Cancer Communications最新文献

{"title":"Immune cell pair ratio captured by imaging mass cytometry has superior predictive value for prognosis of non-small cell lung cancer than cell fraction and density","authors":"Jian-Rong Li, Chao Cheng","doi":"10.1002/cac2.12540","DOIUrl":"10.1002/cac2.12540","url":null,"abstract":"<p>Infiltrating immune cells in the tumor microenvironment (TME) play critical roles in the initiation, progression, and metastasis of cancer [<span>1</span>]. Previous studies have reported that the infiltration levels of various immune cell types are significantly associated with patient prognosis in different cancers [<span>2, 3</span>]. Specifically, in non-small cell lung cancer (NSCLC) the prognostic associations of major immune cell types have been investigated [<span>4-6</span>], however, some of the reported associations are inconsistent and remain debated [<span>7</span>]. Limited by technical issues, most studies focused on a few immune cell lineages or relied on inferred immune cell levels from computational deconvolution. To investigate the prognostic effects of all major immune cell types unbiasedly, more systematic high-quality immune cell profiling data with matched patient survival information are needed.</p><p>Recently, Sorin <i>et al.</i> [<span>8</span>] used imaging mass cytometry (IMC) to characterize the immunological landscape of 416 distinct lung adenocarcinoma (LUAD) samples at single-cell resolution. The IMC images provide the counts and spatial distribution of 16 cell types with high precision in each sample. These cell types include cancer and endothelial cells, along with 14 immune cell types, including CD163<sup>+</sup> and CD163<sup>−</sup> macrophages, CD8<sup>+</sup>, CD4<sup>+</sup>, regulatory, and other T cells, classical, non-classical, and intermediate monocytes, natural killer cells, dendritic cells, mast cells, neutrophils, and other immune cells. Additionally, the data provide patient survival and other clinical information. Using these data, we investigated the prognostic associations of the cell density (#cells/megapixel) and fractions of the 16 cell types as well as the fraction ratio between each pair of cell types (Supplementary Methods). Our results indicated that the relative abundance between cell types (fraction ratios) was more prognostic than cell fractions and densities.</p><p>We calculated the densities of the 16 cell types in each patient's IMC image and applied Cox regression analysis to examine their associations with progression-free survival (PFS) after adjusting for established clinical factors including age, sex, smoking status, and tumor stage. At the significance level of <i>P</i> < 0.05, only the density of non-classical monocytes was found to have a significant association with worse prognosis (hazard ratio [HR] = 1.004, <i>P</i> = 0.040, Figure 1A). After multiple testing corrections, none of the cell types was significant (false discovery rate [FDR] > 0.05). Similar results were obtained when cell fractions among all cells were used for prognostic association analysis (Figure 1B). In addition, we conducted prognostic analysis on 14 immune cell types, focusing on their proportions among immune cells (excluding cancer and endothelial cells), yielding similar results. It has b","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"589-592"},"PeriodicalIF":16.2,"publicationDate":"2024-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12540","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140292888","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 44, Issue 3","authors":"Bin Song,&nbsp;Ping Yang,&nbsp;Shuyu Zhang","doi":"10.1002/cac2.12537","DOIUrl":"https://doi.org/10.1002/cac2.12537","url":null,"abstract":"<p>The cover image is based on the Review Article <i>Cell fate regulation governed by p53: Friends or reversible foes in cancer therapy</i> by Bin Song et al., https://doi.org/10.1002/cac2.12520.