bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2022‒10‒02
eleven papers selected by
Maria-Virginia Giolito
Free University of Brussels

  1. Cancer Treat Res Commun. 2022 Sep 24. pii: S2468-2942(22)00134-4. [Epub ahead of print] 100643
      Immune checkpoint inhibitors (ICIs) have significantly advanced colorectal cancer treatment in recent years. Antibodies that target the proteins programmed cell death-1 (PD-1), programmed cell death-1 ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) are among the ICIs that are currently being used in clinical practice. However, in colorectal cancer, ICI's effectiveness is limited to a fraction of patients with microsatellite instability-high (MSI-H), which only accounts for about 5% of advanced cases. The tumor microenvironment and intrinsic changes in tumor cells are just a couple of the many mechanisms that play a role in ICI primary or secondary resistance. In order to advance precision medicine and broaden the population benefiting from ICI, this paper highlights the main underlying mechanisms of ICIs resistance and suggested techniques to overcome it.
    Keywords:  Colorectal cancer; Combination therapy; Immune checkpoint inhibitors; Mechanism; Resistance
  2. Front Med (Lausanne). 2022 ;9 995882
      Tumor recurrence and chemotherapy resistance are mainly responsible for poor prognosis in colorectal cancer (CRC) patients. Cancer stem cell (CSC) has been identified in many solid tumors, including CRC. Additionally, CSC cannot be completely killed during chemotherapy and develops resistance to chemotherapeutic drugs, which is the main reason for tumor recurrence. This study reviews the main mechanisms of CSC chemotherapy resistance in CRC, including activation of DNA damage checkpoints, epithelial-mesenchymal transition (EMT), inhibition of the overexpression of antiapoptotic regulatory factors, overexpression of ATP-binding cassette (ABC) transporters, maintenance of reactive oxygen species (ROS) levels, and the dormant state of CSC. Advances in research to reverse chemotherapy resistance are also discussed. Our study can provide the promising potential for eliminating CSC and preventing tumor progression for CRC treatment.
    Keywords:  cancer stem cell; chemotherapy resistance; colorectal cancer; reverse; stem cells
  3. Nat Rev Mol Cell Biol. 2022 Sep 29.
      Organ development and homeostasis involve dynamic interactions between individual cells that collectively regulate tissue architecture and function. To ensure the highest tissue fidelity, equally fit cell populations are continuously renewed by stochastic replacement events, while cells perceived as less fit are actively removed by their fitter counterparts. This renewal is mediated by surveillance mechanisms that are collectively known as cell competition. Recent studies have revealed that cell competition has roles in most, if not all, developing and adult tissues. They have also established that cell competition functions both as a tumour-suppressive mechanism and as a tumour-promoting mechanism, thereby critically influencing cancer initiation and development. This Review discusses the latest insights into the mechanisms of cell competition and its different roles during embryonic development, homeostasis and cancer.
  4. Int J Cancer. 2022 Sep 26.
      Adding irinotecan to neoadjuvant chemoradiotherapy (nCRT) in locally advanced rectal cancer (LARC) increases the pathologic complete response (pCR) rate but brings more toxicities. Robust biomarkers to predict response to irinotecan-based nCRT are extremely necessary for selecting the right patients. Our previous study suggests that patient-derived tumor organoids (PDTOs) sensitivity to chemoradiotherapy matches patient responses. In this study, we investigated whether PDTOs sensitivity to irinotecan can predict complete response (CR) and survival. Eligible patients receiving irinotecan-based nCRT between April 5, 2017 and December 11, 2020 were enrolled in the training cohort (n=91) for response prediction and survival analysis. Patients receiving nCRT between February 21, 2021 and September 17, 2021 were included in the validation cohort (n=27). Predictive performances of irinotecan organoid size ratio (OSR) for CR or pCR were evaluated. The irinotecan-sensitive groups had higher response rates compared with the insensitive groups (training cohort: 71.8% vs. 24.4%, p<0.0001; validation cohort, 81.8% vs. 18.8%, p=0.002). Moreover, the irinotecan-sensitive group had higher rates of 3-year disease-free survival (DFS: 71.6% vs. 55.5%, p=0.034) and distant metastasis-free survival (DMFS, 77.9% vs. 57.2%, p=0.015) than the irinotecan-insensitive group. 5-FU and irradiation sensitivities failed to predict 3-year DFS (5-FU: 65.4% vs. 61.9%, p=0.643; irradiation: 84.8% vs. 57.8%; p=0.072). Performances of irinotecan OSR to predict CR or pCR were good in the training cohort (CR: AUC=0.828; 95% CI=0.723-0.932; pCR: AUC=0.864; 95% CI=0.759-0.961). The validation showed robust predictive ability (CR: AUC=0.796, 95% CI=0.5974-0.9952; pCR: AUC=0.917, 95% CI=0.7921-1.0000). Irinotecan sensitivity in PDTOs was a predictive and prognostic factor in LARC. This article is protected by copyright. All rights reserved.
