Cancer Communications最新文献

{"title":"Ex vivo STAT3 phosphorylation in circulating immune cells: a novel biomarker for early cancer diagnosis and response to anti-PD-1 therapy","authors":"Sung-Woo Lee, Young Ju Kim, Saei Jeong, Kyung Na Rho, Jeong Eun Noh, Hee-Ok Kim, Hyun-Ju Cho, Yoo Duk Choi, Deok Hwan Yang, Eu Chang Hwang, Woo Kyun Bae, Sook Jung Yun, Ju Sik Yun, Cheol-Kyu Park, In-Jae Oh, Jae-Ho Cho","doi":"10.1002/cac2.12631","DOIUrl":"10.1002/cac2.12631","url":null,"abstract":"<p>Basal signal transducer and activator of transcription 3 (STAT3) activation is well-documented in the tumor microenvironment (TME) due to its association with cancer prognosis [<span>1</span>]. However, its presence and clinical relevance in the bloodstream remain unexplored. Given that STAT3-inducing cytokines, such as interleukin-6 (IL-6), are often elevated in the bloodstream of various cancer patients [<span>2, 3</span>], we aimed to investigate basal STAT3 activation in blood by developing a methodology to assess <i>ex vivo</i> phosphorylation of STAT3 (pSTAT3<i><sup>ex vivo</sup></i>) in circulating immune cells.</p><p>Since phosphorylation is a transient process prone to dephosphorylation, we sought to minimize the time between blood collection and the experiment. Specifically, 1) we limited the use of peripheral blood mononuclear cell (PBMC) samples to those processed within 1 hour of blood collection, and 2) immediately fixed the samples after thawing (Figure 1A). Notably, 135 non-small cell lung cancer (NSCLC) patient samples processed in this way exhibited significantly higher levels of pSTAT3<i><sup>ex vivo</sup></i>-positive cells compared to healthy controls (Figure 1B and Supplementary Table S1). Prolonged handling and extended experimental steps significantly decreased pSTAT3<i><sup>ex vivo</sup></i> expression (Supplementary Figure S1), underscoring the importance of our novel approach in controlling the time between blood collection and the experiment.</p><p>We next investigated the cell types within PBMCs that express pSTAT3<i><sup>ex vivo</sup></i>. CD4<sup>+</sup> T cells exhibited the highest pSTAT3<i><sup>ex vivo</sup></i> expression, followed by CD8<sup>+</sup> T cells, whereas monocytes, B cells, and natural killer (NK) cells showed minimal pSTAT3<i><sup>ex vivo</sup></i> expression (Figure 1C). Within both CD4<sup>+</sup> and CD8<sup>+</sup> T cells, pSTAT3<i><sup>ex vivo</sup></i> expression was highest in the least differentiated CD27<sup>+</sup> CD45RA<sup>+</sup> naïve subset (Figure 1C) [<span>4</span>]. A similar pattern was observed across multiple other cancer types (Figure 1D and Supplementary Figure S2).</p><p>Focusing on CD4<sup>+</sup> naïve T cells, pSTAT3<i><sup>ex vivo</sup></i> expression showed a stark contrast between NSCLC patients and healthy donors, even at stage I (Figure 1E). The area under the receiver operating characteristic curve for distinguishing stage I NSCLC patients from healthy donors was 0.9851, with a sensitivity of 0.92 at 95% specificity (Figure 1F). No tumor-specific or patient-specific clinical variables correlated with pSTAT3<i><sup>ex vivo</sup></i> expression in NSCLC patients (Supplementary Figure S3), while surgical removal of the tumor decreased pSTAT3<i><sup>ex vivo</sup></i> expression (Figure 1G), supporting a direct association between pSTAT3<i><sup>ex vivo</sup></i> and tumor burden. These findings underscore the potential of pSTAT3<i><sup>ex vivo</sup></i> as a blood-","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"58-62"},"PeriodicalIF":20.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142680963","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":"Anti-tumor drug supervision in China from 2010 to 2024: the evolution and prospect of drug review standards","authors":"Ling Tang, Yuanyuan Song, Hong Zhang, Ruimin Hao, Xin Tong, Xing Ai, Jun Ma, Zhimin Yang","doi":"10.1002/cac2.12630","DOIUrl":"10.1002/cac2.12630","url":null,"abstract":"<p>Over the past decade, the research and development (R&D) of anti-tumor drugs in China has undergone a remarkable leap, maintaining a high level of motivation.