bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2024–10–13
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1.
  2. Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy.
  3. An RNA damage response network mediates the lethality of 5-FU in colorectal cancer.
  4. Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
  5. Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.
  6. DNA demethylation triggers cell free DNA release in colorectal cancer cells.
  7. Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury.
  8. Lipids in the tumor microenvironment: immune modulation and metastasis.
  9. Integrating spatial profiles and cancer genomics to identify immune-infiltrated mismatch repair proficient colorectal cancers.
  10. Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation.
  11. LRG1 promotes metastatic colorectal cancer growth through HER3 signaling.
  12. Therapeutic efficacy of ferroptosis in the treatment of colorectal cancer (Review).
  1. Commun Biol. 2024 Oct 10. 7(1): 1297
    FUT2 promotes colorectal cancer metastasis by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1.
    Chenfei Dong, Yue Zhang, Jiayue Zeng, Suli Chong, Yang Liu, Ziming Bian, Sairong Fan, Xiaoming Chen.
      Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide because of its high rate of metastasis, and approximately 20% of CRC patients have metastases at initial diagnosis. Metabolic reprogramming, a hallmark of cancer cells, has been implicated in the process of metastasis. We previously demonstrated that fucosyltransferase 2 (FUT2) promotes the malignancy of CRC cells, however, the underlying mechanisms remain unclear. Here, bioinformatic analysis revealed that FUT2 is associated with the malignant phenotype and fatty acid metabolism in CRC. FUT2 knockdown decreased glucose uptake and de novo fatty acid synthesis, which in turn inhibited the proliferation and metastasis of CRC cells. Mechanistically, FUT2 promotes YAP1 nuclear translocation and stabilizes mSREBP-1 by fucosylation, thus promoting de novo fatty acid synthesis in CRC cells. In summary, this study demonstrates that FUT2 promotes the proliferation and metastasis of CRC cells by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1, indicating that FUT2 might be a potential target for developing therapeutic strategies against CRC.
    DOI:  https://doi.org/10.1038/s42003-024-06993-x
  2. Mol Biomed. 2024 10 10. 5(1): 46
    Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy.
    Si-Min Chen, Bing-Jie Guo, An-Qiang Feng, Xue-Lian Wang, Sai-Long Zhang, Chao-Yu Miao.
      Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage.
    Keywords:  Biological targets; Intestinal stem cells; Radiation enteropathy; Signaling pathway; Treatment methods
    DOI:  https://doi.org/10.1186/s43556-024-00211-0
  3. Cell Rep Med. 2024 Oct 03. pii: S2666-3791(24)00523-8. [Epub ahead of print] 101778
    An RNA damage response network mediates the lethality of 5-FU in colorectal cancer.
    Jung-Kuei Chen, Karl A Merrick, Yi Wen Kong, Anita Izrael-Tomasevic, George Eng, Erika D Handly, Jesse C Patterson, Ian G Cannell, Lucia Suarez-Lopez, Aaron M Hosios, Anh Dinh, Donald S Kirkpatrick, Kebing Yu, Christopher M Rose, Jonathan M Hernandez, Haeun Hwangbo, Adam C Palmer, Matthew G Vander Heiden, Ömer H Yilmaz, Michael B Yaffe.
      5-fluorouracil (5-FU), a major anti-cancer therapeutic, is believed to function primarily by inhibiting thymidylate synthase, depleting deoxythymidine triphosphate (dTTP), and causing DNA damage. Here, we show that clinical combinations of 5-FU with oxaliplatin or irinotecan show no synergy in human colorectal cancer (CRC) trials and sub-additive killing in CRC cell lines. Using selective 5-FU metabolites, phospho- and ubiquitin proteomics, and primary human CRC organoids, we demonstrate that 5-FU-mediated CRC cell killing primarily involves an RNA damage response during ribosome biogenesis, causing lysosomal degradation of damaged rRNAs and proteasomal degradation of ubiquitinated ribosomal proteins. Tumor types clinically responsive to 5-FU treatment show upregulated rRNA biogenesis while 5-FU clinically non-responsive tumor types do not, instead showing greater sensitivity to 5-FU's DNA damage effects. Finally, we show that treatments upregulating ribosome biogenesis, including KDM2A inhibition, promote RNA-dependent cell killing by 5-FU, demonstrating the potential for combinatorial targeting of this ribosomal RNA damage response for improved cancer therapy.
