Colorectal cancer (CRC) is a prevalent malignant tumor that poses a significant threat to human health; however, the precise mechanism underlying its onset remains elusive. In this study, we utilized metagenomic sequencing to reveal the dysregulation of intestinal microbiota caused by CRC. Single-cell sequencing data showed elevated mRNA expression of methyltransferase-like protein 3 (METTL3) in CRC, which was correlated with the abundance of intestinal microbiota. Furthermore, we found that METTL3 promotion of CRC progression is microbiota-dependent. Using induced METTL3fl/fl Vil1-cre+/− mice, we identified the microbiota regulated by METTL3 in CRC. Our research indicates that METTL3 leads to high expression of HIF1α, which promotes the expression of lipocalin 2 (LCN2) in CRC cells, inhibiting the abundance of Akkermansia muciniphila, thereby promoting CRC progression.
{"title":"METTL3 facilitates colorectal cancer growth through altering the abundance of intestinal Akkermansia muciniphila","authors":"Ling Wu, Weidong Lian, Rui Bai, Hao Chen, Jianghua Wu, Hanyu Li, Liang Zhao","doi":"10.1038/s41417-025-00949-x","DOIUrl":"10.1038/s41417-025-00949-x","url":null,"abstract":"Colorectal cancer (CRC) is a prevalent malignant tumor that poses a significant threat to human health; however, the precise mechanism underlying its onset remains elusive. In this study, we utilized metagenomic sequencing to reveal the dysregulation of intestinal microbiota caused by CRC. Single-cell sequencing data showed elevated mRNA expression of methyltransferase-like protein 3 (METTL3) in CRC, which was correlated with the abundance of intestinal microbiota. Furthermore, we found that METTL3 promotion of CRC progression is microbiota-dependent. Using induced METTL3fl/fl Vil1-cre+/− mice, we identified the microbiota regulated by METTL3 in CRC. Our research indicates that METTL3 leads to high expression of HIF1α, which promotes the expression of lipocalin 2 (LCN2) in CRC cells, inhibiting the abundance of Akkermansia muciniphila, thereby promoting CRC progression.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1098-1106"},"PeriodicalIF":5.0,"publicationDate":"2025-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144820669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-02DOI: 10.1038/s41417-025-00948-y
Claudia Guerrero, Marta Casal, Cristina Alierta, Eduardo Moreo, Miguel Araujo-Voces, Santiago Uranga, Ana Belén Gómez, Carlos Martín, Nacho Aguiló
Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette–Guerin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-γ) to tumor resistance. Tumor cells exposed to IFN-γ were more resistant to BCG in vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-γ signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.
{"title":"NK cells mediate preventive efficacy of intravenous BCG against lung metastasis in mice","authors":"Claudia Guerrero, Marta Casal, Cristina Alierta, Eduardo Moreo, Miguel Araujo-Voces, Santiago Uranga, Ana Belén Gómez, Carlos Martín, Nacho Aguiló","doi":"10.1038/s41417-025-00948-y","DOIUrl":"10.1038/s41417-025-00948-y","url":null,"abstract":"Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette–Guerin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-γ) to tumor resistance. Tumor cells exposed to IFN-γ were more resistant to BCG in vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-γ signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1090-1097"},"PeriodicalIF":5.0,"publicationDate":"2025-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144768393","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-08-01DOI: 10.1038/s41417-025-00946-0
Ziyun Zhang, Lu Liang, Yi Li, Ye Fan, Yao Liu, Zhifei He, Xiumin Wu, Li Cong, Yiqun Jiang, Tao Wan
Hepatocellular carcinoma (HCC) is the most prevalent primary malignant tumor, with sorafenib as the main treatment for advanced cases. However, the development of resistance to sorafenib, often driven by cancer stemness, significantly limits its therapeutic efficacy. Minichromosome maintenance complex component 10 (MCM10), a critical regulator of DNA replication and tumor progression, has been implicated in cancer stemness and therapeutic resistance. This study utilized datasets from TCGA and ICGC alongside in vitro and vivo experiments on clinical HCC tissues and sorafenib-resistant cell lines to evaluate MCM10’s role in HCC. The Connectivity Map (CMap) was employed to identify TW-37, a potential gene silencing agent targeting MCM10 transcription. The effects of TW-37 on MCM10 expression, cancer stemness, and sorafenib sensitivity were assessed. Elevated MCM10 expression was observed in sorafenib-resistant HCC cell lines and was associated with poor patient outcomes. MCM10 knockout diminished cancer stemness and restored sorafenib sensitivity in resistant cells. Furthermore, TW-37, identified via CMap, effectively downregulated MCM10, reduced cancer stemness, and enhanced sorafenib efficacy, offering a promising therapeutic approach. MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients.
