bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–12–03
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Dual function of angiogenin-4 inducing intestinal stem cells and apoptosis.
  2. Contribution of pks+ E. coli mutations to colorectal carcinogenesis.
  3. Paneth cell-derived iNOS is required to maintain homeostasis in the intestinal stem cell niche.
  4. Characterizing heterogeneity along EMT and metabolic axes in colorectal cancer reveals underlying consensus molecular subtype-specific trends.
  5. One mutation to rule them all: Mutant KRAS controls tumor intrinsic and microenvironment signaling.
  6. Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment.
  7. Uncoupling p38α nuclear and cytoplasmic functions and identification of two p38α phosphorylation sites on β-catenin: implications for the Wnt signaling pathway in CRC models.
  8. Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.
  9. An EMC-Hpo-Yki axis maintains intestinal homeostasis under physiological and pathological conditions.
  10. Protective effects of metformin in the pro-inflammatory cytokine induced intestinal organoids injury model.
  11. EGFR inhibitor rechallenge in metastatic colorectal cancer.
  1. Front Cell Dev Biol. 2023 ;11 1181145
    Dual function of angiogenin-4 inducing intestinal stem cells and apoptosis.
    Hirohito Abo, Mst Farzana Sultana, Hiroto Kawashima.
      The intestinal epithelium is the first line of host defense, and its homeostasis is dependent on soluble factors that comprise the crypt niche. Antimicrobial proteins are one of the mediators to maintain gut homeostasis. Angiogenin-4 (Ang4) is a member of the ribonuclease A superfamily and plays a pivotal role in antimicrobial activity against gut microbiota. However, the functions of Ang4 within the intestinal crypt niche, particularly its involvement in the development of intestinal epithelial cells (IECs), remain unknown. Here, we demonstrate that Ang4 plays a significant role in maintaining Lgr5+ intestinal stem cells (ISCs) and induces apoptosis of IECs in a concentration-dependent manner. We revealed that Ang4 is highly expressed by Paneth cells in the small intestine, as well as regenerating islet-derived family member-4 (Reg4) expressing goblet cells in the colon, and both cell subsets highly contribute to ISC maintenance. Functional analysis using intestinal organoids revealed that Ang4 induces Wnt and Notch signaling, increases Lgr5+ stem cell expansion, and promotes organoid growth. Furthermore, high concentrations of Ang4 induced apoptosis in the IEC cell line and organoids. Collectively, we propose that Ang4 is a dual functional protein and is a novel member of the crypt niche factor that promotes the expansion of ISCs and induces apoptosis.
    Keywords:  Wnt signalling; antimicrobial peptide (AMP); cell differentiation; intestinal epithelium; stem cells
    DOI:  https://doi.org/10.3389/fcell.2023.1181145
  2. Nat Commun. 2023 Nov 29. 14(1): 7827
    Contribution of pks+ E. coli mutations to colorectal carcinogenesis.
    Bingjie Chen, Daniele Ramazzotti, Timon Heide, Inmaculada Spiteri, Javier Fernandez-Mateos, Chela James, Luca Magnani, Trevor A Graham, Andrea Sottoriva.
      The dominant mutational signature in colorectal cancer genomes is C > T deamination (COSMIC Signature 1) and, in a small subgroup, mismatch repair signature (COSMIC signatures 6 and 44). Mutations in common colorectal cancer driver genes are often not consistent with those signatures. Here we perform whole-genome sequencing of normal colon crypts from cancer patients, matched to a previous multi-omic tumour dataset. We analyse normal crypts that were distant vs adjacent to the cancer. In contrast to healthy individuals, normal crypts of colon cancer patients have a high incidence of pks + (polyketide synthases) E.coli (Escherichia coli) mutational and indel signatures, and this is confirmed by metagenomics. These signatures are compatible with many clonal driver mutations detected in the corresponding cancer samples, including in chromatin modifier genes, supporting their role in early tumourigenesis. These results provide evidence that pks + E.coli is a potential driver of carcinogenesis in the human gut.
    DOI:  https://doi.org/10.1038/s41467-023-43329-5
  3. J Transl Med. 2023 Nov 25. 21(1): 852
    Paneth cell-derived iNOS is required to maintain homeostasis in the intestinal stem cell niche.
    Lingxiao Huang, Zhenni Xu, Xudan Lei, Yujun Huang, Siyu Tu, Lu Xu, Jieying Xia, Dengqun Liu.
       BACKGROUND: Mammalian intestinal epithelium constantly undergoes rapid self-renewal and regeneration sustained by intestinal stem cells (ISCs) within crypts. Inducible nitric oxide synthase (iNOS) is an important regulator in tissue homeostasis and inflammation. However, the functions of iNOS on ISCs have not been clarified. Here, we aimed to investigate the expression pattern of inducible nitric oxide synthase (iNOS) within crypts and explore its function in the homeostatic maintenance of the ISC niche.
