bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–09–15
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Gut microbial metabolism in ferroptosis and colorectal cancer.
  2. Intestinal organoids with an autologous immune compartment.
  3. Five latent factors underlie response to immunotherapy.
  4. Human intestinal immuno-organoids.
  5. Protocol to characterize mouse intestinal epithelial cell lineage using Opal multiplex immunofluorescence.
  6. CCDC113 promotes colorectal cancer tumorigenesis and metastasis via TGF-β signaling pathway.
  7. Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated colorectal cancer.
  8. The SW480 cell line as a model of resident and migrating colon cancer stem cells.
  9. Identification of PFKFB3 as a key factor in the development of colorectal cancer and immunotherapy resistance.
  10. Short-chain fatty acids play a positive role in colorectal cancer.
  11. Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer.
  1. Trends Cell Biol. 2024 Sep 10. pii: S0962-8924(24)00163-6. [Epub ahead of print]
    Gut microbial metabolism in ferroptosis and colorectal cancer.
    Weiwei Cui, Meng Hao, Xin Yang, Chengqian Yin, Bo Chu.
      Ferroptosis is programmed cell death induced by iron-driven lipid peroxidation. Numerous studies have shown that ferroptosis is implicated in the progression of colorectal cancer (CRC) and has emerged as a promising strategy to combat therapy-resistant CRC. While the intrinsic antiferroptotic and proferroptotic pathways in CRC cells have been well characterized, extrinsic metabolism pathways regulating ferroptosis in CRC pathogenesis remain less understood. Emerging evidence shows that gut microbial metabolism is tightly correlated with the progression of CRC. This review provides an overview of gut microbial metabolism and discusses how these metabolites derived from intestinal microflora contribute to cancer plasticity through ferroptosis. Targeting gut microbe-mediated ferroptosis is a potential approach for CRC treatment.
    Keywords:  colorectal cancer; ferroptosis; gut microbial metabolism; host metabolism
    DOI:  https://doi.org/10.1016/j.tcb.2024.08.006
  2. Nat Biotechnol. 2024 Sep;42(9): 1357
    Intestinal organoids with an autologous immune compartment.
    Iris Marchal.
      
    DOI:  https://doi.org/10.1038/s41587-024-02389-8
  3. Nat Genet. 2024 Sep 12.
    Five latent factors underlie response to immunotherapy.
    Joseph Usset, Axel Rosendahl Huber, Maria A Andrianova, Eduard Batlle, Joan Carles, Edwin Cuppen, Elena Elez, Enriqueta Felip, Marina Gómez-Rey, Deborah Lo Giacco, Francisco Martinez-Jimenez, Eva Muñoz-Couselo, Lillian L Siu, Josep Tabernero, Ana Vivancos, Ferran Muiños, Abel Gonzalez-Perez, Nuria Lopez-Bigas.
      Only a subset of patients treated with immune checkpoint inhibitors (CPIs) respond to the treatment, and distinguishing responders from non-responders is a major challenge. Many proposed biomarkers of CPI response and survival probably represent alternative measurements of the same aspects of the tumor, its microenvironment or the host. Thus, we currently ignore how many truly independent biomarkers there are. With an unbiased analysis of genomics, transcriptomics and clinical data of a cohort of patients with metastatic tumors (n = 479), we discovered five orthogonal latent factors: tumor mutation burden, T cell effective infiltration, transforming growth factor-beta activity in the microenvironment, prior treatment and tumor proliferative potential. Their association with CPI response and survival was observed across all tumor types and validated across six independent cohorts (n = 1,491). These five latent factors constitute a frame of reference to organize current and future knowledge on biomarkers of CPI response and survival.
    DOI:  https://doi.org/10.1038/s41588-024-01899-0
  4. Nat Genet. 2024 Sep;56(9): 1765
    Human intestinal immuno-organoids.
    Chiara Anania.
      
    DOI:  https://doi.org/10.1038/s41588-024-01927-z
  5. STAR Protoc. 2024 Sep 10. pii: S2666-1667(24)00468-4. [Epub ahead of print]5(3): 103303
    Protocol to characterize mouse intestinal epithelial cell lineage using Opal multiplex immunofluorescence.
    Anxo Martinez-Ordoñez, Hiroto Kinoshita, Tania Cid-Diaz, Angeles Duran, Marta Osrodek, Maria T Diaz-Meco, Jorge Moscat.
      Applying Opal multiplex immunofluorescence (OMI) to characterize intestinal tissues of genetically engineered mouse models provides an excellent tool for studying complex processes. However, detecting appropriate signals from multiple target molecules is challenging. Here, we present a protocol to characterize mouse intestinal epithelial cell lineage using OMI. We describe steps for processing small intestine and colonic mouse tissues and designing and optimizing panels for OMI in mouse intestinal tissues. We then detail procedures for performing a quantitative evaluation of acquired images. For complete details on the use and execution of this protocol, please refer to Kinoshita et al.1.
