Molecular Oncology最新文献

{"title":"Response to neoadjuvant chemotherapy in early breast cancers is associated with epithelial-mesenchymal transition and tumor-infiltrating lymphocytes.","authors":"Françoise Derouane, Jérôme Ambroise, Cédric van Marcke, Mieke Van Bockstal, Martine Berlière, Christine Galant, Hélène Dano, Médina Lougué, Elena Benidovskaya, Guy Jerusalem, Vincent Bours, Claire Josse, Jérôme Thiry, Aurélie Daumerie, Caroline Bouzin, Cyril Corbet, François P Duhoux","doi":"10.1002/1878-0261.13813","DOIUrl":"10.1002/1878-0261.13813","url":null,"abstract":"<p><p>Epithelial-mesenchymal transition (EMT) and tumor-infiltrating lymphocytes (TILs) play a central role in early-stage breast cancer (BC) and are associated with chemoresistance, stemness, and invasion. The objective of this study was two fold: (a) by investigating the predictive value of EMT and TILs, we aimed to estimate the chance of achieving a response after neoadjuvant chemotherapy (NAC) and (b) to evaluate the potential changes of EMT and TILs in BC upon NAC. Using bulk RNA sequencing and immunofluorescence (IF) for EMT (E-cadherin and vimentin) and lymphocyte markers (CD3, CD8, FOXP3), we analyzed pre- and post-NAC tumor samples from 100 early-BC patients treated with NAC. For each BC molecular subtype, we compared the expression of EMT and TILs, at the RNA and protein level, between responding and non-responding tumors. Paired analysis of pre- and post-NAC samples was performed for patients with residual disease after NAC. RNA sequencing of pre- and post-NAC samples identified significant differences in EMT-related and inflammation-related gene expression between non-responding (RCB-II/III) and responding (RCB-0/I) tumors. Increased EMT-related marker expression was observed after NAC in cases with residual disease, in particular in the luminal subtype. Characterization of TILs in pre-NAC samples showed substantially more CD3 + CD8-FOXP3-lymphocytes in responding HER2+ tumors compared with non-responding. Paired analyses of pre- and post-NAC samples demonstrated higher levels of CD3 + CD8 + FOXP3-lymphocytes in residual luminal and triple-negative BC and higher levels of CD3 + CD8-FOXP3-lymphocytes in residual triple-negative BC compared with other subtypes of lymphocytes. We found that there is an unmet clinical need for reliable biomarkers to predict response to NAC in BC. Our results suggest that an upregulation of the EMT gene signature in diagnostic biopsies is associated with poor response to NAC in early BC, across all subtypes. Additionally, changes in EMT and in the TIL population occur in residual tumors after NAC. These findings could help to personalize future NAC and adjuvant treatment regimens.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2330-2347"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256005","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The atypical KRAS^Q22K mutation directs TGF-β response towards partial epithelial-to-mesenchymal transition in patient-derived colorectal cancer tumoroids.","authors":"Theresia Mair, Philip König, Milena Mijović, Jessica Kalla, Anil Baskan, Loan Tran, Kristina Draganić, Pedro Morata Saldaña, Carlos Uziel Pérez Malla, Janette Pfneissl, Andreas Tiefenbacher, Julijan Kabiljo, Velina S Atanasova, Lisa Wozelka-Oltjan, Leonhard Müllauer, Michael Bergmann, Raheleh Sheibani-Tezerji, Gerda Egger","doi":"10.1002/1878-0261.70014","DOIUrl":"10.1002/1878-0261.70014","url":null,"abstract":"<p><p>Transforming growth factor beta (TGF-β) exhibits complex and context-dependent cellular responses. While it mostly induces tumor-suppressive effects in early stages of tumorigenesis, tumor-promoting properties are evident in advanced disease. This TGF-β duality is still not fully understood, and whether TGF-β supports invasion and metastasis by influencing cancer cells directly, or rather through the stromal tumor compartment, remains a matter of debate. Here, we utilized a library of colorectal cancer (CRC) patient-derived tumoroids (PDTs), representing a spectrum of tumor stages, to study cancer cell-specific responses to TGF-β. Using conditions allowing for the differentiation of PDTs, we observed TGF-β-induced tumor-suppressive effects in early-stage tumoroids, whereas more advanced tumoroids were less sensitive to the treatment. Notably, one tumoroid line harboring an atypical KRAS^Q22K mutation underwent partial epithelial-to-mesenchymal transition (EMT), which was associated with morphological changes and increased invasiveness. On a molecular level, this was accompanied by elevated expression of mesenchymal genes, as well as deregulation of pathways associated with matrix remodeling and cell adhesion. Our results suggest that tumor cell-intrinsic responses to TGF-β are critical in determining its tumor-suppressive or tumor-promoting effects.