascites). Additionally, 8/63 (12.7%) patients with non-malignant ascites due to liver cirrhosis were included. Patients’ characteristics are displayed in Supplementary Table S1.</p><p>To study differences in the inflammatory profiles based on tumor cells within ascites, nine cytokines (interleukin-6 [IL-6], IL-8, IL-10, IL-17, tumor necrosis factor-alpha [TNF-α], C-reactive protein [CRP], Eotaxin, vascular endothelial growth factor [VEGF], and the soluble programmed death ligand-1 [sPD-L1]) were measured in ascitic supernatant. Malignant ascites showed increased levels of IL-6, IL-8, VEGF, and sPD-L1, compared to paramalignant and non-malignant ascites, respectively (Figure 1A-D). In contrast, no differences in cytokine levels were observed between non-malignant and paramalignant ascites in all measured cytokines, indicating that the inflammatory composition of ascites correlates with the presence of tumor cells.</p><p>To correlate systemic inflammatory processes with local inflammation in ascites supernatant in patients with advanced solid tumors, we measured cytokine levels in serum samples obtained at the timepoint of paracentesis. Strong correlations between ascitic and serum cytokine levels were evident for IL-8 and IL-17 (Figure 1E-F). Additionally, strong correlation was evident for CRP levels (Figure 1G), while no or weak correlations were detected in other cytokines. CRP as well as levels sPD-L1were decreased in ascites compared to serum (Supplementary Table S2). Compared to serum, ascitic IL-6 was significantly elevated (Supplementary Table S2) without a correlation to systemic IL-6 levels (<i>ρ</i> = 0.16, <i>P &gt; 0.05</i>), suggesting IL-6 signaling may be important for local inflammation.</p><p>To tie the link between soluble inflammatory markers and the cellular inflammatory compartment, we investigated correlations between cytokine levels and leukocyte as well as cell count for 19 overlapping samples. While no associations between leukocyte count and cytokine levels were observed, strong correlations betw","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"936-940"},"PeriodicalIF":24.9,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70031","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981511","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":"Semaglutide impairs bioavailability of alectinib: a note of warning based on a cross-over pharmacokinetic drug-drug interaction study","authors":"Niels Heersche,&nbsp;Daan A. C. Lanser,&nbsp;Esther Oomen-de Hoop,&nbsp;Attila Içli,&nbsp;Peter de Bruijn,&nbsp;Marthe S. Paats,&nbsp;Elisabeth F. C. van Rossum,&nbsp;Stijn L. W. Koolen,&nbsp;Ron H. N. van Schaik,&nbsp;Anne-Marie C. Dingemans,&nbsp;G. D. Marijn Veerman,&nbsp;Ron H. J. Mathijssen","doi":"10.1002/cac2.70030","DOIUrl":"10.1002/cac2.70030","url":null,"abstract":"&lt;p&gt;Alectinib is a first-line treatment for patients with advanced non-small cell lung cancer (NSCLC) harboring anaplastic lymphoma kinase-positive (&lt;i&gt;ALK+&lt;/i&gt;) driver aberrations with a median progression-free survival of 35 months and a 5-year overall survival of 63% [&lt;span&gt;1&lt;/span&gt;]. Currently, alectinib also shows improvement as an adjuvant treatment in resected stage IA-IIIB &lt;i&gt;ALK+&lt;/i&gt; NSCLC [&lt;span&gt;2&lt;/span&gt;]. Alectinib has a mild safety profile, but a notable underreported side-effect is weight gain [&lt;span&gt;3&lt;/span&gt;]. Studies show sarcopenic obesity rates doubling from 24% to 47% in the first year of treatment [&lt;span&gt;3&lt;/span&gt;], with persisting weight gain appearing early [&lt;span&gt;4&lt;/span&gt;]. Given patients’ extended survival, this poses risks for metabolic, cardiovascular, and psychological health.