    Keywords:  Cancer; In Situ Hybridization; Microscopy; Model Organisms; Molecular Biology; Molecular/Chemical Probes; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2024.103303
  6. Cell Death Dis. 2024 Sep 11. 15(9): 666
    CCDC113 promotes colorectal cancer tumorigenesis and metastasis via TGF-β signaling pathway.
    Chenying Hou, Yanmei Yang, Peiwen Wang, Huimin Xie, Shuiling Jin, Liangbo Zhao, Guanghua Wu, Hao Xing, Hong Chen, Benyu Liu, Chunyan Du, Xiao Sun, Luyun He.
      Colorectal cancer (CRC) is the second leading cause of cancer-related mortality worldwide. Although CRC patients' survival is improved with surgical resection and immunotherapy, metastasis and recurrence remain major problems leading to poor prognosis. Therefore, exploring pathogenesis and identifying specific biomarkers are crucial for CRC early diagnosis and targeted therapy. CCDC113, a member of CCDC families, has been reported to play roles in ciliary assembly, ciliary activity, PSCI, asthma and early lung cancer diagnosis. However, the functions of CCDC113 in CRC still remain unclear. In this study, we find that CCDC113 is significantly highly expressed in CRC. High expression of CCDC113 is significantly correlated with CRC patients' poor prognosis. CCDC113 is required for CRC tumorigenesis and metastasis. RNA-seq and TCGA database analysis indicate that CCDC113 is positively correlated with TGF-β signaling pathway. TGF-β signaling pathway inhibitor galunisertib could reverse the increased proliferation and migration ability of CRC cells caused by CCDC113 overexpression in vitro and in vivo. These results indicate that CCDC113 promotes CRC tumorigenesis and metastasis via TGF-β signaling pathway. In conclusion, it is the first time to explore the functions and mechanisms of CCDC113 in CRC tumorigenesis and metastasis. And CCDC113 may be a potential biomarker and therapeutic target for CRC intervention.
    DOI:  https://doi.org/10.1038/s41419-024-07036-3
  7. Clin Cancer Res. 2024 Sep 13.
    Epigenome reprogramming through H3K27 and H3K4 trimethylation as a resistance mechanism to DNA methylation inhibition in BRAFV600E-mutated colorectal cancer.
    Hey Min Lee, Ajay Kumar Saw, Van K Morris, Stefania Napolitano, Christopher Bristow, Sanjana Srinivasan, Michael Peoples, Alexey Sorokin, Preeti Kanikarla Marie, Jonathan Schulz, Anand K Singh, Christopher Terranova, Oluwadara Coker, Abhinav Jain, Scott Kopetz, Kunal Rai.
       PURPOSE: BRAFV600E-mutated colorectal cancer (CRC) exhibits a strong correlation with DNA hypermethylation suggesting this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E CRC in vivo.
    EXPERIMENTAL DESIGN: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E CRC models.
    RESULTS: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor suppressor genes. Combined inhibition of PRC activity through EZH2 inhibitor with 5-azacitidine treatment additively improved efficacies in BRAFV600E CRC cells.
    CONCLUSIONS: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E CRC, and simultaneous blockade of DNMT and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated CRC.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-24-1166
  8. iScience. 2024 Sep 20. 27(9): 110658
    The SW480 cell line as a model of resident and migrating colon cancer stem cells.
    Mathijs P Verhagen, Tong Xu, Roberto Stabile, Rosalie Joosten, Francesco A Tucci, Martin van Royen, Marco Trerotola, Saverio Alberti, Andrea Sacchetti, Riccardo Fodde.
      Intra-tumor heterogeneity, i.e., the presence of diverse cell types and subpopulations within tumors, presents a significant obstacle in cancer treatment due to its negative consequences for resistance to therapy and disease recurrence. However, the mechanisms that underlie intra-tumor heterogeneity and result in the plethora of different cancer cells within a single lesion remain poorly understood. Here, we leverage the SW480 cell line as a model system to investigate the molecular and functional diversity of colon cancer cells. Through a combination of fluorescence-activated cell sorting (FACS) analysis and transcriptomic profiling, we identified three distinct subpopulations, namely resident cancer stem cells (rCSCs), migratory CSCs (mCSCs), and high-relapse cells (HRCs). These subpopulations show varying Wnt signaling levels and gene expression profiles mirroring their stem-like and functional properties. Examination of publicly available spatial transcriptomic data confirms the presence of these subpopulations in patient-derived cancers and reveals their distinct spatial distribution relative to the tumor microenvironment.
    Keywords:  cancer; cell biology; molecular biology; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2024.110658
  9. Clin Exp Med. 2024 Sep 12. 24(1): 219
    Identification of PFKFB3 as a key factor in the development of colorectal cancer and immunotherapy resistance.