    Keywords:  5-FU; 5-FU-based chemotherapy; RNA damage; ribosomal RNA; ribosomal protein
    DOI:  https://doi.org/10.1016/j.xcrm.2024.101778
  4. Nat Rev Cancer. 2024 Oct 10.
    Cancer-induced systemic pre-conditioning of distant organs: building a niche for metastatic cells.
    Nicolas Rabas, Rute M M Ferreira, Stefania Di Blasio, Ilaria Malanchi.
      From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.
    DOI:  https://doi.org/10.1038/s41568-024-00752-0
  5. bioRxiv. 2024 Sep 28. pii: 2024.09.26.615226. [Epub ahead of print]
    Tumor Cell Spatial Organization Directs EGFR/RAS/RAF Pathway Primary Therapy Resistance through YAP Signaling.
    Rachel Nakagawa, Andrew Beardsley, Sophia Durney, Mary-Kate Hayward, Vishvak Subramanyam, Nathaniel P Meyer, Harrison Wismer, Hani Goodarzi, Valerie M Weaver, Daniel Van de Mark, Andrei Goga.
      Non-small cell lung cancers (NSCLC) harboring common mutations in EGFR and KRAS characteristically respond transiently to targeted therapies against those mutations, but invariably, tumors recur and progress. Resistance often emerges through mutations in the therapeutic target or activation of alternative signaling pathways. Mechanisms of acute tumor cell resistance to initial EGFR (EGFRi) or KRAS G12C (G12Ci) pathway inhibition remain poorly understood. Our study reveals that acute response to EGFR/RAS/RAF-pathway inhibition is spatial and culture context specific. In vivo, EGFR mutant tumor xenografts shrink by > 90% following acute EGFRi therapy, and residual tumor cells are associated with dense stroma and have increased nuclear YAP. Interestingly, in vitro EGFRi induced cell cycle arrest in NSCLC cells grown in monolayer, while 3D spheroids preferentially die upon inhibitor treatment. We find differential YAP nuclear localization and activity, driven by the distinct culture conditions, as a common resistance mechanism for selective EGFR/KRAS/BRAF pathway therapies. Forced expression of the YAP S127A mutant partially protects cells from EGFR-mediated cell death in spheroid culture. These studies identify YAP activation in monolayer culture as a non-genetic mechanism of acute EGFR/KRAS/BRAF therapy resistance, highlighting that monolayer vs spheroid cell culture systems can model distinct stages of patient cancer progression.
    DOI:  https://doi.org/10.1101/2024.09.26.615226
  6. Genome Med. 2024 Oct 09. 16(1): 118
    DNA demethylation triggers cell free DNA release in colorectal cancer cells.
    Valeria Pessei, Marco Macagno, Elisa Mariella, Noemi Congiusta, Vittorio Battaglieri, Paolo Battuello, Marco Viviani, Giulia Gionfriddo, Simona Lamba, Annalisa Lorenzato, Daniele Oddo, Fariha Idrees, Alessandro Cavaliere, Alice Bartolini, Simonetta Guarrera, Michael Linnebacher, Laura Monteonofrio, Luca Cardone, Michele Milella, Andrea Bertotti, Silvia Soddu, Elena Grassi, Giovanni Crisafulli, Alberto Bardelli, Ludovic Barault, Federica Di Nicolantonio.
       BACKGROUND: Liquid biopsy based on cell-free DNA (cfDNA) analysis holds significant promise as a minimally invasive approach for the diagnosis, genotyping, and monitoring of solid malignancies. Human tumors release cfDNA in the bloodstream through a combination of events, including cell death, active and passive release. However, the precise mechanisms leading to cfDNA shedding remain to be characterized. Addressing this question in patients is confounded by several factors, such as tumor burden extent, anatomical and vasculature barriers, and release of nucleic acids from normal cells. In this work, we exploited cancer models to dissect basic mechanisms of DNA release.
    METHODS: We measured cell loss ratio, doubling time, and cfDNA release in the supernatant of a colorectal cancer (CRC) cell line collection (N = 76) representative of the molecular subtypes previously identified in cancer patients. Association analyses between quantitative parameters of cfDNA release, cell proliferation, and molecular features were evaluated. Functional experiments were performed to test the impact of modulating DNA methylation on cfDNA release.