{"title":"Targeting MCM10 disrupts cancer stemness and counteracts sorafenib resistance in hepatocellular carcinoma","authors":"Ziyun Zhang, Lu Liang, Yi Li, Ye Fan, Yao Liu, Zhifei He, Xiumin Wu, Li Cong, Yiqun Jiang, Tao Wan","doi":"10.1038/s41417-025-00946-0","DOIUrl":"10.1038/s41417-025-00946-0","url":null,"abstract":"Hepatocellular carcinoma (HCC) is the most prevalent primary malignant tumor, with sorafenib as the main treatment for advanced cases. However, the development of resistance to sorafenib, often driven by cancer stemness, significantly limits its therapeutic efficacy. Minichromosome maintenance complex component 10 (MCM10), a critical regulator of DNA replication and tumor progression, has been implicated in cancer stemness and therapeutic resistance. This study utilized datasets from TCGA and ICGC alongside in vitro and vivo experiments on clinical HCC tissues and sorafenib-resistant cell lines to evaluate MCM10’s role in HCC. The Connectivity Map (CMap) was employed to identify TW-37, a potential gene silencing agent targeting MCM10 transcription. The effects of TW-37 on MCM10 expression, cancer stemness, and sorafenib sensitivity were assessed. Elevated MCM10 expression was observed in sorafenib-resistant HCC cell lines and was associated with poor patient outcomes. MCM10 knockout diminished cancer stemness and restored sorafenib sensitivity in resistant cells. Furthermore, TW-37, identified via CMap, effectively downregulated MCM10, reduced cancer stemness, and enhanced sorafenib efficacy, offering a promising therapeutic approach. MCM10 plays a pivotal role in promoting cancer stemness and sorafenib resistance in HCC. Targeting MCM10 transcription with TW-37 represents a novel strategy to overcome sorafenib resistance and improve therapeutic outcomes in HCC patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1076-1089"},"PeriodicalIF":5.0,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00946-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144764629","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Escherichia coli L-asparaginase (EcA), a key component of a multi-drug acute lymphatic leukemia (ALL) treatment regimen, has several limitations that reduce its therapeutic efficacy. The major disadvantages include immunogenicity, serum instability, shorter half-life, and accompanying glutaminase activity that causes neurotoxicity and pancreatitis. Pegylated asparaginase and Erwinase have better therapeutic potential, but they are expensive. Using site-directed mutagenesis, we created several EcA variants by substituting specific amino acid residues at the dimer-dimer interface and B-cell epitope regions. After several rounds of screening and selection, we identified two EcA variants viz. K288S/Y176F (KSY-17) and K288S/Y176F/W66Y (KSYW-17), which showed comparable asparaginase activity to wild-type (WT) and significantly less glutaminase activity (30.36 U/mg for WT vs 1.54 and 0.99 U/mg for KSY-17 and KSYW-17). KSYW-17 was less immunogenic than WT, eliciting 4.8–5.3-fold and 2.4–3.8-fold less IgG and IgM responses, respectively. Compared to WT EcA, we also observed significantly less (~1.5-2-fold) binding of these variants to pre-existing antibodies in ALL patients’ serum. Pharmacokinetic studies showed that KSY-17 (213.3 ± 6.5 min) and KSYW-17 (244.8 ± 35.5 min) had longer plasma half-lives than WT (101.1 ± 5.1 min). Both variants showed no toxicity up to 5000 IU/kg (single dose) and 1600 IU/kg (repeat dose) in mice. ALL xenograft mice studies showed a 90% and 70% reduction in leukemia burden in KSY-17 and KSYW-17 administered mice, respectively, as compared to 30% for WT after repeat dose administration, accompanied by significantly higher mice survival (100% vs. 70% vs. 10% for KSY-17 vs. KSYW-17 vs. WT). Overall, the engineered EcA variants’ showed improved therapeutic efficacy, thus making them promising candidates for primary and relapsed ALL treatment.