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2212-2232"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143605273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcriptome-wide analysis of circRNA and RBP profiles and their molecular relevance for GBM.","authors":"Julia Latowska-Łysiak, Żaneta Zarębska, Marcin P Sajek, Adriana Grabowska, Alessia Buratin, Paweł Głodowicz, Julia O Misiorek, Konrad Kuczyński, Stefania Bortoluzzi, Marek Żywicki, Jan G Kosiński, Agnieszka Rybak-Wolf, Rafał Piestrzeniewicz, Anna M Barciszewska, Katarzyna Rolle","doi":"10.1002/1878-0261.70005","DOIUrl":"10.1002/1878-0261.70005","url":null,"abstract":"<p><p>Glioblastoma (GBM) is the most aggressive and lethal type of glioma, characterized by aberrant expression of noncoding RNAs including circular RNAs (circRNAs). CircRNAs may impact cellular processes by interacting with other molecules-like RNA-binding proteins (RBPs). The diagnostic value of circRNA and circRNA/RBP complexes is still largely unknown. To explore circRNA and RBP transcript expression in GBM, we performed and further analyzed RNA-seq data from GBM patients' primary and recurrent tumor samples. We identified circRNAs differentially expressed in primary tumors, the circRNA progression markers in recurrent GBM samples, and the expression profile of RBP genes. Furthermore, we demonstrated the clinical potential of circRNAs and RBPs in GBM and proposed them as stratification markers in de novo assembled tumor subtypes. Additionally, we experimentally validated the subcellular localization of select circRNAs and their interactions with FUS. Subsequently, we showed that circARID1A may play a role in promoting GBM cell proliferation. Overall, we described circRNA-RBP interactions that could play a regulatory role in gliomagenesis and GBM progression and provided a list of molecular players in GBM for further extensive studies.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2270-2291"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502674","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Thermal proteome profiling and proteome analysis using high-definition mass spectrometry demonstrate modulation of cholesterol biosynthesis by next-generation galeterone analog VNPP433-3β in castration-resistant prostate cancer.","authors":"Retheesh S Thankan, Elizabeth Thomas, Mehari M Weldemariam, Puranik Purushottamachar, Weiliang Huang, Maureen A Kane, Yuji Zhang, Nicholas Ambulos, Bi-Dar Wang, David Weber, Vincent C O Njar","doi":"10.1002/1878-0261.70009","DOIUrl":"10.1002/1878-0261.70009","url":null,"abstract":"<p><p>Cholesterol (CHOL) homeostasis is significantly modulated in prostate cancer (PCa) suggesting an active role in PCa development and progression. Several studies indicate a strong correlation between elevated CHOL levels and increased PCa risk and severity. Inhibition of CHOL biosynthesis at different steps, including lanosterol synthase (LSS), has shown significant efficacy against both hormone-dependent and castration-resistant PCa. Earlier, we reported proteasomal degradation of androgen receptor (AR)/AR-Vs and Mnk1/2 as the primary mechanisms of action of VNPP433-3β in inhibiting PCa cell proliferation and tumor growth. Through thermal proteome profiling, comparative proteomics and cellular thermal shift assay, we identified VNPP433-3β's ancillary effect of lowering CHOL by binding to LSS and lanosterol 14-alpha demethylase, potentially inhibiting CHOL biosynthesis in PCa cells and tumors. Additionally, in conjunction with our previously reported transcriptome analysis, proteomics reveals that VNPP433-3β modulated upstream regulators and pathways critical for PCa stem cell maintenance and recurrence. The inhibition of CHOL biosynthesis by VNPP433-3β reinforces its multifaceted effects in PCa across all stages, highlighting its potential as a single-agent therapy. Achieving reduced CHOL levels aligns with better treatment outcomes, further substantiating VNPP433-3β's therapeutic potential.