bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–06–16
seven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Bioengineered human colon organoids with in vivo-like cellular complexity and function.
  2. Gut microbiota-stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis.
  3. MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration.
  4. The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis.
  5. Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression.
  6. Exploiting ferroptosis vulnerabilities in cancer.
  7. The phosphoinositide PI5P inhibits the Hippo pathway effector YAP.
  1. Cell Stem Cell. 2024 Jun 09. pii: S1934-5909(24)00184-X. [Epub ahead of print]
    Bioengineered human colon organoids with in vivo-like cellular complexity and function.
    Olga Mitrofanova, Mikhail Nikolaev, Quan Xu, Nicolas Broguiere, Irineja Cubela, J Gray Camp, Michael Bscheider, Matthias P Lutolf.
      Organoids and organs-on-a-chip have emerged as powerful tools for modeling human gut physiology and disease in vitro. Although physiologically relevant, these systems often lack the environmental milieu, spatial organization, cell type diversity, and maturity necessary for mimicking human intestinal mucosa. To instead generate models closely resembling in vivo tissue, we herein integrated organoid and organ-on-a-chip technology to develop an advanced human organoid model, called "mini-colons." By employing an asymmetric stimulation with growth factors, we greatly enhanced tissue longevity and replicated in vivo-like diversity and patterning of proliferative and differentiated cell types. Mini-colons contain abundant mucus-producing goblet cells and, signifying mini-colon maturation, single-cell RNA sequencing reveals emerging mature and functional colonocytes. This methodology is expanded to generate microtissues from the small intestine and incorporate additional microenvironmental components. Finally, our bioengineered organoids provide a precise platform to systematically study human gut physiology and pathology, and a reliable preclinical model for drug safety assessment.
    Keywords:  bioengineering; colon; colonocyte; gastrointestinal drug toxicity; gut physiology; mucus; organ-on-chip; organoid; small intestine
    DOI:  https://doi.org/10.1016/j.stem.2024.05.007
  2. Imeta. 2022 Dec;1(4): e54
    Gut microbiota-stem cell niche crosstalk: A new territory for maintaining intestinal homeostasis.
    Ning Ma, Xiyue Chen, Lee J Johnston, Xi Ma.
      Intestinal epithelium undergoes rapid cellular turnover, relying on the local niche, to support intestinal stem cells (ISCs) function and self-renewal. Research into the association between ISCs and disease continues to expand at a rapid rate. However, the detailed interaction of ISCs and gut microbes remains to be elucidated. Thus, this review witnessed major advances in the crosstalk between ISCs and gut microbes, delivering key insights into (1) construction of ISC niche and molecular mechanism of how to jointly govern epithelial homeostasis and protect against intestinal diseases with the participation of Wnt, bone morphogenetic protein, and Notch; (2) differentiation fate of ISCs affect the gut microbiota. Meanwhile, the presence of intestinal microbes also regulates ISC function; (3) microbiota regulation on ISCs by Wnt and Notch signals through pattern recognition receptors; (4) how do specific microbiota-related postbiotics influence ISCs to maintain intestinal epithelial regeneration and homeostasis that provide insights into a promising alternative therapeutic method for intestinal diseases. Considering the detailed interaction is still unclear, it is necessary to further explore the regulatory role of gut microbiota on ISCs to utilize microbes to alleviate gut disorders. Furthermore, these major advances collectively drive us ever closer to breakthroughs in regenerative medicine and cancer treatment by microbial transplantation in the clinic.
    Keywords:  intestinal disease; intestinal stem cell; microbiota; niche; postbiotic
    DOI:  https://doi.org/10.1002/imt2.54
  3. Nat Commun. 2024 Jun 11. 15(1): 4969
    MYG1 drives glycolysis and colorectal cancer development through nuclear-mitochondrial collaboration.
    Jianxiong Chen, Shiyu Duan, Yulu Wang, Yuping Ling, Xiaotao Hou, Sijing Zhang, Xunhua Liu, Xiaoli Long, Jiawen Lan, Miao Zhou, Huimeng Xu, Haoxuan Zheng, Jun Zhou.
      Metabolic remodeling is a strategy for tumor survival under stress. However, the molecular mechanisms during the metabolic remodeling of colorectal cancer (CRC) remain unclear. Melanocyte proliferating gene 1 (MYG1) is a 3'-5' RNA exonuclease and plays a key role in mitochondrial functions. Here, we uncover that MYG1 expression is upregulated in CRC progression and highly expressed MYG1 promotes glycolysis and CRC progression independent of its exonuclease activity. Mechanistically, nuclear MYG1 recruits HSP90/GSK3β complex to promote PKM2 phosphorylation, increasing its stability. PKM2 transcriptionally activates MYC and promotes MYC-medicated glycolysis. Conversely, c-Myc also transcriptionally upregulates MYG1, driving the progression of CRC. Meanwhile, mitochondrial MYG1 on the one hand inhibits oxidative phosphorylation (OXPHOS), and on the other hand blocks the release of Cyt c from mitochondria and inhibits cell apoptosis. Clinically, patients with KRAS mutation show high expression of MYG1, indicating a high level of glycolysis and a poor prognosis. Targeting MYG1 may disturb metabolic balance of CRC and serve as a potential target for the diagnosis and treatment of CRC.