大肠杆菌l -天冬酰胺酶（EcA）是一种多药急性淋巴白血病（ALL）治疗方案的关键组成部分，它的一些局限性降低了其治疗效果。主要的缺点包括免疫原性、血清不稳定、半衰期较短以及伴随的谷氨酰胺酶活性导致神经毒性和胰腺炎。聚乙二醇化天冬酰胺酶和Erwinase具有较好的治疗潜力，但价格昂贵。利用定点诱变技术，我们通过替换二聚体界面和b细胞表位区域的特定氨基酸残基，创造了几种EcA变体。经过多轮筛选和筛选，我们鉴定出两个EcA变异，即K288S/Y176F （KSY-17）和K288S/Y176F/W66Y (KSYW-17)，它们的天冬酰胺酶活性与野生型（WT）相当，谷氨酰胺酶活性显著低于野生型（30.36 U/mg，而KSY-17和KSYW-17分别为1.54和0.99 U/mg）。KSYW-17的免疫原性比WT低，IgG和IgM的应答分别低4.8-5.3倍和2.4-3.8倍。与WT EcA相比，我们还观察到这些变体与ALL患者血清中已有抗体的结合明显减少（约1.5-2倍）。药代动力学研究表明，KSYW-17（213.3±6.5 min）和KSYW-17（244.8±35.5 min）的血浆半衰期比WT（101.1±5.1 min）更长。两种变体在小鼠中高达5000 IU/kg（单次剂量）和1600 IU/kg（重复剂量）均无毒性。所有异种移植小鼠研究显示，KSY-17和KSYW-17给药小鼠白血病负担分别减少90%和70%，而WT重复给药后为30%，同时小鼠存活率显著提高（KSY-17 100% vs. 70% vs. KSYW-17 vs. WT 10%）。总体而言，经工程修饰的EcA变体显示出更好的治疗效果，因此使它们成为原发性和复发性ALL治疗的有希望的候选者。
{"title":"Engineered L-asparaginase variants with enhanced therapeutic properties to improve treatment of childhood acute lymphatic leukemia","authors":"Mainak Biswas, Soumika Sengupta, Khushboo A. Gandhi, Saurabh Kumar Gupta, Poonam B. Gera, Bhagyashri Soumya Nayak, Manaswini Jagadeb, Vikram Gota, Avinash Sonawane","doi":"10.1038/s41417-024-00865-6","DOIUrl":"10.1038/s41417-024-00865-6","url":null,"abstract":"Escherichia coli L-asparaginase (EcA), a key component of a multi-drug acute lymphatic leukemia (ALL) treatment regimen, has several limitations that reduce its therapeutic efficacy. The major disadvantages include immunogenicity, serum instability, shorter half-life, and accompanying glutaminase activity that causes neurotoxicity and pancreatitis. Pegylated asparaginase and Erwinase have better therapeutic potential, but they are expensive. Using site-directed mutagenesis, we created several EcA variants by substituting specific amino acid residues at the dimer-dimer interface and B-cell epitope regions. After several rounds of screening and selection, we identified two EcA variants viz. K288S/Y176F (KSY-17) and K288S/Y176F/W66Y (KSYW-17), which showed comparable asparaginase activity to wild-type (WT) and significantly less glutaminase activity (30.36 U/mg for WT vs 1.54 and 0.99 U/mg for KSY-17 and KSYW-17). KSYW-17 was less immunogenic than WT, eliciting 4.8–5.3-fold and 2.4–3.8-fold less IgG and IgM responses, respectively. Compared to WT EcA, we also observed significantly less (~1.5-2-fold) binding of these variants to pre-existing antibodies in ALL patients’ serum. Pharmacokinetic studies showed that KSY-17 (213.3 ± 6.5 min) and KSYW-17 (244.8 ± 35.5 min) had longer plasma half-lives than WT (101.1 ± 5.1 min). Both variants showed no toxicity up to 5000 IU/kg (single dose) and 1600 IU/kg (repeat dose) in mice. ALL xenograft mice studies showed a 90% and 70% reduction in leukemia burden in KSY-17 and KSYW-17 administered mice, respectively, as compared to 30% for WT after repeat dose administration, accompanied by significantly higher mice survival (100% vs. 70% vs. 10% for KSY-17 vs. KSYW-17 vs. WT). Overall, the engineered EcA variants’ showed improved therapeutic efficacy, thus making them promising candidates for primary and relapsed ALL treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1062-1075"},"PeriodicalIF":5.0,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144752510","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-26DOI: 10.1038/s41417-025-00945-1
Ina Valeria Zurlo, Fausto Rosa, Diana Giannarelli, Giovanni Trovato, Massimiliano Salati, Andrea Spallanzani, Michele Basso, Carmelo Pozzo, Sergio Alfieri, Giampaolo Tortora, Antonia Strippoli
The role of adjuvant chemotherapy (aCT) in gastric and esophago-gastric junction cancer (GC/EGJC) remains controversial. This study (ASTER study) aimed to compare the clinical outcomes of De Gramont (DG) versus XELOX/FOLFOX (OXA) regimens in a European real-world setting. This retrospective, bicentric study included patients treated with aCT between January 2001 and January 2018. A propensity score-matched (PSM) analysis was performed to compare oncological outcomes between DG and OXA regimens. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Statistical analyses included the chi-square test, Kaplan–Meier method, and Cox proportional hazards modeling. Among 255 patients (127 DG, 128 OXA), 160 were matched (80 per arm) by PSM. Median DFS and OS did not differ significantly between groups (mDFS: 102.3 vs. 85.4 months, p = 0.91; mOS: 119.5 vs. 89.8 months, p = 0.69). In PSM-adjusted analysis, DG showed a trend towards longer DFS (p = 0.052) and significantly improved OS (p = 0.016). Multivariate analysis confirmed age, ECOG PS, resection margins, and stage as major prognostic factors. DG and OXA regimens demonstrated similar efficacy in the adjuvant treatment of resected GC/GEJC in a European cohort. Further prospective studies are warranted to optimize regimen selection and refine patient stratification.