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2292-2309"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330945/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143502673","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Concern: Activation of protein phosphatase 2A tumor suppressor as potential treatment of pancreatic cancer.","authors":"","doi":"10.1002/1878-0261.70087","DOIUrl":"10.1002/1878-0261.70087","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2456"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330921/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to \"The polyamine transporter ATP13A3 mediates difluoromethylornithine-induced polyamine uptake in neuroblastoma\".","authors":"","doi":"10.1002/1878-0261.70088","DOIUrl":"10.1002/1878-0261.70088","url":null,"abstract":"","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2457"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144553992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasma lipidomic and metabolomic profiles in high-grade glioma patients before and after 72-h presurgery water-only fasting.","authors":"Iris Divé, Lisa Hahnefeld, Katharina J Wenger, Donat Kögel, Joachim Steinbach, Gerd Geisslinger, Michael W Ronellenfitsch, Irmgard Tegeder","doi":"10.1002/1878-0261.70003","DOIUrl":"10.1002/1878-0261.70003","url":null,"abstract":"<p><p>Glioblastoma (GB) is the most aggressive primary brain tumor with poor prognosis despite multimodal therapy. Calorie-restricted diets have emerged as putative strategies to augment anticancer therapies. We employed UHPLC-high-resolution mass spectrometry analyses of plasma lipids and polar metabolites to assess the systemic metabolic effects of a 72-h preoperative fasting period in IDH-wild-type glioma patients (n = 9 GB and n = 1 diffuse pediatric-type high-grade H3/IDH-wildtype) who participated in the prospective ERGO3 trial (NCT04461938). Fasting reduced lysophosphatidylcholines (LPC, LPC-O), lysophosphatidylethanolamines (LPE, LPE-O), and increased free fatty acids and carnitines. Triglyceride (TG) profiles shifted from short-chain TGs (42-48 C-atoms) to very long-chain TGs (58-60 C-atoms) indicating an exploitation of neutral lipid stores. Branched-chain amino acids, aminobutyric acid, and uric acids were increased, and glucose reduced after fasting. The effects of fasting were comparable in men and women. To our knowledge, this is the first study that evaluated the effects of fasting on systemic lipid/metabolite levels in GB patients. Our results may hold promise for integrating fasting interventions as a component of a potential metabolic tumor therapy.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2249-2269"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330934/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Elucidating prognostic significance of purine metabolism in colorectal cancer through integrating data from transcriptomic, immunohistochemical, and single-cell RNA sequencing analysis.","authors":"Sungyeon Kim, Myunghee Kang, Soyeon Jeong, Jisup Kim, Kyoung Oh Kim, Won-Suk Lee, Jeong-Heum Baek, Jung Ho Kim, Seungyoon Nam","doi":"10.1002/1878-0261.70010","DOIUrl":"10.1002/1878-0261.70010","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is widely recognized for its high prevalence and significant mortality rates, and purine metabolism has been serving as a potential therapeutic target. However, purine metabolism has not yet been validated as a prognostic marker through immunohistochemical analysis. In this study, we utilized a combination of bulk transcriptome analysis, immunohistochemistry (IHC), and single-cell RNA sequencing (scRNA-seq) to assess the clinical relevance of purine metabolism in CRC. Low expression levels of five purine metabolism-related genes-ADSL, APRT, ADCY3, NME3, and NME6-were associated with worse prognosis in CRC patient subgroups, including wild-type TP53, mutant TP53, and microsatellite-stable phenotypes. IHC-based validation showed that NME3 expression was an independent prognostic factor, whereas ADSL and NME6 expressions were associated with clinical variables in prediction of prognosis. Notably, NME3 expression predicted a high risk in patients with early-stage CRC, while ADSL and NME6 expressions were predictive in late-stage CRC. scRNA-seq analysis showed that four genes, excluding NME6, had low expression levels in epithelial cells at the late-stage CRC. Despite the reversible nature of purine metabolism reactions, we demonstrated a consistent directional expression of these five prognostic purine metabolism-related proteins in CRC tissues. We suggest that alterations in purine metabolism could serve as a clinically useful prognostic marker in CRC.