    METHODS: Expression of iNOS was determined by tissue staining and qPCR. iNOS-/- and Lgr5 transgenic mice were used to explore the influence of iNOS ablation on ISC proliferation and differentiation. Enteroids were cultured to study the effect of iNOS on ISCs in vitro. Ileum samples from wild-type and iNOS-/- mice were collected for RNA-Seq to explore the molecular mechanisms by which iNOS regulates ISCs.
    RESULTS: iNOS was physiologically expressed in Paneth cells. Knockout of iNOS led to apparent morphological changes in the intestine, including a decrease in the small intestine length and in the heights of both villi and crypts. Knockout of iNOS decreased the number of Ki67+ or BrdU+ proliferative cells in crypts. Loss of iNOS increased the number of Olfm4+ ISCs but inhibited the differentiation and migration of Lgr5+ ISCs in vivo. iNOS depletion also inhibited enteroid formation and the budding efficiency of crypts in vitro. Moreover, iNOS deficiency altered gluconeogenesis and the adaptive immune response in the ileum transcriptome.
    CONCLUSION: Paneth cell-derived iNOS is required to maintain a healthy ISC niche, and Knockout of iNOS hinders ISC function in mice. Therefore, iNOS represents a potential target for the development of new drugs and other therapeutic interventions for intestinal disorders.
    Keywords:  Differentiation; Intestinal stem cell; Paneth cell; Proliferation; iNOS
    DOI:  https://doi.org/10.1186/s12967-023-04744-w
  4. Transl Oncol. 2023 Nov 28. pii: S1936-5233(23)00231-0. [Epub ahead of print]40 101845
    Characterizing heterogeneity along EMT and metabolic axes in colorectal cancer reveals underlying consensus molecular subtype-specific trends.
    Manas Sehgal, Soundharya Ramu, Joel Markus Vaz, Yogheshwer Raja Ganapathy, Srinath Muralidharan, Sankalpa Venkatraghavan, Mohit Kumar Jolly.
      Colorectal cancer (CRC) is highly heterogeneous with variable survival outcomes and therapeutic vulnerabilities. A commonly used classification system in CRC is the Consensus Molecular Subtypes (CMS) based on gene expression patterns. However, how these CMS categories connect to axes of phenotypic plasticity and heterogeneity remains unclear. Here, in our analysis of CMS-specific TCGA data and 101 bulk transcriptomic datasets, we found the epithelial phenotype score to be consistently positively correlated with scores of glycolysis, OXPHOS and FAO pathways, while PD-L1 activity scores positively correlated with mesenchymal phenotype scoring, revealing possible interconnections among plasticity axes. Single-cell RNA-sequencing analysis of patient samples revealed that that CMS2 and CMS3 subtype samples were relatively more epithelial as compared to CMS1 and CMS4. CMS1 revealed two subpopulations: one close to CMS4 (more mesenchymal) and the other closer to CMS2 or CMS3 (more epithelial), indicating a partial EMT-like behavior. Consistent observations were made in single-cell analysis of metabolic axes and PD-L1 activity scores. Together, our results quantify the patterns of two functional interconnected axes of phenotypic heterogeneity - EMT and metabolic reprogramming - in a CMS-specific manner in CRC.
    Keywords:  Colorectal cancer; EMT; Meta-analysis; Metabolic plasticity; Phenotypic heterogeneity
    DOI:  https://doi.org/10.1016/j.tranon.2023.101845
  5. Cancer Res. 2023 Nov 28.
    One mutation to rule them all: Mutant KRAS controls tumor intrinsic and microenvironment signaling.
    Sören Müller, Akshay T Krishnamurty.
      In a recent study published in Cancer Discovery, Hsu and colleagues employ an elegant combination of single-cell and bulk RNA-seq experiments from mouse and human colorectal cancer (CRC) samples, patient-derived organoids, 2D in vitro systems, and in vivo validation in genetically engineered CRC mouse models to investigate how mutant KRAS (KRAS*) impacts the tumor microenvironment. They identify a molecular signaling cascade downstream of KRAS* that activates a specific program of lipid-rich CAFs, promoting tumor angiogenesis and progression. These findings may lead to new therapeutic strategies for CRC patients with KRAS*.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3682
  6. Nat Commun. 2023 Nov 30. 14(1): 7915
    Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment.