\u0000\u0000 <figure>\u0000 <div><picture>\u0000 <source></source></picture><p></p>\u0000 </div>\u0000 </figure></p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 3","pages":""},"PeriodicalIF":16.2,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12537","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140188610","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 reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer","authors":"Jiayao Wang,&nbsp;Jiehao Zhang,&nbsp;Hao Liu,&nbsp;Lingnan Meng,&nbsp;Xianchun Gao,&nbsp;Yihan Zhao,&nbsp;Chen Wang,&nbsp;Xiaoliang Gao,&nbsp;Ahui Fan,&nbsp;Tianyu Cao,&nbsp;Daiming Fan,&nbsp;Xiaodi Zhao,&nbsp;Yuanyuan Lu","doi":"10.1002/cac2.12534","DOIUrl":"10.1002/cac2.12534","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Chemoresistance is a major cause of treatment failure in gastric cancer (GC). Heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1) is an N6-methyladenosine (m⁶A)-binding protein involved in a variety of cancers. However, whether m⁶A modification and hnRNPA2B1 play a role in GC chemoresistance is largely unknown. In this study, we aimed to investigate the role of hnRNPA2B1 and the downstream mechanism in GC chemoresistance.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The expression of hnRNPA2B1 among public datasets were analyzed and validated by quantitative PCR (qPCR), Western blotting, immunofluorescence, and immunohistochemical staining. The biological functions of hnRNPA2B1 in GC chemoresistance were investigated both in vitro and in vivo. RNA sequencing, methylated RNA immunoprecipitation, RNA immunoprecipitation, and RNA stability assay were performed to assess the association between hnRNPA2B1 and the binding RNA. The role of hnRNPA2B1 in maintenance of GC stemness was evaluated by bioinformatic analysis, qPCR, Western blotting, immunofluorescence, and sphere formation assays. The expression patterns of hnRNPA2B1 and downstream regulators in GC specimens from patients who received adjuvant chemotherapy were analyzed by RNAscope and multiplex immunohistochemistry.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated expression of hnRNPA2B1 was found in GC cells and tissues, especially in multidrug-resistant (MDR) GC cell lines. The expression of hnRNPA2B1 was associated with poor outcomes of GC patients, especially in those who received 5-fluorouracil treatment. Silencing hnRNPA2B1 effectively sensitized GC cells to chemotherapy by inhibiting cell proliferation and inducing apoptosis both in vitro and in vivo. Mechanically, hnRNPA2B1 interacted with and stabilized long noncoding RNA NEAT1 in an m⁶A-dependent manner. Furthermore, hnRNPA2B1 and NEAT1 worked together to enhance the stemness properties of GC cells via Wnt/β-catenin signaling pathway. In clinical specimens from GC patients subjected to chemotherapy, the expression levels of hnRNPA2B1, NEAT1, CD133, and CD44 were markedly elevated in non-responders compared with responders.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our findings indicated that hnRNPA2B1 interacts with and stabilizes lncRNA NEAT1, which contribute to the maintenance of stemness property via Wnt/β-catenin pathway and exacerbate chemoresistance in GC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"469-490"},"PeriodicalIF":16.2,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12534","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183845","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":"Sexual dimorphism in the antitumor immune responses elicited by the combination of fasting and chemotherapy","authors":"Andrés Pastor-Fernández,&nbsp;Manuel Montero Gómez de las Heras,&nbsp;Jose Ignacio Escrig-Larena,&nbsp;Marta Barradas,&nbsp;Cristina Pantoja,&nbsp;Adrian Plaza,&nbsp;Jose Luis Lopez-Aceituno,&nbsp;Esther Durán,&nbsp;Alejo Efeyan,&nbsp;Maria Mittelbrunn,&nbsp;Lola Martinez,&nbsp;Pablo Jose Fernandez-Marcos","doi":"10.1002/cac2.12535","DOIUrl":"10.1002/cac2.12535","url":null,"abstract":"&lt;p&gt;Fasting reduces chemotherapy toxicity [&lt;span&gt;1&lt;/span&gt;], enhances immunogenic tumor cell death [&lt;span&gt;2, 3&lt;/span&gt;] and increases CD8&lt;sup&gt;+&lt;/sup&gt; T cell infiltration in tumors, particularly when combined with chemotherapy [&lt;span&gt;2, 3&lt;/span&gt;] or immunotherapy [&lt;span&gt;4&lt;/span&gt;]. Moreover, fasting exhibits a sexual dimorphism in the immune system [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;The aim of our study was to elucidate the role of sex in the beneficial anti-tumoral effects of combining fasting