    DOI:  https://doi.org/10.1038/s41467-024-49221-0
  4. Life Sci Alliance. 2024 Sep;pii: e202402593. [Epub ahead of print]7(9):
    The transcription factor HIF-1α in NKp46+ ILCs limits chronic intestinal inflammation and fibrosis.
    Eric Nelius, Zheng Fan, Michal Sobecki, Ewelina Krzywinska, Shunmugam Nagarajan, Irina Ferapontova, Dagmar Gotthardt, Norihiko Takeda, Veronika Sexl, Christian Stockmann.
      Innate lymphoid cells (ILCs) are critical for intestinal adaptation to microenvironmental challenges, and the gut mucosa is characterized by low oxygen. Adaptation to low oxygen is mediated by hypoxia-inducible transcription factors (HIFs), and the HIF-1α subunit shapes an ILC phenotype upon acute colitis that contributes to intestinal damage. However, the impact of HIF signaling in NKp46+ ILCs in the context of repetitive mucosal damage and chronic inflammation, as it typically occurs during inflammatory bowel disease, is unknown. In chronic colitis, mice lacking the HIF-1α isoform in NKp46+ ILCs show a decrease in NKp46+ ILC1s but a concomitant rise in neutrophils and Ly6Chigh macrophages. Single-nucleus RNA sequencing suggests enhanced interaction of mesenchymal cells with other cell compartments in the colon of HIF-1α KO mice and a loss of mucus-producing enterocytes and intestinal stem cells. This was, furthermore, associated with increased bone morphogenetic pathway-integrin signaling, expansion of fibroblast subsets, and intestinal fibrosis. In summary, this suggests that HIF-1α-mediated ILC1 activation, although detrimental upon acute colitis, protects against excessive inflammation and fibrosis during chronic intestinal damage.
    DOI:  https://doi.org/10.26508/lsa.202402593
  5. Cancer Res. 2024 Jun 11.
    Comprehensive Proteogenomic Profiling Reveals the Molecular Characteristics of Colorectal Cancer at Distinct Stages of Progression.
    Lingling Li, Dongxian Jiang, Hui Liu, Chunmei Guo, Qiao Zhang, Xuedong Li, Xiaojian Chen, Zheqi Chen, Jinwen Feng, Subei Tan, Wen Huang, Jie Huang, Chen Xu, Chen-Ying Liu, Wei Yu, Yingyong Hou, Chen Ding.
      Colorectal cancer (CRC) is the second most common malignant tumor world-wide. Analysis of the changes that occur during CRC progression could provide insights into the molecular mechanisms driving CRC development and identify improved treatment strategies. Here, we performed an integrated multi-omics analysis of 435 trace-tumor-samples from 148 colorectal cancer (CRC) patients, covering non-tumor (NT), intraepithelial neoplasia (IEN), infiltration (IFT), and advanced-stage CRC (A-CRC) phases. Proteogenomics analyses demonstrated that KRAS and BRAF mutations were mutually exclusive and elevated oxidation phosphorylation in the IEN phase. Chr17q loss and chr20q gain were also mutually exclusive, occurred predominantly in the IEN and IFT phases, respectively, and impacted the cell cycle. Mutation of TP53 was frequent in the A-CRC phase and associated with tumor microenvironment, including increased extracellular matrix rigidity and stromal infiltration. Analysis of the profiles of CRC based on CMS and CRIS classifications revealed the progression paths of each subtype and indicated that microsatellite instability was associated with specific subtype classifications. Additional comparison of molecular characteristics of CRC based on location showed that ANKRD22 amplification by chr10q23.31 gain enhanced glycolysis in the right-sided CRC. The AOM/DSS-induced CRC carcinogenesis mouse model in mice indicated that DDX5 deletion due to chr17q loss promoted CRC development, consistent with the findings from the patient samples. Collectively, this study provides an informative resource for understanding the driving events of different stages of CRC and identifying the potential therapeutic targets.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-1878
  6. Nat Cell Biol. 2024 Jun 10.
    Exploiting ferroptosis vulnerabilities in cancer.
    Toshitaka Nakamura, Marcus Conrad.
      Ferroptosis is a distinct lipid peroxidation-dependent form of necrotic cell death. This process has been increasingly contemplated as a new target for cancer therapy because of an intrinsic or acquired ferroptosis vulnerability in difficult-to-treat cancers and tumour microenvironments. Here we review recent advances in our understanding of the molecular mechanisms that underlie ferroptosis and highlight available tools for the modulation of ferroptosis sensitivity in cancer cells and communication with immune cells within the tumour microenvironment. We further discuss how these new insights into ferroptosis-activating pathways can become new armouries in the fight against cancer.
    DOI:  https://doi.org/10.1038/s41556-024-01425-8
  7. Nat Rev Mol Cell Biol. 2024 Jun 10.
    The phosphoinositide PI5P inhibits the Hippo pathway effector YAP.
    Kim Baumann.
      
    DOI:  https://doi.org/10.1038/s41580-024-00750-y
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