&lt;/p&gt;&lt;p&gt;Interestingly, over the past few years, glucagon-like peptide 1 (GLP-1) receptor agonists semaglutide, liraglutide, and tirzepatide, have been approved as promising anti-obesity drugs [&lt;span&gt;5&lt;/span&gt;]. Subcutaneous, once-weekly semaglutide induces a weight loss of 15% after 68 weeks [&lt;span&gt;5&lt;/span&gt;]. Hence, semaglutide might pose an interesting means of treating alectinib-induced weight gain. Recently, it was reported that a patient who experienced 20 kg weight gain during treatment with alectinib and lorlatinib, achieved 5 kg weight loss in just 6 months with semaglutide [&lt;span&gt;6&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;In a retrospective analysis, alectinib plasma trough levels above 435 ng/mL correlated with prolonged effectiveness compared to lower exposures [&lt;span&gt;7&lt;/span&gt;]. Despite moderate interpatient variability of 40%-45%, the lipophilicity of alectinib makes it highly dependent on dietary fat for sufficient dissolution and subsequent absorption in the gastro-intestinal tract to maintain adequate trough concentrations [&lt;span&gt;7, 8&lt;/span&gt;]. Considering that semaglutide decreases appetite, patients may inadvertently decrease their dietary (fat) intake, hampering absorption of alectinib. Hence, we investigated the effects of semaglutide on the pharmacokinetics of alectinib to gain insight into the pharmacokinetic interplay between both.&lt;/p&gt;&lt;p&gt;Therefore, we included 10 patients in a two-period cross-over study comparing alectinib exposure on alectinib monotherapy (period A) versus co-administration of semaglutide (period B) (Supplementary Table S1). Each treatment period lasted one week. Semaglutide was administrated as a single dose of 2.0 mg subcutaneously. Further details on the methodology of this study and baseline patient characteristics are provided in the Supplementary Materials.&lt;/p&gt;&lt;p&gt;After alectinib monotherapy (period A), a geometric mean of the area under the curve (AUC&lt;sub&gt;0-10h&lt;/sub&gt;) of 7,114 ng × h/mL (coefficient of variation [CV] = 34%) was observed, compared to an AUC&lt;sub&gt;0-10h&lt;/sub&gt; of 4,843 ng × h/mL (CV = 47%) after co-administering alectinib with subcutaneous semaglutide (period B). This change in alectinib geometric mean AUC&lt;sub&gt;0-10h&lt;/sub&gt; ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"914-918"},"PeriodicalIF":24.9,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70030","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981512","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":"Neutrophils in cancer: At the crucial crossroads of anti-tumor and pro-tumor","authors":"Wenpeng Cai,&nbsp;Tao Fan,&nbsp;Chu Xiao,&nbsp;Ziqin Deng,&nbsp;Yixiao Liu,&nbsp;Chunxiang Li,&nbsp;Jie He","doi":"10.1002/cac2.70027","DOIUrl":"10.1002/cac2.70027","url":null,"abstract":"<p>Neutrophils are important components of the immune system and play a key role in defending against pathogenic infections and responding to inflammatory cues, including cancer. Their dysregulation indicates potential disease risk factors. However, their functional importance in disease progression has often been underestimated due to their short half-life, especially as there is limited information on the role of intratumoral neutrophils. Recent studies on their prominent role in cancer have led to a paradigm shift in our understanding of the functional diversity of neutrophils. These studies highlight that neutrophils have emerged as key components of the tumor microenvironment, where they can play a dual role in promoting and suppressing cancer. Moreover, several approaches to therapeutically target neutrophils have emerged, and clinical trials are investigating their efficacy. In this review, we discussed the involvement of neutrophils in cancer initiation and progression. We summarized recent advances in therapeutic strategies targeting neutrophils and, most importantly, suggested future research directions that could facilitate the manipulation of neutrophils for therapeutic purposes in cancer patients.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"888-913"},"PeriodicalIF":24.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70027","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143989948","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":"Cover Image, Volume 45, Issue 3","authors":"Chloé Bessière,&nbsp;Ahmed Zamani,&nbsp;Romain Pfeifer,&nbsp;Sandra Dailhau,&nbsp;Camille Marchet,&nbsp;Benoit Guibert,&nbsp;Anthony Boureux,&nbsp;Raïssa Silva Da Silva,&nbsp;Nicolas Gilbert,&nbsp;Thérèse Commes,&nbsp;Fabienne Meggetto,&nbsp;Christian Touriol,&nbsp;Christian Récher,&nbsp;Marina Bousquet,&nbsp;Stéphane Pyronnet","doi":"10.1002/cac2.12555","DOIUrl":"https://doi.org/10.1002/cac2.12555","url":null,"abstract":"<p>The cover image is based on the article <i>A strong internal promoter drives massive expression of YEATS-domain devoid</i> MLLT3 <i>transcripts in HSC and most lethal AML</i> by Chloé Bessière et al., https://doi.org/10.1002/cac2.12650.