and chemotherapy. For this, we inoculated B16-F10-derived melanoma allografts into immunocompetent male and female mice. Three days later, the mice were divided into: (1) not treated; (2) two cycles of 48-hour fasting; (3) two cycles of 10 mg/kg doxorubicin; (4) two cycles of doxorubicin and fasting for 24 hours before and 24 hours after doxorubicin inoculation (“combination treatment” or “CT”). The study methods are shown in the Supplementary Material file. Doxorubicin and fasting alone reduced tumor growth in both sexes with the same efficacy, and CT amplified this effect only in males (Figure 1A and Supplementary Figure S1A-C). Male mice bearing YUMM1.7 melanoma-derived tumors responded to fasting and doxorubicin, but females were insensitive to any of them (Figure 1B and Supplementary Figure S2A-C). Oxaliplatin did not affect B16-F10 tumor growth (Supplementary Figure S3A-D). Fasting reduced serum levels of testosterone only in males ([&lt;span&gt;6, 7&lt;/span&gt;] and Supplementary Figure S4A). To explore the role of testosterone, we castrated males or implanted testosterone pellets in females. CT lost efficacy in castrated males and became efficient in females with testosterone pellets (Figure 1C and Supplementary Figure S4B-E). Next, we inoculated mice with MC38 colon carcinoma cells [&lt;span&gt;8&lt;/span&gt;]. Oxaliplatin or fasting reduced tumor growth, and CT amplified this effect in both sexes (Figure 1D and Supplementary Figure S5A-C). Our findings indicate that sexual dimorphism occurs in different tumor types, is dependent on tumor and chemotherapy type, and testosterone is a key player in this sexual dimorphism.&lt;/p&gt;&lt;p&gt;To study the immune response in B16-F10 allografts treated with doxorubicin and/or fasting (Supplementary Figure S6A-D), we analyzed relevant immune cell types in inguinal lymph nodes (LN), peripheral blood (B) and tumors (T) (Supplementary Table S1-S4). CT increased stage II Natural Killer (NK) and Natural Killer T (NKT) cells in B16-F10 tumors only in males (Figure 1E-F and Supplementary Figure S6E-H). Females on CT had more exhausted CD8&lt;sup&gt;+&lt;/sup&gt; T cells in their tumors (Figure 1G and Supplementary Figure S6I-K). Tumor-infiltrated CD8&lt;sup&gt;+&lt;/sup&gt; T cells were functionally more active in CT in males (Supplementary Figure S7A-C), while serum TNFα did not change (Supplementary Figure S7D-E). Immunoablation of CD8 cells in male mice tended to reduce CT efficacy, which still improved the antitumor response (Supplementary Figure S8A-F and Supplementary Table S5), ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"508-513"},"PeriodicalIF":16.2,"publicationDate":"2024-03-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12535","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140183846","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":"Conserved immuno-collagenic subtypes predict response to immune checkpoint blockade","authors":"Jie Mei,&nbsp;Yun Cai,&nbsp;Rui Xu,&nbsp;Qing Li,&nbsp;Jiahui Chu,&nbsp;Zhiwen Luo,&nbsp;Yaying Sun,&nbsp;Yuxin Shi,&nbsp;Junying Xu,&nbsp;Di Li,&nbsp;Shuai Liang,&nbsp;Ying Jiang,&nbsp;Jiayu Liu,&nbsp;Zhiwen Qian,&nbsp;Jiaofeng Zhou,&nbsp;Mengyun Wan,&nbsp;Yunlong Yang,&nbsp;Yichao Zhu,&nbsp;Yan Zhang,&nbsp;Yongmei Yin","doi":"10.1002/cac2.12538","DOIUrl":"10.1002/cac2.12538","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Immune checkpoint blockade (ICB) has revolutionized the treatment of various cancer types. Despite significant preclinical advancements in understanding mechanisms, identifying the molecular basis and predictive biomarkers for clinical ICB responses remains challenging. Recent evidence, both preclinical and clinical, underscores the pivotal role of the extracellular matrix (ECM) in modulating immune cell infiltration and behaviors. This study aimed to create an innovative classifier that leverages ECM characteristics to enhance the effectiveness of ICB therapy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We analyzed transcriptomic collagen activity and immune signatures in 649 patients with cancer undergoing ICB therapy. This analysis led to the identification of three distinct immuno-collagenic subtypes predictive of ICB responses. We validated these subtypes