</p><p>With respect to pharmaceutical R&D paradigms in China, the domestic market was once dominated by generic drugs. A progressive transition towards the development of innovative pharmaceuticals is emerging, consequent to the reforms in drug evaluation and approval mechanisms and the promotion of novel drug development in China. The introduction of new drugs from other countries to China used to lag behind. Now a progressive approach is being taken towards synchronization in global R&D. The emergence of new players in the pharmaceutical industry and the enhancement of corporate R&D competencies have further facilitated the internationalization of China's drug R&D endeavors. The rapid advancement in pharmaceutical R&D has significantly enhanced China's drug regulatory capabilities. In August 2015, the State Council of the People's Republic of China promulgated the “<i>Opinions on Reforming the Approval Procedures for Drugs and Medical Devices</i>” marking the official commencement of reforms in the drug evaluation and approval system. The Chinese drug regulatory authorities are integrating resources and optimizing drug review processes through the development of a scientifically complete system of Good Review Practice.</p><p>Innovative drugs, including new drugs, improved new drugs (those improved formulations or dose forms with existing active ingredients), biosimilars, and domestic generic drugs with unimported original drugs, constitute essential assurances for patients in China and offer better accessibility of medications. To better understand the changes since the inception of the drug evaluation and approval reforms in 2015, we have collected data on new drug applications (NDAs) for the aforementioned types of drugs submitted to the Center for Drug Evaluation (CDE) under the National Medical Products Administration (NMPA) in China, spanning from January 2010 to March 2024.</p><p>A total of 374 NDAs for anti-tumor drugs had been approved from January 1, 2010 to March 31, 2024, including 186 (49.7%) imported drugs and 188 (50.3%) domestic drugs. The domestic drugs included 139 (37.1%) innovative/improved new drugs, 31 (8.3%) generic drugs, and 18 (4.8%) biosimilars, respectively.</p><p>Before 2018, China's pharmaceutical market mainly relied on domestic generic drugs. However, since 2018, the number of drug authorizations granted to innovative drugs has been on the rise, with a notable increase in domestically developed innovative drugs (Figure 1). The emergence of an upward trend in domestically R&D innovative drugs is due to better regulatory frameworks, faster review processes, and the introduction of technical standards. The Chinese government has implemented policies promoting anti-tumor drug R&D, including priority review, conditional approval,","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"63-67"},"PeriodicalIF":20.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758239/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675158","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":"Targeting IL-17A to manage immunotherapy-induced toxicity in melanoma","authors":"Kai Huang","doi":"10.1002/cac2.12628","DOIUrl":"10.1002/cac2.12628","url":null,"abstract":"<p>The landscape of cancer treatment has been dramatically transformed by the advent of immune checkpoint inhibitors (ICIs), particularly in the management of advanced melanoma. However, despite their revolutionary success, the use of ICIs is often complicated by immune-related adverse events (irAEs), which can range from mild symptoms to severe, life-threatening conditions. Understanding the underlying mechanisms of these toxicities is crucial to enhancing the safety and effectiveness of immunotherapy [<span>1</span>].</p><p>In a recent study published in <i>Nature Cancer</i>, Dimitriou <i>et al.</i> [<span>2</span>] provide novel insights into the immunological processes driving irAEs in melanoma patients treated with ICIs. The researchers identified a significant increase in interleukin-17A (IL-17A) expressing CD4<sup>+</sup> T cells at the onset of irAEs, pointing to a type III immune response as a key factor in these adverse events. This discovery not only deepens our understanding of irAEs but also suggests a potential therapeutic target for mitigating these toxicities without compromising the antitumor efficacy of ICIs.</p><p>What sets these findings apart is their contribution to a broader understanding of the mechanisms behind ICIs’ AEs compared to primary autoimmune diseases. While irAEs share certain immune mechanisms with autoimmune diseases, such as rheumatoid arthritis or psoriasis, the immunological context of ICIs is distinct because of the pharmacological disruption of immune checkpoints [<span>3</span>]. The study highlights the difference between irAEs and primary autoimmune disease by showing that IL-17A expressing CD4<sup>+</sup> T cells are particularly implicated in ICI-induced toxicity, which is not a prominent feature of many primary autoimmune conditions.