{"title":"Real-world outcomes of Adjuvant De Gramont versus Xelox chemotherapy in reSected gasTric cancER: a propensity score-matched analysis (ASTER study)","authors":"Ina Valeria Zurlo, Fausto Rosa, Diana Giannarelli, Giovanni Trovato, Massimiliano Salati, Andrea Spallanzani, Michele Basso, Carmelo Pozzo, Sergio Alfieri, Giampaolo Tortora, Antonia Strippoli","doi":"10.1038/s41417-025-00945-1","DOIUrl":"10.1038/s41417-025-00945-1","url":null,"abstract":"The role of adjuvant chemotherapy (aCT) in gastric and esophago-gastric junction cancer (GC/EGJC) remains controversial. This study (ASTER study) aimed to compare the clinical outcomes of De Gramont (DG) versus XELOX/FOLFOX (OXA) regimens in a European real-world setting. This retrospective, bicentric study included patients treated with aCT between January 2001 and January 2018. A propensity score-matched (PSM) analysis was performed to compare oncological outcomes between DG and OXA regimens. Primary endpoints were disease-free survival (DFS) and overall survival (OS). Statistical analyses included the chi-square test, Kaplan–Meier method, and Cox proportional hazards modeling. Among 255 patients (127 DG, 128 OXA), 160 were matched (80 per arm) by PSM. Median DFS and OS did not differ significantly between groups (mDFS: 102.3 vs. 85.4 months, p = 0.91; mOS: 119.5 vs. 89.8 months, p = 0.69). In PSM-adjusted analysis, DG showed a trend towards longer DFS (p = 0.052) and significantly improved OS (p = 0.016). Multivariate analysis confirmed age, ECOG PS, resection margins, and stage as major prognostic factors. DG and OXA regimens demonstrated similar efficacy in the adjuvant treatment of resected GC/GEJC in a European cohort. Further prospective studies are warranted to optimize regimen selection and refine patient stratification.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 10","pages":"1054-1061"},"PeriodicalIF":5.0,"publicationDate":"2025-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.comhttps://www.nature.com/articles/s41417-025-00945-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717621","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Breast cancer (BC) remains a leading cause of cancer-related mortality, largely due to its aggressive proliferation and metastatic potential. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumor development and progression. This study explored the functional role and mechanism of Lnc-PRSS23-AS1 in BC. We assessed Lnc-PRSS23-AS1 expression and localization using fluorescence in situ hybridization, qRT-PCR, and Western blotting in BC tissues and cell lines. Binding interactions between Lnc-PRSS23-AS1, miR-3176, and Y-box binding protein 1 (YBX1) were validated through dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation. Lnc-PRSS23-AS1 was significantly upregulated in BC and predominantly localized in the cytoplasm. Silencing Lnc-PRSS23-AS1 or overexpressing miR-3176 suppressed BC cell proliferation, migration, and invasion in vitro and in vivo. Conversely, miR-3176 inhibition or YBX1 overexpression reversed these effects. Mechanistically, Lnc-PRSS23-AS1 promoted YBX1 protein expression by acting as a molecular sponge for miR-3176. These findings highlight the Lnc-PRSS23-AS1/miR-3176/YBX1 axis as a driver of BC progression and suggest Lnc-PRSS23-AS1 as a potential therapeutic target for breast cancer treatment.
{"title":"Long non-coding RNA PRSS23-AS1 as ceRNA promotes breast cancer progression by regulating EMT via miR-3176 /YBX1 axis","authors":"Yun Huang, Mudan Feng, Yiwei Jiang, Maihuan Wang, Mingkun Wang, Zhen Cao","doi":"10.1038/s41417-025-00943-3","DOIUrl":"10.1038/s41417-025-00943-3","url":null,"abstract":"Breast cancer (BC) remains a leading cause of cancer-related mortality, largely due to its aggressive proliferation and metastatic potential. Long non-coding RNAs (lncRNAs) have emerged as key regulators in tumor development and progression. This study explored the functional role and mechanism of Lnc-PRSS23-AS1 in BC. We assessed Lnc-PRSS23-AS1 expression and localization using fluorescence in situ hybridization, qRT-PCR, and Western blotting in BC tissues and cell lines. Binding interactions between Lnc-PRSS23-AS1, miR-3176, and Y-box binding protein 1 (YBX1) were validated through dual-luciferase reporter assays, RNA pulldown, and RNA immunoprecipitation. Lnc-PRSS23-AS1 was significantly upregulated in BC and predominantly localized in the cytoplasm. Silencing Lnc-PRSS23-AS1 or overexpressing miR-3176 suppressed BC cell proliferation, migration, and invasion in vitro and in vivo. Conversely, miR-3176 inhibition or YBX1 overexpression reversed these effects. Mechanistically, Lnc-PRSS23-AS1 promoted YBX1 protein expression by acting as a molecular sponge for miR-3176. These findings highlight the Lnc-PRSS23-AS1/miR-3176/YBX1 axis as a driver of BC progression and suggest Lnc-PRSS23-AS1 as a potential therapeutic target for breast cancer treatment.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"1018-1029"},"PeriodicalIF":5.0,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144706424","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-23DOI: 10.1038/s41417-025-00935-3
Aline Habib, Rose Mamistvalov, Dalit Ben-Yosef
Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients.