using the transcriptome data from 9,363 cancer patients from The Cancer Genome Atlas (TCGA) dataset and 1,084 in-house samples. Additionally, novel therapeutic targets were identified based on these established immuno-collagenic subtypes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our categorization divided tumors into three subtypes: “soft &amp; hot” (low collagen activity and high immune infiltration), “armored &amp; cold” (high collagen activity and low immune infiltration), and “quiescent” (low collagen activity and immune infiltration). Notably, “soft &amp; hot” tumors exhibited the most robust response to ICB therapy across various cancer types. Mechanistically, inhibiting collagen augmented the response to ICB in preclinical models. Furthermore, these subtypes demonstrated associations with immune activity and prognostic predictive potential across multiple cancer types. Additionally, an unbiased approach identified B7 homolog 3 (B7-H3), an available drug target, as strongly expressed in “armored &amp; cold” tumors, relating with poor prognosis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>This study introduces histopathology-based universal immuno-collagenic subtypes capable of predicting ICB responses across diverse cancer types. These findings offer insights that could contribute to tailoring personalized immunotherapeutic strategies for patients with cancer.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"554-575"},"PeriodicalIF":16.2,"publicationDate":"2024-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12538","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140165459","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":"Positive regulation of cell proliferation by the miR-1290-EHHADH axis in hepatocellular carcinoma","authors":"Jinkwon Lee,&nbsp;Gyeonghwa Kim,&nbsp;Tae-Su Han,&nbsp;Eunsun Jung,&nbsp;Taesang Son,&nbsp;Kwangho Kim,&nbsp;Kiyoon Kwon,&nbsp;Yuna Roh,&nbsp;Tae Young Ryu,&nbsp;In Hwan Tae,&nbsp;Yunsang Kang,&nbsp;Byungheon Lee,&nbsp;Yu Rim Lee,&nbsp;Soo Young Park,&nbsp;Won Young Tak,&nbsp;Dae-Soo Kim,&nbsp;Mi-Young Son,&nbsp;Keun Hur,&nbsp;Hyun-Soo Cho","doi":"10.1002/cac2.12536","DOIUrl":"10.1002/cac2.12536","url":null,"abstract":"&lt;p&gt;Hepatocellular carcinoma (HCC) is the second most common cancer and the third leading cause of cancer-related death worldwide [&lt;span&gt;1&lt;/span&gt;]. Recently, HCC incidence and mortality rates have further increased due to changes in the global social environment and dietary habits [&lt;span&gt;2&lt;/span&gt;]. HCC is treated by surgical resection or combination chemotherapy, but the overall survival rate of HCC patients has not improved, and the recurrence rate is still high due to strong invasiveness and resistance to chemotherapy [&lt;span&gt;3&lt;/span&gt;]. Therefore, it is necessary to understand the pathogenesis of HCC and identify novel diagnostic biomarkers and therapeutic targets for the treatment of HCC. Recently, microRNA-1290 (miR-1290) has been reported to regulate the progression of many types of malignant cancers, such as colorectal cancer [&lt;span&gt;4&lt;/span&gt;], lung cancer [&lt;span&gt;5&lt;/span&gt;], and HCC [&lt;span&gt;6&lt;/span&gt;]. However, research on the therapeutic targets of miR-1290 is still needed. Thus, in this study, we will use HCC patient samples to assess the potential of miR-1290 as both a diagnostic marker and a therapeutic target, and we will demonstrate its oncogenic properties through functional and mechanistic studies. The methods and materials were described in Supplementary Materials andMethods.&lt;/p&gt;&lt;p&gt;To discover HCC development-specific microRNAs (miRNAs), we performed NanoString-based miRNA expression profiling in 5 steatohepatitis cirrhosis (SHC) tissues and 5 early-stage HCC tissues. Eleven miRNAs were discovered to be differentially expressed between SHC and HCC tissues (Figure 1A). Among them, miR-1290 was upregulated in HCC compared to SHC and was selected based on its cell proliferation and differentiation function in cancers [&lt;span&gt;7, 8&lt;/span&gt;]. In a subsequent validation step, the miR-1290 was found to be significantly elevated in HCC tissues compared to either SHC (&lt;i&gt;P&lt;/i&gt; = 0.043) or normal healthy