</p><p>The study utilized a comprehensive approach, including proteomic analyses, multiplex cytokine and chemokine assays, and flow cytometry, to examine the immune profiles of melanoma patients undergoing ICI therapy. A critical finding was the consistent upregulation of IL-17A, along with other type I and III cytokines, at the onset of irAEs. These results were corroborated by the observation that IL-17A expressing CD4<sup>+</sup> T cells were significantly elevated in patients experiencing irAEs compared to those who did not.</p><p>Importantly, the authors provided proof-of-principle evidence for the therapeutic potential of targeting IL-17A in managing irAEs. In a small cohort of patients with severe, corticosteroid-refractory irAEs, treatment with the anti-IL-17A monoclonal antibody secukinumab led to a resolution of symptoms. Secukinumab, primarily used in the treatment of psoriasis, where IL-17A plays a well-established pathogenic role, offers a novel therapeutic option for managing irAEs [<span>4</span>]. Its efficacy in these patients not only underscores the importance of IL-17A in both conditions but also suggests that treatment strategies from autoimmune dise","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"56-57"},"PeriodicalIF":20.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615171","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":"Epigenomic exploration of disease status of EGFR-mutated non-small cell lung cancer using plasma cell-free DNA hydroxymethylomes","authors":"Yong Peng, Jason Karpus, Jyoti D. Patel, Everett E. Vokes, Marina Chiara Garassino, Kirsteen Lugtu, Zhou Zhang, Wei Zhang, Mengjie Chen, Chuan He, Christine M. Bestvina","doi":"10.1002/cac2.12606","DOIUrl":"10.1002/cac2.12606","url":null,"abstract":"<p>Non-small cell lung cancer (NSCLC) represents about 85% of histological diagnoses of lung cancer [<span>1</span>]. Epidermal growth factor receptor (<i>EGFR</i>) mutations occur in 12.7%-40.3% of NSCLC [<span>2</span>], and 5-hydroxymethylcytosine (5hmC) signatures and pathways can be inhibited by EGFR signaling [<span>3</span>]. The epigenome of plasma cell-free DNA (cfDNA), including 5hmC, has demonstrated promise as a cancer biomarker [<span>4</span>]. Currently, it remains unknown whether cfDNA 5hmC can identify disease status of NSCLC. Here, we performed 5hmC Seal-sequencing of 302 plasma cfDNA samples from 113 patients with metastatic <i>EGFR</i>-mutated NSCLC, which included 240 samples reflecting stable disease (SD) and 62 samples reflecting progressive disease (PD) (Figure 1A, Supplementary Table S1). SD and PD were clinically defined by the treating physician (Supplementary Methods).</p><p>High quality was ensured, 11 samples as outliers were discarded, and batch effects were removed effectively (Supplementary Figures S1, Supplementary Tables S2-S3). The remaining 291 samples were classified by disease status and various potential confounding factors (Figure 1A, Supplementary Tables S4-S7). The relative frequency of disease status in each group was nearly identical to that of the overall 291 samples (Supplementary Figure S4). cfDNA 5hmC peaks of each sample displayed proper reproducibility (Supplementary Figure S5A). Interestingly, 123 cfDNA 5hmC peaks were located on the <i>EGFR</i> gene (Supplementary Figure S5B, Supplementary Table S8). Genomewide cfDNA 5hmC levels were overall similar between PD and SD samples, as well as various potential confounders (Supplementary Figures S5C-E and S6).</p><p>A substantial portion of 5hmC peaks displayed high heterogeneity of 5hmC levels among the 291 samples (Supplementary Figure S7A), which were not derived from disease status and potential confounders (Supplementary Figure S7B-E, Supplementary Table S9). With 1,000 bp bins instead of peaks, similar results were observed (Supplementary Figure S8). We found that <i>EGFR</i> mutations were associated with 5hmC heterogeneity (Supplementary Figure S9A) and identified 4,743 cfDNA 5hmC peaks (Supplementary Table S10) with 5hmC levels differing among intergroups of <i>EGFR</i> mutation subtypes more than that of intragroups (<i>P</i> < 0.005) (Supplementary Figure S9B). Interestingly, the 4,743 cfDNA 5hmC peaks were strongly associated with the function of <i>EGFR</i> (Supplementary Figure S10A), but not associated with disease status (Supplementary Figure 10B-E). This result was further confirmed by a nearly identical 5hmC level between PD and SD samples (Supplementary Figure 10F), as well as distribution of false discovery rate and <i>P</i> values (Figure 1B).