    Ning Li, Qin Zhu, Yuhua Tian, Kyung Jin Ahn, Xin Wang, Zvi Cramer, Justine Jou, Ian W Folkert, Pengfei Yu, Stephanie Adams-Tzivelekidis, Priyanka Sehgal, Najia N Mahmoud, Cary B Aarons, Robert E Roses, Andrei Thomas-Tikhonenko, Emma E Furth, Ben Z Stanger, Anil Rustgi, Malay Haldar, Bryson W Katona, Kai Tan, Christopher J Lengner.
      The initiation and progression of cancer are intricately linked to the tumor microenvironment (TME). Understanding the function of specific cancer-TME interactions poses a major challenge due in part to the complexity of the in vivo microenvironment. Here we predict cancer-TME interactions from single cell transcriptomic maps of both human colorectal cancers (CRCs) and mouse CRC models, ask how these interactions are altered in human tumor organoid (tumoroid) cultures, and functionally recapitulate human myeloid-carcinoma interactions in vitro. Tumoroid cultures suppress gene expression programs involved in inflammation and immune cell migration, providing a reductive platform for re-establishing carcinoma-immune cell interactions in vitro. Introduction of human monocyte-derived macrophages into tumoroid cultures instructs macrophages to acquire immunosuppressive and pro-tumorigenic gene expression programs similar to those observed in vivo. This includes hallmark induction of SPP1, encoding Osteopontin, an extracellular CD44 ligand with established oncogenic effects. Taken together, these findings offer a framework for understanding CRC-TME interactions and provide a reductionist tool for modeling specific aspects of these interactions.
    DOI:  https://doi.org/10.1038/s41467-023-43746-6
  7. Cell Biosci. 2023 Dec 01. 13(1): 223
    Uncoupling p38α nuclear and cytoplasmic functions and identification of two p38α phosphorylation sites on β-catenin: implications for the Wnt signaling pathway in CRC models.
    Martina Lepore Signorile, Candida Fasano, Giovanna Forte, Katia De Marco, Paola Sanese, Vittoria Disciglio, Elisabetta Di Nicola, Antonino Pantaleo, Cristiano Simone, Valentina Grossi.
       BACKGROUND: Activation of the Wnt pathway has been linked to colorectal cancer (CRC). Previous reports suggest that Wnt3a can activate p38. Besides, p38α feeds into the canonical Wnt/β-catenin pathway by inhibiting GSK3β through phosphorylation. Recently, we identified p38α as a new druggable member of β-catenin chromatin-associated kinase complexes in CRC.
    METHODS: The functional relationship between p38α and β-catenin was characterized in CRC cells, patient-derived CRC stem cells, patient-derived tumor intestinal organoids, and in vivo models (C57BL/6-APCMin/+ mice). The role of p38α in β-catenin transcriptional activity was assessed by pharmacological inhibition with ralimetinib.
    RESULTS: We used the GSK3β inhibitor TWS-119, which promotes the activation of Wnt signaling, to uncouple p38α nuclear/cytoplasmatic functions in the Wnt pathway. Upon GSK3β inhibition, nuclear p38α phosphorylates β-catenin at residues S111 and T112, allowing its binding to promoter regions of Wnt target genes and the activation of a transcriptional program implicated in cancer progression. If p38α is pharmacologically inhibited in addition to GSK3β, β-catenin is prevented from promoting target gene transcription, which is expected to impair carcinogenesis.
    CONCLUSIONS: p38α seems to play a dual role as a member of the β-catenin destruction complex and as a β-catenin chromatin-associated kinase in CRC. This finding may help elucidate mechanisms contributing to human colon tumor pathogenesis and devise new strategies for personalized CRC treatment.
    Keywords:  Chromatin-associated kinase; Colorectal cancer; Wnt/β-catenin pathway; p38α
    DOI:  https://doi.org/10.1186/s13578-023-01175-4
  8. Cell Biosci. 2023 Nov 29. 13(1): 217
    Single-cell analysis unveils activation of mast cells in colorectal cancer microenvironment.
    Zhenyu Xie, Liaoran Niu, Gaozan Zheng, Kunli Du, Songchen Dai, Ruikai Li, Hanjun Dan, Lili Duan, Hongze Wu, Guangming Ren, Xinyu Dou, Fan Feng, Jian Zhang, Jianyong Zheng.