liver tissues (NT) (&lt;i&gt;P&lt;/i&gt; = 0.019) (Figure 1B). In addition, miR-1290 expression was significantly upregulated as the TNM stage increased in an independent cohort of 111 HCC patients (Figure 1C; ANOVA test &lt;i&gt;P&lt;/i&gt; = 0.002). To demonstrate the clinical relevance of miR-1290 expression in patients with HCC, we determined the association between miR-1290 expression and various clinicopathological variables in a cohort of 111 HCC patients (Supplementary Table S1). The expression of miR-1290 was associated with factors reflecting disease progression, such as T stage (&lt;i&gt;P&lt;/i&gt; &lt; 0.001), M stage (&lt;i&gt;P&lt;/i&gt; = 0.011), TNM stage (&lt;i&gt;P&lt;/i&gt; = 0.003), and BCLC stage (&lt;i&gt;P&lt;/i&gt; &lt; 0.001). Moreover, the 5-year overall survival rate was significantly lower in high miR-1290-expressing HCC patients (log-rank &lt;i&gt;P&lt;/i&gt; &lt; 0.001) (Figure 1D). Next, the Univariate Cox proportional hazards analysis (Supplementary Table S2) revealed that T stage (HR 4.60; 95% CI 2.76 to 7.66; &lt;i&gt;P&lt;/i&gt; &lt; 0.001), N stage (HR 3.21; 95% CI 1.52 to 6.78; &lt;i&gt;P&lt;/i&gt; = 0.002), M stage (H","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 6","pages":"705-709"},"PeriodicalIF":20.1,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194445/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140157621","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":"Disclosing the true impact of screening endoscopy in colorectal cancer prevention","authors":"Thomas Heisser,&nbsp;Carlo Senore,&nbsp;Michael Hoffmeister,&nbsp;Lina Jansen,&nbsp;Hermann Brenner","doi":"10.1002/cac2.12531","DOIUrl":"10.1002/cac2.12531","url":null,"abstract":"&lt;p&gt;Preprint: https://doi.org/10.1101/2022.11.22.22282622&lt;/p&gt;&lt;p&gt;Randomized trials, cohort and modeling studies have consistently demonstrated a major impact of screening endoscopies on reducing colorectal cancer (CRC) incidence and mortality [&lt;span&gt;1&lt;/span&gt;]. Over time, CRC mortality starts to be lower in those who underwent screening compared to those who did not due to earlier detection of prevalent, preclinical (asymptomatic) cases and lowering incidence through removing precancerous lesions. By contrast, measured incidence shows an initial apparent increase in the screening group due to the detection of preclinical (i.e., already prevalent) cancer. Only after around 4-6 years of follow-up, the measured cumulative incidence also starts to be lower in the screening group due to later manifestation of the initially preclinical cases in the control group and removal of precancerous lesions in the screening group [&lt;span&gt;2-6&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;However, measured incidence rates do not reflect true incidence rates as they are a mix of truly incident cases and cases that are already prevalent in the preclinical stage at baseline. As screening endoscopies cannot prevent prevalent CRC cases (but only remove precursor lesions at risk of developing into CRC), the commonly measured and reported effects on CRC incidence do not quantify the true endoscopy impact on CRC incidence, i.e., the impact on preventing newly developing CRC cases. In the present study, we sought to quantify the true impact of screening endoscopy on CRC incidence.&lt;/p&gt;&lt;p&gt;First, by re-calibrating the Colorectal Cancer Multistate Simulation Model (COSIMO), a thoroughly validated modeling approach, we replicated the Screening for COlon REctum trial (SCORE), a large, randomized trial (&lt;i&gt;n&lt;/i&gt; = 34,292) examining the effect of a single flexible sigmoidoscopy in reducing CRC incidence and mortality by matching the numbers of simulated subjects and allocation per group with reported baseline numbers by sex and age, also taking into account colonoscopy referral and background endoscopy use [&lt;span&gt;5&lt;/span&gt;]. Further details are provided in the Supplementary Material and Methods. The primary validation objective was the agreement between modeled and in SCORE reported incidence rate ratios (in the following: incidence rate ratio [unadjusted], IRR&lt;sub&gt;Unadjusted&lt;/sub&gt;). The results were considered consistent if modeled estimates were within the 95% confidence intervals of the corresponding outcomes reported for SCORE.