</p><p>Disease status-associated 5hmC peaks were completely different from potential confounder-associated 5hmC peaks, except for smoking status (Supplementary Figure S11). Consistently, 5","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"51-55"},"PeriodicalIF":20.1,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615168","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":"Discovery of a novel viroid-like circular RNA in colorectal cancer","authors":"Meini Wu, Wenliang Li, Ningzhu Hu, Changning Liu, Jianfang Li, Yanhan Li, Ning Xu, Jiandong Shi, Jing Sun, Jing Li, Yunzhang Hu","doi":"10.1002/cac2.12626","DOIUrl":"10.1002/cac2.12626","url":null,"abstract":"<p>Viroids, the smallest known infectious agents, were initially discovered in plants [<span>1</span>], and have caused significant agricultural diseases [<span>2-4</span>]. Recently, viroids have been identified in fungi [<span>5-7</span>] and bacteria [<span>8</span>], but none have been identified in animals. To date, no studies have explored the presence of viroids in colorectal cancer (CRC). We employed a reference-free computational method to identify a novel viroid-like circular RNA (circRNA) in CRC patients. Our study suggests that a broader class of viroids may exist in living systems.</p><p>We utilized a computer algorithm developed by Qingfa Wu's team [<span>9, 10</span>], which is unique in its homology independence. It employs the splitting longer reads into shorter fragments (SLS) technique and progressively filters overlapping small RNAs 2 (PFOR2), facilitating the detection of novel viroid-like circRNAs through deep RNA sequencing. SLS segments long RNA sequences into 21-nt virtual small RNAs, followed by PFOR2 analysis, which retains only 21-nt virtual internal small RNAs (ISRs) for circRNA assembly [<span>9</span>]. Our goal was to employ reference-free computer algorithms to investigate the existence of viroids in CRC tissues, aiming to gain new insights into the pathogenesis and treatment of CRC.</p><p>Through deep sequencing, we compiled whole transcriptome data from 12 clinical pairs of CRC samples (Supplementary Table S1). The data analysis flowchart is depicted in Figure 1A. After excluding low-quality bases and irrelevant reads, clean, high-quality reads were aligned to the human genome (hg38) using Tophat, with matched reads being discarded. The remaining reads were transformed into virtual small RNAs using the SLS program, followed by contig assembly using PFOR2. To enhance computational efficiency, the “step” parameter in the SLS program was set to 8. During this process, over 10,000 contigs were assembled. These contigs were compared to the human genome (hg38) using BLAST, and highly homologous contigs were removed, leaving only nonhomologous ones. After screening, 5,235 contigs remained, with a GC content of 51.35% and a total length of 1,114,562 bp. The length distribution is illustrated in Figure 1B, with most fragment lengths clustered between 100 bp and 200 bp. To more accurately eliminate contigs derived from the human genome, the 5,235 contigs were individually aligned to the human genome under more stringent conditions, resulting in the identification of 130 contigs (Supplementary Table S2). Throughout the experimental design, we systematically discarded sequencing data homologous to the human genome whenever possible and used non-homologous data as the foundational dataset for PFOR2 program operations.</p><p>A total of 130 primer pairs were designed based on these sequences (Supplementary Table S3) and subsequently verified through PCR and Sanger sequencing in CRC tissues, ultimately identifying three contigs","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"46-50"},"PeriodicalIF":20.1,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142614992","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":"FOXO1 or not FOXO1: that is the question","authors":"Maude Marchais, Marianne Mangeney","doi":"10.1002/cac2.12624","DOIUrl":"10.1002/cac2.12624","url":null,"abstract":"<p>Two groundbreaking articles in <i>Nature</i> by Evan W. Weber [<span>1</span>] and Philippe Darcy teams [<span>2</span>] revealed that overexpressing the transcription factor Forkhead Box O1 (FOXO1) boosts Chimeric Antigen Receptor-T (CAR-T) cell antitumor activity against various tumors, including solid ones. Paradoxically, we recently described that pharmacological inhibition of FOXO1 transcriptional activity by AS184856 treatment in resting T cells enables the generation of non-activated CAR-T cells that outperforms solid tumor eradication compared to <i>ex vivo</i>-activated CAR-T cells [<span>3</span>]. Our findings confirm the interest in using non-activated CAR-T cells, echoing two other studies that achieved more potent CAR-T cells by transducing resting T cells cultured with interleukin 7 (IL-7), with [<span>4</span>] or without [<span>5</span>] the addition of IL-15.