    Si Lu, Rongjie Zhao, Yicheng Han, Shengpeng Shao, Yaming Ji, Jinku Zhang, Hongming Pan, Jiachun Sun, Yuxiong Feng.
      Resistance to immunotherapy poses a significant challenge in the treatment of colorectal cancer (CRC), and the underlying mechanisms are not fully understood. Recent studies have implicated PFKFB3, a crucial glycolytic enzyme, in shaping the tumor microenvironment in CRC. Our study aimed to systematically study the role of PFKFB3 in CRC. Bioinformatic analysis revealed that PFKFB3 expression is notably elevated in CRC tissues compared to normal counterparts. In vivo experiments confirmed that suppressing PFKFB3 reduces the tumorigenesis of CRC. We identified multiple cancer-associated pathways positively correlated with high expression of PFKFB3, such as epithelial-mesenchymal transition (EMT), hypoxia, KRAS signaling, angiogenesis, PI3K/AKT/mTOR, Hedgehog, and Notch pathways. Additionally, PFKFB3 exhibited significant correlations with various immune-related pathways, including complement, IL-2/STAT5, IL-6/JAK/STAT3, IFN-α/IFN-γ, TGF-β, and TNF-α/NF-κB, as well as several immunosuppressive cell markers found in regulatory T cells (CCR8, TGFB1, STAT5B, FOXP3), M2 macrophages (CD163, VSIG4, MS4A4A), T cell exhaustion markers (CTLA-4, PDCD1, LAG3), and PD-L1. Intriguingly, increased PFKFB3 expression was observed in PD-L1 blockade-resistant patients and was associated with shorter overall survival. In a nutshell, PFKFB3 plays an important role in CRC tumorigenesis and resistance to immunotherapy. Targeting PFKFB3 inhibits tumor formation and enhances the efficacy of immunotherapy. Our findings underscore the functions of PFKFB3 in CRC, shedding light on both cancer-related and immunosuppressive pathways.
    Keywords:  Colorectal cancer; Immunotherapy resistance; PFKFB3; Tumorigenesis
    DOI:  https://doi.org/10.1007/s10238-024-01479-w
  10. Discov Oncol. 2024 Sep 10. 15(1): 425
    Short-chain fatty acids play a positive role in colorectal cancer.
    Gang Liu, Jingtong Tang, Jianping Zhou, Ming Dong.
      Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the colon and are thought to be protective against gastrointestinal disease. SCFAs such as acetate, propionate and butyrate are important metabolites in the maintenance of intestinal homeostasis and have been shown to be beneficial in colorectal cancer (CRC). SCFAs are responsible for maintaining a normal intestinal barrier and exhibit numerous immunomodulatory functions. In this review article, we will discuss the metabolism and mechanism of action of SCFAs and their effects on the CRC, with particular emphasis on dietary fiber treatment and the clinical research progress.
    Keywords:  Colorectal cancer; Research progress; Short-chain fatty acids
    DOI:  https://doi.org/10.1007/s12672-024-01313-5
  11. Cancer Res. 2024 Sep 09.
    Cancer-Associated Fibroblasts Expressing Sulfatase 1 Facilitate VEGFA-Dependent Microenvironmental Remodeling to Support Colorectal Cancer.
    Huijuan Wang, Jiaxin Chen, Xiaoyu Chen, Yingqiang Liu, Jiawei Wang, Qing Meng, Huogang Wang, Ying He, Yujia Song, Jingyun Li, Zhenyu Ju, Peng Xiao, Junbin Qian, Zhangfa Song.
      Tumor stroma plays a critical role in fostering tumor progression and metastasis. Cancer-associated fibroblasts (CAFs) are a major component of the tumor stroma. Identifying the key molecular determinants for the pro-tumor properties of CAFs could enable the development of more effective treatment strategies. Herein, through analyses of single-cell sequencing data, we identified a population of CAFs expressing high levels of sulfatase 1 (SULF1), which was associated with poor prognosis in colorectal cancer (CRC) patients. CRC models using mice with conditional SULF1 knockout in fibroblasts revealed the tumor-supportive function of SULF1+ CAFs. Mechanistically, SULF1+ CAFs enhanced the release of vascular endothelial growth factor A (VEGFA) from heparan sulfate proteoglycan (HSPG). The increased bioavailability of VEGFA initiated the deposition of extracellular matrix (ECM) and enhanced angiogenesis. In addition, intestinal microbiota-produced butyrate suppressed SULF1 expression in CAFs through its HDAC inhibitory activity. The insufficient butyrate production in CRC patients increased the abundance of SULF1+ CAFs, thereby promoting tumor progression. Importantly, tumor growth inhibition by HDAC inhibition was dependent on SULF1 expression in CAFs, and CRC patients with more SULF1+ CAFs were more responsive to treatment with the HDAC inhibitor chidamide. Collectively, these findings unveil the critical role of SULF1+ CAFs in CRC and provide a strategy to stratify CRC patients for HDAC inhibitor treatment.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3987
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