    RESULTS: Higher levels of supernatant cfDNA were significantly associated with slower cell cycling and increased cell death. In addition, a higher cfDNA shedding was found in non-CpG Island Methylator Phenotype (CIMP) models. These results indicate a positive correlation between lower methylation and increased cfDNA levels. To explore this further, we exploited methylation microarrays to identify a subset of probes significantly associated with cfDNA shedding and derive a methylation signature capable of discriminating high from low cfDNA releasers. We applied this signature to an independent set of 176 CRC cell lines and patient derived organoids to select 14 models predicted to be low or high releasers. The methylation profile successfully predicted the amount of cfDNA released in the supernatant. At the functional level, genetic ablation of DNA methyl-transferases increased chromatin accessibility and DNA fragmentation, leading to increased cfDNA release in isogenic CRC cell lines. Furthermore, in vitro treatment of five low releaser CRC cells with a demethylating agent was able to induce a significant increase in cfDNA shedding.
    CONCLUSIONS: Methylation status of cancer cell lines contributes to the variability of cfDNA shedding in vitro. Changes in methylation pattern are associated with cfDNA release levels and might be exploited to increase sensitivity of liquid biopsy assays.
    Keywords:  Cell cycle; Cell death; Colorectal cancer; DNA methylation; Liquid biopsy; MSI; cfDNA
    DOI:  https://doi.org/10.1186/s13073-024-01386-5
  7. Stem Cell Res Ther. 2024 Oct 08. 15(1): 348
    Vasoactive intestinal peptide promotes secretory differentiation and mitigates radiation-induced intestinal injury.
    Tatiana Agibalova, Anneke Hempel, H Carlo Maurer, Mohab Ragab, Anastasia Ermolova, Jessica Wieland, Caroline Waldherr Ávila de Melo, Fabian Heindl, Maximilian Giller, Julius Clemens Fischer, Markus Tschurtschenthaler, Birgit Kohnke-Ertel, Rupert Öllinger, Katja Steiger, Ihsan Ekin Demir, Dieter Saur, Michael Quante, Roland M Schmid, Moritz Middelhoff.
       BACKGROUND: Vasoactive intestinal peptide (VIP) is a neuronal peptide with prominent distribution along the enteric nervous system. While effects of VIP on intestinal motility, mucosal vasodilation, secretion, and mucosal immune cell function are well-studied, the direct impact of VIP on intestinal epithelial cell turnover and differentiation remains less understood. Intestinal stem and progenitor cells are essential for the maintenance of intestinal homeostasis and regeneration, and their functions can be modulated by factors of the stem cell niche, including neuronal mediators. Here, we investigated the role of VIP in regulating intestinal epithelial homeostasis and regeneration following irradiation-induced injury.
    METHODS: Jejunal organoids were derived from male and female C57Bl6/J, Lgr5-EGFP-IRES-CreERT2 or Lgr5-EGFP-IRES-CreERT2/R26R-LSL-TdTomato mice and treated with VIP prior to analysis. Injury conditions were induced by exposing organoids to 6 Gy of irradiation (IR). To investigate protective effects of VIP in vivo, mice received 12 Gy of abdominal IR followed by intraperitoneal injections of VIP.
    RESULTS: We observed that VIP promotes epithelial differentiation towards a secretory phenotype predominantly via the p38 MAPK pathway. Moreover, VIP prominently modulated epithelial proliferation as well as the number and proliferative activity of Lgr5-EGFP+ progenitor cells under homeostatic conditions. In the context of acute irradiation injury in vitro, we observed that IR injury renders Lgr5-EGFP+ progenitor cells more susceptible to VIP-induced modulations, which coincided with the strong promotion of epithelial regeneration by VIP. Finally, the observed effects translate into an in vivo model of abdominal irradiation, where VIP showed to prominently mitigate radiation-induced injury.
    CONCLUSIONS: VIP prominently governs intestinal homeostasis by regulating epithelial progenitor cell proliferation and differentiation and promotes intestinal regeneration following acute irradiation injury.
    Keywords:  Intestinal progenitor cells; Irradiation; Regeneration; VIP
    DOI:  https://doi.org/10.1186/s13287-024-03958-z
  8. Front Oncol. 2024 ;14 1435480
    Lipids in the tumor microenvironment: immune modulation and metastasis.