</p><p>Although these results may seem contradictory at first, experimental evidence shows that this contradiction is only apparent and can be resolved by taking into account the initial status of the cells: activated versus resting T cells. Overexpressing FOXO1 in activated T cells leads to a similar phenotypic and functional differentiation state as inhibiting FOXO1 activity in resting T cells. Indeed, both strategies lead to significant changes in cell metabolism, specifically to an increase in mitochondrial activity [<span>1, 2, 6</span>]. Similarly, both of these apparently opposed processes also lead to an increase in cytotoxic functions. One of the proteins essential for cytotoxic activity, granzyme B, was described to be increased at the transcriptomic and protein level, either after inhibition of FOXO1 in resting T cells [<span>3, 6</span>] or after FOXO1 overexpression in activated T cells [<span>2</span>]. In both cases, granzyme B rise is associated with an in vivo tumor killing increase [<span>1-3</span>]. Finally, in both configurations, T cells show no exhaustion markers and differentiate into stem cell memory T (TSCM)-like cells [<span>1-3</span>], a T cell differentiation stage associated with a greater antitumor activity [<span>7</span>].</p><p>Taken together, these results suggest that the correlation between the level of FOXO1 transcriptional activity and the antitumor potential of CAR-T cells is not straightforward. FOXO1 maintains quiescence in unstimulated cells. In naïve T cells, TCR triggering (or cytokines) allows a rapid, yet prolonged nuclear exclusion of this transcription factor, downstream the PI3K/Akt pathway [<span>8</span>]. Since T cell activation leads to the shutdown of FOXO1 transcriptional activity [<span>8</span>], one would expect that FOXO1 overexpression in activated T cells would have no effect. Instead, the results from Weber's and Darcy's teams show that overexpression may maintain a small but sufficient amount of FOXO1 activity, responsible for the beneficial effects observed in CAR-T cells [<span>1, 2</span>]. Similarly, inh","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 1","pages":"43-45"},"PeriodicalIF":20.1,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11758247/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142603059","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":"Tryptophan 2,3-dioxygenase-positive matrix fibroblasts fuel breast cancer lung metastasis via kynurenine-mediated ferroptosis resistance of metastatic cells and T cell dysfunction.","authors":"Yongcan Liu, Shanchun Chen, Xueying Wan, Rui Wang, Haojun Luo, Chao Chang, Peijin Dai, Yubi Gan, Yuetong Guo, Yixuan Hou, Yan Sun, Yong Teng, Xiaojiang Cui, Manran Liu","doi":"10.1002/cac2.12608","DOIUrl":"10.1002/cac2.12608","url":null,"abstract":"<p><strong>Background: </strong>Tumor metastasis is a major threat to cancer patient survival. The organ-specific niche plays a pivotal role in tumor organotropic metastasis. Fibroblasts serve as a vital component of the metastatic microenvironment, but how heterogeneous metastasis-associated fibroblasts (MAFs) promote organotropic metastasis is poorly characterized. Here, we aimed to decipher the heterogeneity of MAFs and elucidate the distinct roles of these fibroblasts in pulmonary metastasis formation in breast cancer.</p><p><strong>Methods: </strong>Mouse models of breast cancer pulmonary metastasis were established using an in vivo selection method of repeated injections of metastatic cells purified from the mouse lung. Single-cell RNA-sequencing (scRNA-seq) was employed to investigate the heterogeneity of MAFs. Transgenic mice were used to examine the contribution of tryptophan 2,3-dioxygenase-positive matrix fibroblasts (TDO2⁺ MFs) in lung metastasis.