      The role of mast cells (MCs) in colorectal cancer (CRC) remains unclear, and a comprehensive single-cell study on CRC MCs has not been conducted. This study used a multi-omics approach, integrating single-cell sequencing, spatial transcriptomics, and bulk tissue sequencing data to investigate the heterogeneity and impact of MCs in CRC. Five MC signature genes (TPSAB1, TPSB2, CPA3, HPGDS, and MS4A2) were identified, and their average expression was used as a marker of MCs. The MC density was found to be lower in CRC compared to normal tissue, but MCs in CRC demonstrated distinct activation features. Activated MCs were defined by high expression of receptors and MC mediators, while resting MCs had low expression. Most genes, including the five MC signature genes, were expressed at higher levels in activated MCs. The MC signature was linked to a better prognosis in both CRC and pan-cancer patient cohorts. Elevated KITLG expression was observed in fibroblasts and endothelial cells in CRC samples compared to normal tissue, and co-localization of MCs with these cell types was revealed by spatial transcriptome analysis. In conclusion, this study finds decreased MC density in CRC compared to normal tissue, but highlights a shift in MC phenotype from CMA1high resting cells to activated TPSAB1high, CPA3high, and KIThigh cells. The elevated KITLG expression in the tumor microenvironment's fibroblasts and endothelial cells may activate MCs through the KITLG-KIT axis, potentially suppressing tumor progression.
    Keywords:  Activation; Colorectal cancer; Heterogeneity; Mast cells; Prognosis; Single-cell analysis
    DOI:  https://doi.org/10.1186/s13578-023-01144-x
  9. Development. 2023 Nov 30. pii: dev.201958. [Epub ahead of print]
    An EMC-Hpo-Yki axis maintains intestinal homeostasis under physiological and pathological conditions.
    Lin Shi, Hubing Ma, Jinjun Wang, Meifang Ma, Hang Zhao, Zhengran Li, Jian-Hua Wang, Shian Wu, Zizhang Zhou, Meng-Qiu Dong, Zhouhua Li.
      Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. Disruption of tissue homeostasis often results in many diseases. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological and pathological conditions remains not fully understood. Here, we find that the evolutionarily conserved endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation and intestinal homeostasis. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, EMC associates with and stabilizes Hippo (Hpo) protein, the key component of the Hpo signaling pathway. In the absence of EMC, Yorkie (Yki) is activated to promote ISC proliferation due to Hpo destruction. The EMC-Hpo-Yki axis also functions in enterocytes to maintain intestinal homeostasis. Importantly, the levels of EMC are dramatically diminished in tunicamycin (TM)-treated animals, leading to Hpo destruction, thereby resulting in intestinal homeostasis disruption due to Yki activation. Thus, our study uncovers the molecular mechanism of EMC in intestinal homeostasis maintenance under physiological and pathological conditions and provide new insight into the pathogenesis of TM-induced tumorigenesis.
    Keywords:   Drosophila ; Endoplasmic reticulum; Enterocyte; Intestinal stem cell; Tumorigenesis
    DOI:  https://doi.org/10.1242/dev.201958
  10. Biochem Biophys Res Commun. 2023 Nov 22. pii: S0006-291X(23)01385-2. [Epub ahead of print]690 149291
    Protective effects of metformin in the pro-inflammatory cytokine induced intestinal organoids injury model.
    Soojung Hahn, Gyuri Kim, Sang-Man Jin, Jae Hyeon Kim.
      Pathogenesis of inflammatory bowel disease (IBD) accompanies disrupted intestinal tight junctions. However, many approaches of therapeutics for IBD are focused only on anti-inflammatory effects and most cellular experiments are based on two-dimensional cell lines which have insufficient circumstances of intestine. Thus, here, we used three-dimensional structure intestinal organoids to investigate effects of metformin in the in vitro IBD condition. In this study, we focused on both tight junctions and the levels of inflammatory cytokines. Metformin enhances the intestinal barrier in injured intestine via upregulation of AMP-activated protein kinase, dysfunction of which contributes to the pathogenesis of intestinal diseases. We aim to investigate the effects of metformin on cytokine-induced injured intestinal organoids. Tumor necrosis factor-alpha (TNF-α) was used to induce intestinal injury in an organoid model, and the effects of metformin were assessed. Cell viability and levels of inflammatory cytokines were quantified in addition to tight junction markers. Furthermore, 4 kDa FITC-dextran was used to assess intestinal permeability. The upregulation of inflammatory cytokine levels was alleviated by metformin, which also restored the intestinal epithelium permeability in TNF-α-treated injury organoids. We confirmed that claudin-2 and claudin-7, representative tight junction markers, were also protected by metformin treatment. This study confirms the protective effects of metformin, which could be used as a therapeutic strategy for inflammatory intestinal diseases.
    Keywords:  Gut barrier; Intestinal injury; Intestinal organoids; Metformin; Tight junction
    DOI:  https://doi.org/10.1016/j.bbrc.2023.149291
  11. Clin Adv Hematol Oncol. 2023 Dec;21(12): 670-672
    EGFR inhibitor rechallenge in metastatic colorectal cancer.
    Jun Gong.
      
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