    Gloria Pascual, Salvador Aznar Benitah.
      Tumor cells can undergo metabolic adaptations that support their growth, invasion, and metastasis, such as reprogramming lipid metabolism to meet their energy demands and to promote survival in harsh microenvironmental conditions, including hypoxia and acidification. Metabolic rewiring, and especially alterations in lipid metabolism, not only fuel tumor progression but also influence immune cell behavior within the tumor microenvironment (TME), leading to immunosuppression and immune evasion. These processes, in turn, may contribute to the metastatic spread of cancer. The diverse metabolic profiles of immune cell subsets, driven by the TME and tumor-derived signals, contribute to the complex immune landscape in tumors, affecting immune cell activation, differentiation, and effector functions. Understanding and targeting metabolic heterogeneity among immune cell subsets will be crucial for developing effective cancer immunotherapies that can overcome immune evasion mechanisms and enhance antitumor immunity.
    Keywords:  cancer immunotherapy; lipid metabolism; metabolic adaptations; tumor metabolism; tumor micreoenvironment (TME)
    DOI:  https://doi.org/10.3389/fonc.2024.1435480
  9. bioRxiv. 2024 Sep 26. pii: 2024.09.24.614701. [Epub ahead of print]
    Integrating spatial profiles and cancer genomics to identify immune-infiltrated mismatch repair proficient colorectal cancers.
    Jeremiah Wala, Ino de Bruijn, Shannon Coy, Andréanne Gagné, Sabrina Chan, Yu-An Chen, John Hoffer, Jeremy Muhlich, Nikolaus Schultz, Sandro Santagata, Peter K Sorger.
      Predicting the progression of solid cancers based solely on genetics is challenging due to the influence of the tumor microenvironment (TME). For colorectal cancer (CRC), tumors deficient in mismatch repair (dMMR) are more immune infiltrated than mismatch repair proficient (pMMR) tumors and have better prognosis following resection. Here we quantify features of the CRC TME by combining spatial profiling with genetic analysis and release our findings via a spatially enhanced version of cBioPortal that facilitates multi-modal data exploration and analysis. We find that ∼20% of pMMR tumors exhibit similar levels of T cell infiltration as dMMR tumors and that this is associated with better survival but not any specific somatic mutation. These T cell-infiltrated pMMR (tipMMR) tumors contain abundant cells expressing PD1 and PDL1 as well as T regulatory cells, consistent with a suppressed immune response. Thus, like dMMR CRC, tipMMR CRC may benefit from immune checkpoint inhibitor therapy.
    SIGNIFICANCE: pMMR tumors with high T cell infiltration and active immunosuppression are identifiable with a mid-plex imaging assay whose clinical deployment might double the number of treatment-naïve CRCs eligible for ICIs. Moreover, the low tumor mutational burden in tipMMR CRC shows that MMR status is not the only factor promoting immune infiltration.
    DOI:  https://doi.org/10.1101/2024.09.24.614701
  10. Nat Commun. 2024 Oct 07. 15(1): 8613
    Xenotransplanted human organoids identify transepithelial zinc transport as a key mediator of intestinal adaptation.
    Maame Efua S Sampah, Hannah Moore, Raheel Ahmad, Johannes Duess, Peng Lu, Carla Lopez, Steve Steinway, Daniel Scheese, Zachariah Raouf, Koichi Tsuboi, Jeffrey Ding, Connor Caputo, Madison McFarland, William B Fulton, Sanxia Wang, Meghan Wang, Thomas Prindle, Vered Gazit, Deborah C Rubin, Samuel Alaish, Chhinder P Sodhi, David J Hackam.
      Short bowel syndrome (SBS) leads to severe morbidity and mortality. Intestinal adaptation is crucial in improving outcomes. To understand the human gene pathways associated with adaptation, we perform single-cell transcriptomic analysis of human small intestinal organoids explanted from mice with experimental SBS. We show that transmembrane ion pathways, specifically the transepithelial zinc transport pathway genes SLC39A4 and SLC39A5, are upregulated in SBS. This discovery is corroborated by an external dataset, bulk RT-qPCR, and Western blots. Oral zinc supplementation is shown to improve survival and weight gain of SBS mice and increase the proliferation of intestinal crypt cells in vitro. Finally, we identify the upregulation of SLC39A5 and associated transcription factor KLF5 in biopsied intestinal tissue specimens from patients with SBS. Thus, we identify zinc supplementation as a potential therapy for SBS and describe a xenotransplantation model that provides a platform for discovery in other intestinal diseases.