</p><p><strong>Results: </strong>We uncovered 3 subtypes of MAFs in the lung metastatic microenvironment, and their transcriptome profiles changed dynamically as lung metastasis evolved. As the predominant subtype, MFs were exclusively marked by platelet-derived growth factor receptor alpha (PDGFRA) and mainly located on the edge of the metastasis, and T cells were enriched around MFs. Notably, high MF signatures were significantly associated with poor survival in breast cancer patients. Lung metastases were markedly diminished, and the suppression of T cells was dramatically attenuated in MF-depleted experimental metastatic mouse models. We found that TDO2⁺ MFs controlled pulmonary metastasis by producing kynurenine (KYN), which upregulated ferritin heavy chain 1 (FTH1) level in disseminated tumor cells (DTCs), enabling DTCs to resist ferroptosis. Moreover, TDO2⁺ MF-secreted chemokines C-C motif chemokine ligand 8 (CCL8) and C-C motif chemokine ligand 11 (CCL11) recruited T cells. TDO2⁺ MF-derived KYN induced T cell dysfunction. Conditional knockout of Tdo2 in MFs diminished lung metastasis and enhanced immune activation.</p><p><strong>Conclusions: </strong>Our study reveals crucial roles of TDO2⁺ MFs in promoting lung metastasis and DTCs' immune evasion in the metastatic niche. It suggests that targeting the metabolism of lung-specific stromal cells may be an effective treatment strategy for breast cancer patients with lung metastasis.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1261-1286"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142104686","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":"Partial hepatectomy versus interventional treatment in patients with hepatitis B virus-related hepatocellular carcinoma and clinically significant portal hypertension: a randomized comparative clinical trial.","authors":"Yichuan Yuan, Hong Peng, Wei He, Yun Zheng, Jiliang Qiu, Bin Chen, Ruhai Zou, Chenwei Wang, Wan Yee Lau, Binkui Li, Yunfei Yuan","doi":"10.1002/cac2.12614","DOIUrl":"10.1002/cac2.12614","url":null,"abstract":"<p><strong>Background: </strong>The widely accepted view that portal hypertension (PHT) is a contraindication to hepatectomy for patients with hepatocellular carcinoma (HCC) is being increasingly challenged. The long-term survival outcomes and safety of partial hepatectomy versus interventional treatment using ablation with or without pre-ablation transarterial chemoembolization (TACE) in patients with HBV-related HCC within the Milan criteria and with clinically significant PHT were compared in this study.</p><p><strong>Methods: </strong>This open-label randomized clinical trial was conducted on consecutive patients with clinically PHT and hepatitis B virus (HBV)-related HCC with tumors which were within the Milan criteria. These patients were randomized 1:1 to receive either partial hepatectomy or interventional treatment between December 2012 and June 2018. The primary endpoint was overall survival (OS); secondary endpoints included recurrence-free survival (RFS) and therapeutic safety.</p><p><strong>Results: </strong>Each of the 2 groups had 80 patients. The 1-, 3- and 5-year OS rates in the partial hepatectomy group and the interventional treatment group were 95.0%, 86.2%, 69.5% versus 93.8%, 77.5%, 64.9%, respectively (P = 0.325). The corresponding RFS rates were 78.8%, 55.0%, 46.2% versus 71.3%, 52.5%, 45.0%, respectively (P = 0.783). The partial hepatectomy group had a higher complication rate compared to the interventional group (67.5% vs. 20%, P < 0.001). However, the differences were mainly in Clavien-Dindo Grade I complications (P < 0.001), while not significant in Grade II/III/IV/V (All P > 0.05).</p><p><strong>Conclusions: </strong>This study shows that partial hepatectomy treatment did not meet prespecified significance for improved OS and RFS compared to interventional treatment for patients with HBV-related HCC within the Milan criteria and with clinically significant PHT. However, partial hepatectomy is still a safe procedure and should be considered as a treatment option rather than a contraindication.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1337-1349"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12614","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342200","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":"Targeting SRSF10 might inhibit M2 macrophage polarization and potentiate anti-PD-1 therapy in hepatocellular carcinoma.","authors":"Jialiang Cai, Lina Song, Feng Zhang, Suiyi Wu, Guiqi Zhu, Peiling Zhang, Shiping Chen, Junxian Du, Biao Wang, Yufan Cai, Yi Yang, Jinglei Wan, Jian Zhou, Jia Fan, Zhi Dai","doi":"10.1002/cac2.12607","DOIUrl":"10.1002/cac2.12607","url":null,"abstract":"<p><strong>Background: </strong>The efficacy of immune checkpoint blockade therapy in patients with hepatocellular carcinoma (HCC) remains poor. Although serine- and arginine-rich splicing factor (SRSF) family members play crucial roles in tumors, their impact on tumor immunology remains unclear. This study aimed to elucidate the role of SRSF10 in HCC immunotherapy.