    Keywords:  Complete response; Irinotecan; Organoid; Survival; locally advanced rectal cancer
  5. Front Immunol. 2022 ;13 961350
      Background: The main objective of this study was to analyze the effects of KRAS/TP53 mutation status and tumor sideness on the immune microenvironment of colorectal cancer using integrated scRNA-seq data.Methods: A total of 78 scRNA-seq datasets, comprising 42 treatment-naive colorectal tumors, 13 tumor adjacent tissues and 23 normal mucosa tissues were included. Standardized Seurat procedures were applied to identify cellular components with canonical cell marks. The batch-effect was assessed and corrected using harmony algorithm. The scMetabolism algorithm was used for single-cell metabolic analysis. The results and clinical significance were further validated using immunofluorescent-staining and TCGA-COAD datasets. Immune-infiltration scores of bulk-RNA-seq data were estimated using ssGSEA. The presto-wilcoxauc algorithm was used to identify differentially enriched genes or pathways across different subgroups. Two-sided p-value less than 0.05 was considered statistically significant.
    Results: We refined the landscape of functional immune cell subtypes, especially T cells and myeloid cells, across normal mucosa, tumor adjacent and tumor tissue. The existence and function of two states of exhausted CD8+ T (Tex) subtypes in colorectal cancer, and FOLR2+ LYVE1+ macrophages indicating unfavorable prognosis in colorectal cancer were identified and validated. The diverse tumor mutation status reshaped the immune cell function and immune checkpoint ligands/receptors (ICLs/ICRs) expression pattern. Importantly, the KRAS/TP53 dual mutations significantly reduced the major energy metabolic functions in immune cells, and promoted the cell-to-cell communications towards immunosuppression in colorectal cancers. The results revealed LAG3, CD24-SIGLEC10 and HBEGF-CD9 pathways as potential therapeutic targets for dual mutant colorectal cancers.
    Conclusions: We revealed that the immune microenvironment underwent a gradual remodeling with an enrichment of immunosuppressive myeloid cells from normal mucosa to tumor regions in colorectal cancers. Moreover, we revealed the metabolic heterogeneity of tumor-infiltrating immune cells and suggested that the KRAS/TP53 dual mutation may impair antitumor immunity by reducing T and myeloid cell energy metabolism and reshaping cellular interactions toward immunosuppression.
    Keywords:  KRAS mutation; TP53 mutation; clinical prognosis; colorectal cancer; therapeutic targets; tumor immune microenvironment; tumor sideness
  6. Med Oncol. 2022 Sep 29. 39(12): 211
      Colorectal cancer (CRC) is a cancer with a high morbidity and mortality worldwide. Hence, developing new therapeutic drugs for CRC is very important. Moxidectin (MOX) has shown good anti-glioblastoma effect both in vitro and in vivo. This study aimed to elucidate the anti-CRC effect of MOX and its potential mechanism by investigating the influence of MOX on the viability, apoptosis, necrosis and autophagy of colorectal cancer cells (HCT15 and SW620) and its underlying mechanisms. It was found that MOX can induce autophagy arrest, promote autophagy initiation, inhibit autophagic flux and cell proliferation, simultaneously PI3K-Akt-mTOR signaling pathway and microtubule acetylation. Furthermore, MOX suppressed the growth of xenograft tumors, which was consistent with the in vitro results.
    Keywords:  Accumulation; Autophagosome; CFTR; Colorectal cancer; Moxidectin
  7. J Exp Clin Cancer Res. 2022 Sep 26. 41(1): 284
      BACKGROUND: Oxidative stress is a highly active metabolic process in the liver, that poses great threats to disseminated tumor cells during their colonization. Here, we aimed to investigate how colorectal cancer (CRC) cells overcome lipid peroxidation to sustain their metastatic colonization in the liver.METHODS: Orthotopic colorectal liver metastasis (CRLM) and CRC liver colonization mouse models were constructed to determine the roles of lipid peroxidation and AADAC in CRC liver colonization. The levels of lipid peroxidation were detected in cells or tissues. AADAC overexpression in LMs and its clinical relevance were analyzed. The oncogenic role of AADAC in CRC liver colonization was evaluated in cell experiments.
    RESULTS: Compared with primary tumors (PTs), liver metastases (LMs) showed significantly lower glutathione to oxidized glutathione (GSH/GSSG) ratio and higher malondialdehyde (MDA) levels in CRLM patients and orthotopic mouse models. Inhibition of lipid peroxidation by liproxstatin-1 promoted CRC liver colonization in mouse models. RNA-seq results revealed AADAC as the most significantly upregulated lipid metabolism related gene in LMs compared with PTs. Analyses of datasets and patient and mouse model samples confirmed that AADAC was upregulated in LMs compared with PTs, and was correlated with poor prognosis. AADAC promoted cell proliferation, and facilitated liver colonization in a mouse model by reducing ROS accumulation, which led to lipid peroxidation and ferroptosis. Mechanistically, AADAC upregulated SLC7A11 by activating NRF2 to inhibit lipid peroxidation, thereby protecting metastatic cells from ferroptosis.