&lt;/p&gt;&lt;p&gt;Then, to determine the impact of prevalent preclinical CRCs on IRR&lt;sub&gt;Unadjusted&lt;/sub&gt;, we calculated the adjusted IRR (incidence rate ratio (adjusted), IRR&lt;sub&gt;Adjusted&lt;/sub&gt;, excluding prevalent CRCs at baseline) for the screening versus control groups by omitting the sex- and age-specific number of cases arising from prevalent preclinical CRC from the model calculation of IRRs for each year of follow-up.&lt;/p&gt;&lt;p&gt;Incidence rates and IRR&lt;sub&gt;Unadjusted&lt;/sub&gt; predicted by COSIMO foll","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"504-507"},"PeriodicalIF":16.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12531","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140142785","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":"Deciphering metastatic route-specific signals and their microenvironment interactions in peritoneal metastasis of gastric cancer","authors":"Ki Tae Kim,&nbsp;Jae Eun Lee,&nbsp;Jae-Ho Cheong,&nbsp;In Cho,&nbsp;Yoon Young Choi","doi":"10.1002/cac2.12533","DOIUrl":"10.1002/cac2.12533","url":null,"abstract":"&lt;p&gt;Gastric cancer (GC) is a pervasive global malignancy with high mortality rates due to distant metastasis [&lt;span&gt;1&lt;/span&gt;]. GC metastasis can occur via hematogenous route, peritoneal route, and specifically through ovarian spread in females [&lt;span&gt;2&lt;/span&gt;]. Among these, peritoneal metastasis is the most prevalent and challenging condition to treat [&lt;span&gt;3&lt;/span&gt;]. The Cancer Genome Atlas (TCGA) has uncovered four molecular subtypes of GC: microsatellite instability, Epstein-Barr virus-related, chromosomal instability, and genomically stable [&lt;span&gt;4&lt;/span&gt;]. These subtypes exhibit unique features and metastatic behaviors [&lt;span&gt;5&lt;/span&gt;], providing valuable insights into the molecular characteristics of GC. Nevertheless, there remains a gap in understanding gene expression feature in metastatic GC compared to corresponding primary tumors, particularly regarding its biological and clinical relevance in different metastatic patterns.&lt;/p&gt;&lt;p&gt;A whole-transcriptome sequencing analysis was conducted to investigate the characteristics of metastatic GC. We examined 66 paired primary and metastatic tumors, categorized according to their sites (38 primary, 9 hematogenous, 6 peritoneal, and 13 ovarian metastases), collected from 14 patients with GC metastasis (Supplementary Tables S1-S2 and Supplementary Figure S1). To corroborate the biological and clinical relevance of the identified metastatic GC-specific signals, we utilized publicly available databases containing expression data on primary GC, including TCGA (&lt;i&gt;n&lt;/i&gt; = 415) [&lt;span&gt;4&lt;/span&gt;], Asian Cancer Research Group (ACRG, &lt;i&gt;n&lt;/i&gt; = 300) [&lt;span&gt;6&lt;/span&gt;], and Yonsei Cancer Center (YCC, &lt;i&gt;n&lt;/i&gt; = 433) cohorts [&lt;span&gt;7&lt;/span&gt;]. For in-depth analysis at the single-cell resolution, we accessed a public dataset comprising 5 primary GC samples [&lt;span&gt;8&lt;/span&gt;] and performed a single-cell RNA sequencing (scRNA-seq) analysis on ascites obtained from 4 patients with GC (Supplementary Tables S3-S4). The flow of analysis is summarized in Supplementary Figure S2. Details of the patient demographics, samples, and data analysis methods used are outlined in the Supplementary Methods.&lt;/p&gt;&lt;p&gt;Through a differential expression analysis of the 66 paired primary and metastatic tumors, we identified 949 genes uniquely associated with metastatic GC tumors (Supplementary Figure S3). Subsequent over-representation analysis of these metastatic GC-specific genes indicated that hematogenous metastatic tumors exhibited an up-regulation of receptor tyrosine kinase-related signals, while simultaneously showing a down-regulation of pathways associated with epithelial-mesenchymal transition (EMT) (Supplementary Figure S4). Conversely, peritoneal/ovarian metastatic tumors demonstrated an upregulation of the Hedgehog pathway, a key player in EMT signaling. These findings suggest that the mechanisms underlying GC metastasis vary by route [&lt;span&gt;5&lt;/span&gt;], thus underscoring the need for route-specific clinical considerations.