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2310-2329"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330927/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TOMM20 as a driver of cancer aggressiveness via oxidative phosphorylation, maintenance of a reduced state, and resistance to apoptosis.","authors":"Ranakul Islam, Megan E Roche, Zhao Lin, Diana Whitaker-Menezes, Victor Diaz-Barros, Eurico Serrano, Maria Paula Martinez Cantarin, Nancy J Philp, Atrayee Basu Mallick, Ubaldo Martinez-Outschoorn","doi":"10.1002/1878-0261.70002","DOIUrl":"10.1002/1878-0261.70002","url":null,"abstract":"<p><p>Chondrosarcomas are common bone sarcomas frequently resistant to radiation and chemotherapy, with high recurrence rates, development of metastatic disease, and death. Fibrosarcomas are soft tissue sarcomas associated with poor outcomes. Translocase of outer mitochondrial membrane receptor 20 (TOMM20) is a mitochondrial receptor protein associated with cancer aggressiveness in many cancer subtypes, but the mechanisms remain poorly understood. Here, we studied the effects of TOMM20 overexpression and downregulation on the redox state, mitochondrial oxidative phosphorylation (OXPHOS), and tumor growth using fibrosarcoma and chondrosarcoma models. TOMM20 overexpression increased OXPHOS, NADH, and NADPH with reduced cellular reactive oxygen species (ROS). TOMM20 induced resistance to apoptosis, including with BCL-2 and OXPHOS complex IV inhibitors, but with increased sensitivity to an OXPHOS complex I inhibitor. Also, TOMM20 induced cell growth and migration in vitro and promoted tumor growth in vivo. Conversely, knocking down TOMM20 using CRISPR-Cas9 reduced cancer aggressiveness in vivo in both chondrosarcoma and fibrosarcoma mouse models. In conclusion, TOMM20 is a driver of cancer aggressiveness by OXPHOS, apoptosis resistance, and the maintenance of a reduced state.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2431-2455"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143492933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peripheral blood proteome biomarkers distinguish immunosuppressive features of cancer progression.","authors":"Yeon Ji Park, Jae Won Oh, Hyewon Chung, Jung Won Kwon, Yi Rang Na, Kwang Pyo Kim, Seung Hyeok Seok","doi":"10.1002/1878-0261.13817","DOIUrl":"10.1002/1878-0261.13817","url":null,"abstract":"<p><p>Immune status critically affects cancer progression and therapy responses. This study aimed to identify plasma proteome changes in immunosuppressive cancer and potential biomarkers predicting systemic immunosuppression. Mouse models of syngeneic breast tumors (benign 67NR and malignant 4T1) were used to collect plasma samples. Plasma samples from naive mice and both early- and late-stage tumor-bearing mice were subjected to liquid chromatography-mass spectrometry (LC-MS) analysis. 4T1-bearing mice showed systemic immunosuppression characterized by significant generation of myeloid-derived suppressor cells (MDSCs) as early as 7 days after tumor implantation, unlike 67NR tumors. LC-MS identified 1086 proteins across the five experimental groups, with 27 proteins showing group-specific expression in 4T1 blood compared with 67NR blood. Immune-related proteins osteopontin, lactotransferrin, calreticulin, and peroxiredoxin 2 were selected as potential biomarkers of MDSC-producing breast cancer. These markers were expressed in cancer cells or MDSC in the 4T1 model, and osteopontin and peroxiredoxin 2 were associated with low survival probability and high recurrence in patients with triple-negative breast cancer. Our findings suggest that MDSC-producing immunosuppressive cancers have unique plasma proteomes, offering additional insights into cancer immune status.</p>","PeriodicalId":18764,"journal":{"name":"Molecular Oncology","volume":" ","pages":"2233-2248"},"PeriodicalIF":4.5,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12330930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}