{"title":"Rapamycin rescues APC-mutated colon organoid differentiation","authors":"Aline Habib, Rose Mamistvalov, Dalit Ben-Yosef","doi":"10.1038/s41417-025-00935-3","DOIUrl":"10.1038/s41417-025-00935-3","url":null,"abstract":"Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by germline mutations in the adenomatous polyposis coli (APC) gene. This leads to numerous colorectal adenomas and a high risk of colorectal cancer (CRC). Our stem cell-derived colon organoid model revealed that a heterozygous APC mutation is sufficient to induce colorectal cancer formation. We found a link between APC mutation type, organoid maturation and FAP severity. Here, we show that severe germline mutations in hESCs employ diverse mechanisms of carcinogenesis. FAP1-hESCs expressing a truncated 332-amino acid protein exhibited a hyperactivated mTOR pathway, including PTEN inactivation and increased S6K1 and eIF4E activation. This affected oncogenic c-Myc expression and contributed to apoptosis resistance. Rapamycin treatment restored differentiation potential in FAP1 organoids but not FAP2 organoids, which expressed a larger truncated protein without mTOR pathway activation. Our in vitro colon organoids system findings were validated in human patients. Notably, a colon from a FAP1 patient exhibited high expression of mTOR pathway proteins. These findings highlight the potential of rapamycin for personalized therapy in FAP patients with distinct mTOR-mediated APC mutations. Our colon organoid model is valuable for studying CRC and developing new diagnostic, preventive, and therapeutic approaches to prevent or delay tumorigenesis in FAP patients.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"1008-1017"},"PeriodicalIF":5.0,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396962/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144697725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-22DOI: 10.1038/s41417-025-00923-7
Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef
Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins’ mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.
{"title":"Predicting colorectal cancer risk in FAP patients using patient-specific organoids","authors":"Aline Habib, Rose Mamistvalov, Mira Malcov, Dalit Ben-Yosef","doi":"10.1038/s41417-025-00923-7","DOIUrl":"10.1038/s41417-025-00923-7","url":null,"abstract":"Colorectal cancer (CRC), a prevalent global cancer, is mostly sporadic. Familial adenomatous polyposis (FAP), arises from APC germline mutations. We established FAP-human embryonic stem cell lines (FAP1,2,3) with distinct APC mutations and differentiated them into colon organoids to study cancer development. While normal expressing APC lines and FAP3 formed complex organoids, FAP1,2 failed to differentiate. By utilizing CRISPR editing to correct APC mutations in FAP1,2, we succeeded in restoring their ability to form complex organoids expressing colon gene (CDX2). To elucidate the truncated APC proteins’ mechanism of action, we used AlphaFold2 algorithm to model their secondary structures. Structural analysis of the normal phenotype organoids (normal and FAP3) revealed 5-6 salt bridges only at the N-terminal oligomerization domain. In contrast, analysis of disease organoids-phenotype (FAP1,2) revealed a production of novel salt bridges, likely act in a dominant-negative manner on full-length APC, disrupting APC function and promoting tumorigenesis. Our study underscores the critical role of germline APC mutations in colon cancer initiation, revealing how specific mutations influence disease severity. By deciphering APC structure-function relationships, we illuminate potential therapies and the molecular underpinnings of APC mutations that precede clinical presentation.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"997-1007"},"PeriodicalIF":5.0,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396958/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144688941","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-19DOI: 10.1038/s41417-025-00941-5
Kristin M. Adams, Jae-Rim Wendt, Josie Wood, Sydney Olson, Ryan Moreno, Zhongmou Jin, Srihari Gopalan, Jessica D. Lang
Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes. This is the largest quantitative database of quantitative cisplatin and carboplatin response in ovarian cancer cell lines. Our results demonstrate that cell lines largely fall either well above or below the clinical maximally achievable dose (Cmax) of each compound. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4. Combined with clinically resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models, we performed differential expression analysis for seven platinum-resistant isogenic pairs. Common themes in differential expression were innate immunity/STAT activation, epithelial-to-mesenchymal transition (EMT) and stemness, and platinum influx/efflux regulators. We also performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, suggesting that this is a transient state. Overall, this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.