&lt;/p&gt;","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 4","pages":"514-517"},"PeriodicalIF":16.2,"publicationDate":"2024-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12533","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140148000","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":"Impact of pre-existing cardiometabolic diseases on metastatic cancer stage at diagnosis: a prospective multinational cohort study","authors":"Anna Jansana,&nbsp;Aviane Auguste,&nbsp;Marina Kvaskoff,&nbsp;Agnès Fournier,&nbsp;Emma Fontvieille,&nbsp;Laia Peruchet-Noray,&nbsp;Carine Biessy,&nbsp;Reynalda Cordova,&nbsp;Kristina Elin Nielsen Petersen,&nbsp;Anne Tjønneland,&nbsp;Verena Katzke,&nbsp;Rudolf Kaaks,&nbsp;Fulvio Ricceri,&nbsp;Salvatore Panico,&nbsp;Paolo Contiero,&nbsp;Maria-Jose Sánchez,&nbsp;Jesus Castilla,&nbsp;Marta Crous-Bou,&nbsp;Alicia Heath,&nbsp;Elom Kouassivi Aglago,&nbsp;Elisabete Weiderpass,&nbsp;Marc James Gunter,&nbsp;Pietro Ferrari,&nbsp;Elio Riboli,&nbsp;Vivian Viallon,&nbsp;Heinz Freisling","doi":"10.1002/cac2.12526","DOIUrl":"10.1002/cac2.12526","url":null,"abstract":"&lt;p&gt;Owing to shared risk factors between cardiometabolic diseases (CMDs) and cancer, coupled with population aging, the lifetime risk of an individual developing cancer after a CMD is increasing. Furthermore, biological mechanisms such as insulin resistance or inflammation may not only predispose individuals with CMD to an elevated risk of certain types of cancer but also to a diagnosis of cancer at an advanced stage [&lt;span&gt;1, 2&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;Cancer stage at diagnosis strongly correlates with cancer survival rates and impacts treatment decisions. Early cancer detection is key to improving cancer outcomes, especially for cancers with poor prognosis. Factors associated with a higher risk of an advanced-stage diagnosis may differ from those associated with cancer incidence. Previous studies support an association between advanced-stage cancer at diagnosis and certain patient characteristics, such as higher body mass index (BMI), older age, smoking, comorbidities, and cancer type. Studies examining the influence of comorbidities on cancer stage at diagnosis have suggested that a CMD requiring regular medical follow-up is associated with earlier cancer detection [&lt;span&gt;3, 4&lt;/span&gt;]. However, studies have also suggested that overall participation rates in cancer screening programs may be lower among individuals with type 2 diabetes (T2D) or cardiovascular diseases (CVD), which may lead to later cancer detection and a more advanced stage at diagnosis [&lt;span&gt;5&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;A better understanding of how CMDs prior to cancer are associated with stage at cancer diagnosis may inform cancer screening recommendations. This study aimed to investigate whether having a pre-existing CMD is associated with late-stage cancer diagnosis and to identify potential modifiers of this association in the European Prospective Investigation into Cancer and Nutrition study (EPIC).&lt;/p&gt;&lt;p&gt;This multinational prospective cohort study included 11,945 individuals diagnosed with first primary cancer between 1992 and 2012. Of all the diagnosed cancers, 64.9% were localized, 35.1% were metastatic, 53.6% were diagnosed in women, and 4.8%, a, 7.1%, and 1.3% had a history of CVD, of T2D, and of both CVD and T2D, respectively (Supplementary Figure S1, Supplementary Table S1). In addition to overall cancer, breast and colorectal cancers (38.1% of all cancers) were also investigated separately because of the well-established population-based cancer screening programs for these two cancers at the time of cancer diagnosis in the countries included in this study (i.e., Denmark, Germany, Italy, Spain, Sweden, and the UK). Detailed methods are described in Supplementary Materials.