Cancer Communications最新文献

{"title":"Targeted reactivation of the novel tumor suppressor DAPK1, an upstream regulator of p53, in high-grade serous ovarian cancer by mRNA liposomes reduces viability and enhances drug sensitivity in preclinical models","authors":"Monika Raab, Balázs Győrffy, Samuel Peña-Llopis, Daniela Fietz, Monika Kressin, Margareta Kolaric, Matthias Ebert, Khayal Gasimli, Sven Becker, Mourad Sanhaji, Klaus Strebhardt","doi":"10.1002/cac2.70029","DOIUrl":"10.1002/cac2.70029","url":null,"abstract":"<p>Ovarian cancer, particularly high-grade serous ovarian cancer (HGSOC), remains the most lethal gynecological malignancy, with a 5-year survival rate of around 40% due to late diagnosis, recurrence, and the development of chemoresistance [<span>1, 2</span>]. Mutations in tumor protein 53 (<i>TP53</i>) occur in over 96% of HGSOC cases, impairing its tumor-suppressive functions, including cell cycle control, DNA repair, and apoptosis. Mutant <i>TP53</i> promotes tumor progression, genomic instability, and resistance to standard therapies, thereby worsening patient outcomes [<span>3, 4</span>]. Death-associated protein kinase 1 (<i>DAPK1</i>) is a key regulator of apoptosis and autophagy [<span>5, 6</span>]. While p53 can upregulate <i>DAPK1</i> expression, DAPK1 in turn stabilizes p53 by inhibiting its negative regulator, murine double minute 2 (MDM2). This reciprocal regulation forms a feedback loop that reinforces p53's tumor-suppressive function. We identified aberrant DAPK1 expression in ovarian cancer and sought to investigate whether restoring DAPK1 function could serve as a potential therapeutic strategy. Recent advancements in mRNA-based therapies offer a promising approach to gene restoration. Thus, we investigated whether in vitro-transcribed (IVT)-mRNA encoding DAPK1 could serve as an effective therapeutic strategy for HGSOC. Here, we explore the potential of mRNA-based reactivation of DAPK1 to regulate cell survival and apoptosis in HGSOC.</p><p>In studies using mammalian vectors to deliver functional proteins for replacement therapy, reducing the length of recombinant DNA vectors has been shown to enhance transfection efficiency, translation, and persistence in cells [<span>7-9</span>]. Given the relatively long open reading frame of <i>DAPK1</i> (4,290 base pairs), we generated a series of constructs containing different functional domains of DAPK1 and assessed their anti-tumor efficacy in ovarian cancer cells. We found that a truncated <i>DAPK1</i> variant, containing the kinase domain, ankyrin repeats, and death domain (KD-AR-DD), retained potent tumor-suppressive activity despite being approximately 50% shorter than the wild-type protein. Compared to other truncated constructs, mammalian vector-based expression of KD-AR-DD strongly activated Caspase-3/7 and significantly sensitized OVCAR-3 cells to paclitaxel treatment (Supplementary Figure S1A-C). Based on these findings, we selected KD-AR-DD as the basis for designing an IVT-mRNA construct, referred to as ∆DAPK1-mRNA (Figure 1A), optimized to induce cell death in ovarian cancer cells. For IVT-mRNA synthesis, we employed a bacterial vector containing a T7 RNA polymerase promoter to drive transcription of human truncated <i>DAPK1</i>, focusing on optimizing translational efficacy and mRNA stability [<span>9</span>]. To deliver ∆DAPK1-mRNA to HGSOC cells, we utilized a liposomal system with Lipofectamine MessengerMAX Transfection Reagent. Treatment of OVCAR-8 cells with increasing","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 8","pages":"966-970"},"PeriodicalIF":24.9,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70029","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109779","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":"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":"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":"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":"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}