{"title":"Cell-intrinsic platinum response and associated genetic and gene expression signatures in ovarian cancer","authors":"Kristin M. Adams, Jae-Rim Wendt, Josie Wood, Sydney Olson, Ryan Moreno, Zhongmou Jin, Srihari Gopalan, Jessica D. Lang","doi":"10.1038/s41417-025-00941-5","DOIUrl":"10.1038/s41417-025-00941-5","url":null,"abstract":"Ovarian cancers are still largely treated with platinum-based chemotherapy as the standard of care, yet few biomarkers of clinical response have had an impact on clinical decision making. Previous work has relied on poor models of the most common subtypes of epithelial ovarian cancers and necessitates a careful examination of the most suitable in vitro models. We performed extensive drug dose response assays and gene expression profiling on 36 ovarian cancer cell lines across over seven subtypes. This is the largest quantitative database of quantitative cisplatin and carboplatin response in ovarian cancer cell lines. Our results demonstrate that cell lines largely fall either well above or below the clinical maximally achievable dose (Cmax) of each compound. We performed differential expression analysis for high-grade serous ovarian carcinoma cell lines. Further, we generated two platinum-resistant derivatives each for OVCAR3 and OVCAR4. Combined with clinically resistant PEO1/PEO4/PEO6 and PEA1/PEA2 isogenic models, we performed differential expression analysis for seven platinum-resistant isogenic pairs. Common themes in differential expression were innate immunity/STAT activation, epithelial-to-mesenchymal transition (EMT) and stemness, and platinum influx/efflux regulators. We also performed copy number signature analysis and orthogonal measures of homologous recombination deficiency (HRD) scar scores and copy number burden, which is the first report to our knowledge applying field-standard copy number signatures to ovarian cancer cell lines. We also examined markers and functional readouts of stemness that revealed that cell lines are poor models for examination of stemness contributions to platinum resistance, suggesting that this is a transient state. Overall, this study serves as a resource to determine the best cell lines to utilize for ovarian cancer research on certain subtypes and platinum response studies, as well as sparks new hypotheses for future study in ovarian cancer.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"985-996"},"PeriodicalIF":5.0,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12396967/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-07-18DOI: 10.1038/s41417-025-00917-5
Xiaopeng Yu, Yutian Tang, Junjie Niu, Jinyang Hu
This study aimed to investigate the molecular mechanisms underlying ulcerative colitis (UC)-associated colorectal cancer (CRC) development and identify potential therapeutic targets through integrated multi-omics analysis. Mendelian randomization (MR) analysis, combined with bioinformatics approaches including differential gene expression analysis, protein-protein interaction network construction, gene set enrichment analysis, and single-cell RNA sequencing, was employed. Data were obtained from GEO, TCGA, and genome-wide association study (GWAS) databases. Drug prediction and molecular docking were performed using DSigDB and AutoDockTools. A total of 48 shared genes were identified between UC and CRC, with MMP1 emerging as a significant protective factor (OR = 0.766; 95% CI = 0.593–0.989, P = 0.041). MMP1 demonstrated strong diagnostic potential (AUC = 0.927, 95% CI = 0.895–0.959) and was functionally associated with immune regulation and metabolic pathways. Single-cell analysis revealed predominant MMP1 expression in fibroblasts and immune cells, while immune infiltration analysis showed significant correlations with CD8⁺ T cells and NK cells. Mediation MR analysis indicated that 63.33% of MMP1’s protective effect was mediated through naive-mature B cells. Drug prediction identified ilomastat as a potential MMP1 inhibitor with strong binding affinity (binding energy = –7.17 kcal/mol). These findings provide evidence for MMP1’s protective role in UC-associated CRC through immune microenvironment modulation, highlighting its potential as a diagnostic biomarker and therapeutic target. The identification of ilomastat as a potential MMP1 inhibitor offers new avenues for targeted therapy in inflammation-associated cancers.