&lt;/p&gt;&lt;p&gt;We found that the adjusted odds ratios (ORs) of developing metastatic cancer (vs. localized) comparing individuals with pre-existing CVD, T2D or both to those without a CMD prior to cancer were 0.92 (95% confidence interval [CI] = 0.65-1.01), 1.04 (95% CI = 0.83-1.18) and 1.06 (95% CI = 0.60-1.36), respectively ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 5","pages":"593-597"},"PeriodicalIF":16.2,"publicationDate":"2024-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12526","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140130795","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":"The mechanism of resistance to CDK4/6 inhibition and novel combination therapy with RNR inhibition for chemo-resistant bladder cancer","authors":"Zhichao Tong,&nbsp;Yubo Zhao,&nbsp;Shiyu Bai,&nbsp;Benedikt Ebner,&nbsp;Lou Lienhard,&nbsp;Yuling Zhao,&nbsp;Ziqi Wang,&nbsp;Qi Pan,&nbsp;Pengyu Guo,&nbsp;Thilo Bracht,&nbsp;Barbara Sitek,&nbsp;Jürgen E. Gschwend,&nbsp;Wanhai Xu,&nbsp;Roman Nawroth","doi":"10.1002/cac2.12532","DOIUrl":"10.1002/cac2.12532","url":null,"abstract":"&lt;p&gt;Bladder cancer (BCa) is the most prevalent urological cancer worldwide [&lt;span&gt;1&lt;/span&gt;]. A significant proportion of BCa (89%) exhibits molecular alterations in the cell cycle pathway, and targeting cyclin-dependent kinases 4 and 6 (CDK4/6) is deemed as a promising therapeutic strategy [&lt;span&gt;2&lt;/span&gt;]. Selective inhibitors of CDK4/6 (CDK4/6is) have been approved by the US Food and Drug Administration (FDA) [&lt;span&gt;3&lt;/span&gt;]. They could induce cell cycle arrest in BCa immediately, and after this “sensitive stage”, unknown compensatory mechanism may cause acquired resistance [&lt;span&gt;4, 5&lt;/span&gt;]. To address this issue, our study employed multi-omics and identified ribonucleotide reductase regulatory subunit M2 (RRM2), a crucial component of the ribonucleotide reductase (RNR) complex [&lt;span&gt;6&lt;/span&gt;], as a key mediator in conferring acquired resistance. We further investigated whether Palbociclib activates proteolysis of RRM2 by the ubiquitin-proteasome system (UPS) and the ubiquitin-like proteins (UBLs) during the sensitive stage. Additionally, we explored whether RRM2 is controlled by E2F transcription factor 3 (E2F3) when acquired resistance is established. Interestingly, upregulation of RRM2 may also cause chemotherapy resistance [&lt;span&gt;7&lt;/span&gt;]. Thus, we verified if concurrent inhibition of RNR and CDK4/6 holds promise as a novel therapeutic strategy for BCa patients, especially those exhibit resistance to chemotherapy. All the study designs and methods are described in the Supplementary file.&lt;/p&gt;&lt;p&gt;Retinoblastoma (RB)-positive BCa elicits a sequential progression from sensitivity to resistance to Palbociclib [&lt;span&gt;8&lt;/span&gt;]. We utilized multi-omics to identify key regulators of this process (Figure 1A, Supplementary Tables S1-S5). The only candidate matching all three high-throughput screening approaches was RRM2, and pathway analysis further demonstrated related mechanisms (Supplementary Figures S1-S2). To validate this finding, we examined the cell cycle distribution and expression levels of the other RNR subunit RRM1 and RRM2 in a time kinetic (Figure 1B-C, Supplementary Figure S3A-D). Transcript levels were initially downregulated, followed by a partial recovery, while the decline and recovery pattern of proteins mirrored this. We then transduced single-guide RNAs of RRM1 and RRM2 into T24 synergistic activation mediator (SAM) cells and confirmed partial resistance (Figure 1D-E, Supplementary Figure S3E). However, degradation of RRM2 was still observed at early time points (Supplementary Figure S3F), indicating that proteolysis might be essential for therapy response. We then applied the proteasome inhibitors Epoxomicin/MG-132 in combination with Palbociclib. As shown, protein degradation of RRM2 was effectively blocked, but only partially for RRM1 (Figure 1F, Supplementary Figure S4A-B). We next tested the combination of Palbociclib with ubiquitin-like proteins (UBLs) inhibitor MLN4924 and proved that the initial degradation of RRM1/2","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"44 6","pages":"700-704"},"PeriodicalIF":20.1,"publicationDate":"2024-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11194448/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140101078","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}