</p><p><strong>Methods: </strong>To identify the key genes associated with immunotherapy resistance, we conducted single-nuclear RNA sequencing, multiplex immunofluorescence, and The Cancer Genome Atlas and Gene Expression Omnibus database analyses. We investigated the biological functions of SRSF10 in immune evasion using in vitro co-culture systems, flow cytometry, various tumor-bearing mouse models, and patient-derived organotypic tumor spheroids.</p><p><strong>Results: </strong>SRSF10 was upregulated in various tumors and associated with poor prognosis. Moreover, SRSF10 positively regulated lactate production, and SRSF10/glycolysis/ histone H3 lysine 18 lactylation (H3K18la) formed a positive feedback loop in tumor cells. Increased lactate levels promoted M2 macrophage polarization, thereby inhibiting CD8⁺ T cell activity. Mechanistically, SRSF10 interacted with the 3'-untranslated region of MYB, enhancing MYB RNA stability, and subsequently upregulating key glycolysis-related enzymes including glucose transporter 1 (GLUT1), hexokinase 1 (HK1), lactate dehydrogenase A (LDHA), resulting in elevated intracellular and extracellular lactate levels. Lactate accumulation induced histone lactylation, which further upregulated SRSF10 expression. Additionally, lactate produced by tumors induced lactylation of the histone H3K18la site upon transport into macrophages, thereby activating transcription and enhancing pro-tumor macrophage activity. M2 macrophages, in turn, inhibited the enrichment of CD8⁺ T cells and the proportion of interferon-γ⁺CD8⁺ T cells in the tumor microenvironment (TME), thus creating an immunosuppressive TME. Clinically, SRSF10 could serve as a biomarker for assessing immunotherapy resistance in various solid tumors. Pharmacological targeting of SRSF10 with a selective inhibitor 1C8 enhanced the efficacy of programmed cell death 1 (PD-1) monoclonal antibodies (mAbs) in both murine and human preclinical models.</p><p><strong>Conclusions: </strong>The SRSF10/MYB/glycolysis/lactate axis is critical for triggering immune evasion and anti-PD-1 resistance. Inhibiting SRSF10 by 1C8 may overcome anti-PD-1 tolerance in HCC.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1231-1260"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12607","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142119068","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":"Altered glycosylation in cancer: molecular functions and therapeutic potential.","authors":"Xuemeng Xu, Qiu Peng, Xianjie Jiang, Shiming Tan, Wenjuan Yang, Yaqian Han, Linda Oyang, Jinguan Lin, Mengzhou Shen, Jiewen Wang, Haofan Li, Longzheng Xia, Mingjing Peng, Nayiyuan Wu, Yanyan Tang, Hui Wang, Qianjin Liao, Yujuan Zhou","doi":"10.1002/cac2.12610","DOIUrl":"10.1002/cac2.12610","url":null,"abstract":"<p><p>Glycosylation, a key mode of protein modification in living organisms, is critical in regulating various biological functions by influencing protein folding, transportation, and localization. Changes in glycosylation patterns are a significant feature of cancer, are associated with a range of pathological activities in cancer-related processes, and serve as critical biomarkers providing new targets for cancer diagnosis and treatment. Glycoproteins like human epidermal growth factor receptor 2 (HER2) for breast cancer, alpha-fetoprotein (AFP) for liver cancer, carcinoembryonic antigen (CEA) for colon cancer, and prostate-specific antigen (PSA) for prostate cancer are all tumor biomarkers approved for clinical use. Here, we introduce the diversity of glycosylation structures and newly discovered glycosylation substrate-glycosylated RNA (glycoRNA). This article focuses primarily on tumor metastasis, immune evasion, metabolic reprogramming, aberrant ferroptosis responses, and cellular senescence to illustrate the role of glycosylation in cancer. Additionally, we summarize the clinical applications of protein glycosylation in cancer diagnostics, treatment, and multidrug resistance. We envision a promising future for the clinical applications of protein glycosylation.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":" ","pages":"1316-1336"},"PeriodicalIF":20.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.12610","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142280530","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}