本研究旨在通过综合多组学分析探讨溃疡性结肠炎（UC）相关结直肠癌（CRC）发展的分子机制，并确定潜在的治疗靶点。采用孟德尔随机化（MR）分析，结合生物信息学方法，包括差异基因表达分析、蛋白质相互作用网络构建、基因集富集分析和单细胞RNA测序。数据来自GEO、TCGA和全基因组关联研究（GWAS）数据库。使用DSigDB和AutoDockTools进行药物预测和分子对接。UC和CRC共有48个共享基因，其中MMP1是一个重要的保护因子(OR = 0.766；95% ci = 0.593-0.989, p = 0.041)。MMP1表现出较强的诊断潜力（AUC = 0.927, 95% CI = 0.895-0.959），并与免疫调节和代谢途径相关。单细胞分析显示MMP1在成纤维细胞和免疫细胞中主要表达，免疫浸润分析显示CD8 +与T细胞和NK细胞有显著相关性。介导MR分析表明，63.33%的MMP1保护作用是通过幼稚成熟B细胞介导的。药物预测发现伊洛司他是一种潜在的MMP1抑制剂，具有很强的结合亲和力（结合能= -7.17 kcal/mol）。这些发现为MMP1通过免疫微环境调节在uc相关结直肠癌中发挥保护作用提供了证据，突出了其作为诊断生物标志物和治疗靶点的潜力。伊洛马司他作为潜在的MMP1抑制剂的鉴定为炎症相关癌症的靶向治疗提供了新的途径。
{"title":"Integrated multidimensional bioinformatics analysis of the molecular mechanisms of ulcerative colitis-associated colorectal cancer and MMP1 as a potential therapeutic target","authors":"Xiaopeng Yu, Yutian Tang, Junjie Niu, Jinyang Hu","doi":"10.1038/s41417-025-00917-5","DOIUrl":"10.1038/s41417-025-00917-5","url":null,"abstract":"This study aimed to investigate the molecular mechanisms underlying ulcerative colitis (UC)-associated colorectal cancer (CRC) development and identify potential therapeutic targets through integrated multi-omics analysis. Mendelian randomization (MR) analysis, combined with bioinformatics approaches including differential gene expression analysis, protein-protein interaction network construction, gene set enrichment analysis, and single-cell RNA sequencing, was employed. Data were obtained from GEO, TCGA, and genome-wide association study (GWAS) databases. Drug prediction and molecular docking were performed using DSigDB and AutoDockTools. A total of 48 shared genes were identified between UC and CRC, with MMP1 emerging as a significant protective factor (OR = 0.766; 95% CI = 0.593–0.989, P = 0.041). MMP1 demonstrated strong diagnostic potential (AUC = 0.927, 95% CI = 0.895–0.959) and was functionally associated with immune regulation and metabolic pathways. Single-cell analysis revealed predominant MMP1 expression in fibroblasts and immune cells, while immune infiltration analysis showed significant correlations with CD8⁺ T cells and NK cells. Mediation MR analysis indicated that 63.33% of MMP1’s protective effect was mediated through naive-mature B cells. Drug prediction identified ilomastat as a potential MMP1 inhibitor with strong binding affinity (binding energy = –7.17 kcal/mol). These findings provide evidence for MMP1’s protective role in UC-associated CRC through immune microenvironment modulation, highlighting its potential as a diagnostic biomarker and therapeutic target. The identification of ilomastat as a potential MMP1 inhibitor offers new avenues for targeted therapy in inflammation-associated cancers.","PeriodicalId":9577,"journal":{"name":"Cancer gene therapy","volume":"32 9","pages":"973-984"},"PeriodicalIF":5.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667264","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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