    CONCLUSIONS: AADAC protects metastatic CRC cells from ferroptosis by inhibiting lipid peroxidation in an SLC7A11-dependent manner, thus effectively promoting their metastatic colonization and growth in the liver. Together, our findings suggest that AADAC can act as a prognostic indicator and potential therapeutic target for CRLM.
    Keywords:  AADAC; Colorectal cancer; Ferroptosis; Liver colonization; SLC7A11
  8. Front Genet. 2022 ;13 993714
      Long non-coding RNAs (lncRNAs) remodel the tumor immune microenvironment (TIME) by regulating the functions of tumor-infiltrating immune cells. It remains uncertain the way that TIME-related lncRNAs (TRLs) influence the prognosis and immunotherapy response of colorectal cancer (CRC). Aiming at providing survival and immunotherapy response predictions, a CRC TIME-related lncRNA signature (TRLs signature) was developed and the related potential regulatory mechanisms were explored with a comprehensive analysis on gene expression profiles from 97 immune cell lines, 61 CRC cell lines and 1807 CRC patients. Stratifying CRC patients with the TRLs signature, prolonged survival was observed in the low-risk group, while the patients in the high-risk group had significantly higher pro-tumor immune cells infiltration and higher immunotherapy response rate. Through the complex TRLs-mRNA regulation network, immunoregulation pathways and immunotherapy response pathways were found to be differently activated between the groups. In conclusion, the CRC TRLs signature is capable of making prognosis and immunotherapy response predictions, which may find application in stratifying patients for immunotherapy in the bedside.
    Keywords:  colorectal cancer; immunotherapy; long non-coding RNA; tumor immune microenvironment; tumor microenvironment
  9. Nat Commun. 2022 Sep 26. 13(1): 5644
      Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.
  10. Cell Rep. 2022 Sep 27. pii: S2211-1247(22)01280-3. [Epub ahead of print]40(13): 111439
      Interactions between the epithelium and the immune system are critical in the pathogenesis of inflammatory bowel disease (IBD). In this study, we mapped the transcriptional landscape of human colonic epithelial organoids in response to different cytokines responsible for mediating canonical mucosal immune responses. By profiling the transcriptome of human colonic organoids treated with the canonical cytokines interferon gamma, interleukin-13, -17A, and tumor necrosis factor alpha with next-generation sequencing, we unveil shared and distinct regulation patterns of epithelial function by different cytokines. An integrative analysis of cytokine responses in diseased tissue from patients with IBD (n = 1,009) reveals a molecular classification of mucosal inflammation defined by gradients of cytokine-responsive transcriptional signatures. Our systems biology approach detected signaling bottlenecks in cytokine-responsive networks and highlighted their translational potential as theragnostic targets in intestinal inflammation.
    Keywords:  CP: Immunology; IBD; cytokine signaling; organoids; personalized medicine; transcriptomics
  11. Br J Pharmacol. 2022 Sep 27.
      BACKGROUND AND PURPOSE: Transient receptor potential melastatin type-8 (TRPM8) is a cold-sensitive cation channel protein belonging to the TRP superfamily of ion channels. Here, we revealed the molecular mechanism of TRPM8 and its clinical relevance in colorectal cancer (CRC).EXPERIMENTAL APPROACH: TRPM8 expression as well as its correlation with the survival rate of CRC patients was analysed. To identify the key pathways and genes related to TRPM8 high expression, KEGG pathway enrichment analyses were conducted in CRC patients. TRPM8 functional role was assessed by using Trpm8-/- mice in models of sporadic and colitis-associated colon cancer. TRPM8 pharmacological targeting by WS12 was evaluated in human CRC cell-derived xenograft tumors.
    KEY RESULTS: TRPM8 is overexpressed in colon primary tumors as well as in CD326+ tumor cell fraction. TRPM8 high expression was related with lower survival rate of CRC patients, Wnt-Frizzled signalling hyperactivation and adenomatous polyposis coli (APC) down-regulation. In sporadic and colitis-associated models of colon cancer, either absence or pharmacological desensitization of TRPM8 reduced tumor development, via inhibition of the oncogenic Wnt/β-catenin signalling. TRPM8 pharmacological blockade reduced tumor growth in CRC xenograft mice by reducing the transcription of Wnt signaling regulators as well as the activation of β-catenin and its target oncogenes such as c-Myc and CyclinD-1.
    CONCLUSION AND IMPLICATIONS: Human data provide valuable insights to propose TRPM8 as a prognostic marker with a negative predictive value for CRC patient survival. Animal experiments depict TRPM8 involvement in colon cancer pathophysiology and its potential as drug target for CRC.
    Keywords:  TRPM8; Transient receptor potential channels; Wnt/β-catenin; colon cancer; pharmacology