    DOI:  https://doi.org/10.1038/s41467-024-52216-6
  11. Gastroenterology. 2024 Oct 09. pii: S0016-5085(24)05566-5. [Epub ahead of print]
    LRG1 promotes metastatic colorectal cancer growth through HER3 signaling.
    Moeez Rathore, Kimberly Curry, Wei Huang, Michel'le Wright, Daniel Martin, Jiyeon Baek, Derek Taylor, Masaru Miyagi, Wen Tang, Hao Feng, Yamu Li, Zhenghe Wang, Hallie Graor, Joseph Willis, Elizabeth Bryson, Christina S Boutros, Omkar Desai, Bianca Islam, Lee M Elis, Stephen E Moss, Jordan M Winter, John Greenwood, Rui Wang.
       BACKGROUND AND AIMS: Therapy failure in patients with metastatic colorectal cancer (mCRC, ∼80% occur in the liver) remains an overarching challenge. Preclinical studies demonstrated that HER3 promotes CRC cell survival, but therapies blocking the neuregulin-induced canonical HER3 signaling have made little impact in the clinic. Recent studies suggest that the liver microenvironment promotes CRC growth by activating HER3 in a neuregulin-independent fashion, thus elucidation of these mechanisms may reveal new strategies for treating patients with mCRC.
    METHODS: Patient-derived primary liver endothelial cells (ECs) were used to interrogate EC-CRC crosstalk. We conducted proteomic analysis to identify EC-secreted factor(s) that triggers non-canonical HER3 activation in CRC, and determined the subsequent effects on mCRC using diverse murine mCRC models. In vitro studies with genetic and pharmacological interventions were used to map the non-canonical HER3 pathway.
    RESULTS: We demonstrated that EC-secreted leucine-rich alpha-2-glycoprotein 1 (LRG1) directly binds and activates HER3 and promotes CRC growth distinct from neuregulin, the canonical HER3 ligand. Blocking host-derived LRG1 by gene knockout or a neutralizing antibody impaired mCRC outgrowth in the liver and prolonged mouse survival. We identified protein synthesis activated by the PI3K-PDK1-RSK-eIF4B axis as the biologically relevant signaling cascade downstream of the LRG1-HER3 interaction, which was not blocked by conventional HER3-specific antibodies that failed in prior clinical trials.
    CONCLUSIONS: LRG1 is a novel HER3 ligand and mediates liver-mCRC crosstalk. The LRG1-HER3 signaling axis is distinct from canonical HER3 signaling and represents a new therapeutic opportunity to treat patients with mCRC, and potentially other types of liver metastases.
    Keywords:  GI cancer; liver metastases; liver microenvironment; paracrine
    DOI:  https://doi.org/10.1053/j.gastro.2024.10.004
  12. Oncol Lett. 2024 Dec;28(6): 563
    Therapeutic efficacy of ferroptosis in the treatment of colorectal cancer (Review).
    Zhao Guo, Haoyan Zhuang, Xuewen Shi.
      Colorectal cancer (CRC) is the third most common malignancy worldwide, and the second leading cause of cancer-associated mortality. The incidence and mortality rates of CRC remain high, posing a significant threat to humans and overall quality of life. Current therapeutic strategies, such as surgery and chemotherapy, are limited due to disease recurrence, chemotherapeutic drug resistance and toxicity. Thus, research is focused on the development of novel treatment approaches. In 2012, ferroptosis was identified as a form of regulated cell death that is iron-dependent and driven by lipid peroxidation. Notably, therapies targeting ferroptosis exhibit potential in the treatment of disease; however, their role in CRC treatment remains controversial. The present study aimed to systematically review the mechanisms and signaling pathways of ferroptosis in CRC, and the specific role within the tumor microenvironment. Moreover, the present study aimed to review the role of ferroptosis in drug resistance, offering novel perspectives for the diagnosis and treatment of CRC.
    Keywords:  colorectal cancer; drug resistance; ferroptosis; mechanism of action; signaling pathway; tumor microenvironment
    DOI:  https://doi.org/10.3892/ol.2024.14697
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