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 3","pages":""},"PeriodicalIF":20.1,"publicationDate":"2025-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12555","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143707366","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":"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":"<p>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 [<span>1</span>], making them resistant to conventional chemo- and radiotherapies [<span>2</span>]. 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.</p><p>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 [<span>3</span>]. However, its externalization occurs on dying and diseased cells, and as we demonstrated, on stem cells [<span>4</span>]. PS-targeting agents like Annexin V (AnnV) [<span>5</span>] and the monoclonal antibody bavituxumab (Bavi) [<span>6</span>] 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 [<span>4</span>] enabling delivery of payloads to the cytoplasm of cells with externalized PS, which would include CSC in the hypoxic regions of tumors.</p><p>We used patient derived models of human breast cancer which are enriched in CD44⁺CD24⁻ 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 [<span>7</span>] were exposed to an oxygen level in culture that mimics the tumor microenvironment (TME) [<span>8, 9</span>], 4% O₂ (hypoxia), and compared to cells exposed to 7% O₂ (physoxia) and 21% O₂ (hyperoxia, typical cell culture). The percentage of CD44⁺ cells did not show significant differences at different oxygen levels (F_2,36 = 1.32, <i>P</i> = 0.28, Figure 1A-B, Supplemental Figure S1A). However, the percentage of CD44⁺GlaS⁺ cells (indicating GlaS binding) varied significantly (F_2,36 = 27.69, <i>P</i> &lt; 0.001, Figure 1C-D, Supplemental Figure S1B). Hypoxic conditions showed increased GlaS binding, with 61% of cells being CD44⁺GlaS⁺ under hypoxic conditions, compared to 47% in physoxia (<i>P</i> = 0.01) and 28% in hyperoxia (<i>P</i> &lt; 0.001). There were no significant differences in GlaS binding in CD44⁻ cells (<i>P</i> = 0.054), suggesting that oxygen dependent binding is specific to CD44⁺ 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":"<p>Mutations in the oncogene <i>NRAS</i> 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 [<span>1</span>]. These mutations occur in approximately 20% of melanomas and very rarely coexist with <i>BRAF</i> V600 mutations. <i>NRAS</i>-mutant melanoma is associated with poor survival [<span>2</span>] and represents an unmet clinical need, with no effective therapies available following immunotherapy failure.</p><p>Identification of contextual essential genes that exert stronger fitness effects on <i>NRAS</i>-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 <i>NRAS</i>-mutant melanoma. Typically, melanoma cell lines are cultured under ambient (∼20%) O₂ conditions, despite O₂ concentrations of &lt; 8% at the epidermal-dermal junction where melanocytes reside, resulting in adaptations in gene and protein expression [<span>3</span>]. 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%) O₂ conditions [<span>4</span>].</p><p>Six <i>NRAS</i>-mutant and seven <i>NRAS</i>-wildtype (five <i>BRAF</i>-mutant, two <i>BRAF</i>/<i>NRAS</i>/<i>NF1</i>-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% O₂ 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.</p><p>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 [<span>5</span>], 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":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Mesenchymal GBM (MES-GBM) cells, which were associated with a poor prognosis, and secreted phosphoprotein 1 (SPP1)⁺ myeloid-derived macrophages (SPP1⁺ 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⁺ 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⁺ 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⁺ 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.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>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}