bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2023–10–22
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells.
  2. The roles of the native cell differentiation program aberrantly recapitulated in Drosophila intestinal tumors.
  3. Inhibition of the RBMS1/PRNP axis improves ferroptosis resistance-mediated oxaliplatin chemoresistance in colorectal cancer.
  4. The cellular states and fates of shed intestinal cells.
  5. Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
  6. Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development.
  7. Delineating a role for methionine metabolism in colorectal cancer.
  8. ATP ion channel P2X7 receptor as a regulatory molecule in the progression of colorectal cancer.
  9. Dissecting the cellular states and fates of shed mouse intestinal cells.
  10. Current and potential treatment of colorectal cancer metastasis to bone.
  11. The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers.
  1. Sci Rep. 2023 Oct 16. 13(1): 17597
    Core clock gene BMAL1 and RNA-binding protein MEX3A collaboratively regulate Lgr5 expression in intestinal crypt cells.
    Li-Tzu Cheng, Grace Y T Tan, Fang-Pei Chang, Cheng-Kai Wang, Yu-Chi Chou, Pang-Hung Hsu, Wendy W Hwang-Verslues.
      The intestinal epithelium is highly regenerative. Rapidly proliferating LGR5+ crypt base columnar (CBC) cells are responsible for epithelial turnover needed to maintain intestinal homeostasis. Upon tissue damage, loss of LGR5+ CBCs can be compensated by activation of quiescent +4 intestinal stem cells (ISCs) or early progenitor cells to restore intestinal regeneration. LGR5+ CBC self-renewal and ISC conversion to LGR5+ cells are regulated by external signals originating from the ISC niche. In contrast, little is known about intrinsic regulatory mechanisms critical for maintenance of LGR5+ CBC homeostasis. We found that LGR5 expression in intestinal crypt cells is controlled by the circadian core clock gene BMAL1 and the BMAL1-regulated RNA-binding protein MEX3A. BMAL1 directly activated transcription of Mex3a. MEX3A in turn bound to and stabilized Lgr5 mRNA. Bmal1 depletion reduced Mex3a and Lgr5 expression and led to increased ferroptosis, which consequently decreased LGR5+ CBC numbers and increased the number of crypt cells expressing +4 ISC marker BMI1. Together, these findings reveal a BMAL1-centered intrinsic regulatory pathway that maintains LGR5 expression in the crypt cells and suggest a potential mechanism contributing to ISC homeostasis.
    DOI:  https://doi.org/10.1038/s41598-023-44997-5
  2. Cell Rep. 2023 Oct 12. pii: S2211-1247(23)01257-3. [Epub ahead of print]42(10): 113245
    The roles of the native cell differentiation program aberrantly recapitulated in Drosophila intestinal tumors.
    Inez Keiko Arlyne Pranoto, Jiae Lee, Young V Kwon.
      Many tumors recapitulate the developmental and differentiation program of their tissue of origin, a basis for tumor cell heterogeneity. Although stem-cell-like tumor cells are well studied, the roles of tumor cells undergoing differentiation remain to be elucidated. We employ Drosophila genetics to demonstrate that the differentiation program of intestinal stem cells is crucial for enabling intestinal tumors to invade and induce non-tumor-autonomous phenotypes. The differentiation program that generates absorptive cells is aberrantly recapitulated in the intestinal tumors generated by activation of the Yap1 ortholog Yorkie. Inhibiting it allows stem-cell-like tumor cells to grow but suppresses invasiveness and reshapes various phenotypes associated with cachexia-like wasting by altering the expression of tumor-derived factors. Our study provides insight into how a native differentiation program determines a tumor's capacity to induce advanced cancer phenotypes and suggests that manipulating the differentiation programs co-opted in tumors might alleviate complications of cancer, including cachexia.
    Keywords:  CP: Cancer; CP: Cell biology; Notch signaling; cachexia; cell differentiation; dissemination; focal adhesion; intestine; protrusions; stem cells; tumor cell heterogeneity
    DOI:  https://doi.org/10.1016/j.celrep.2023.113245
  3. Mol Carcinog. 2023 Oct 20.
    Inhibition of the RBMS1/PRNP axis improves ferroptosis resistance-mediated oxaliplatin chemoresistance in colorectal cancer.
    Yini Xu, Jingpeng Hao, Qiang Chen, Yafei Qin, Hong Qin, Shaohua Ren, Chenglu Sun, Yanglin Zhu, Bo Shao, Jingyi Zhang, Hao Wang.
      The majority of patients with advanced colorectal cancer have chemoresistance to oxaliplatin, and studies on oxaliplatin resistance are limited. Our research showed that RNA-binding motif single-stranded interacting protein 1 (RBMS1) caused ferroptosis resistance in tumor cells, leading to oxaliplatin resistance. We employed bioinformatics to evaluate publically accessible data sets and discovered that RBMS1 was significantly upregulated in oxaliplatin-resistant colorectal cancer cells, in tandem with ferroptosis suppression. In vivo and in vitro studies revealed that inhibiting RBMS1 expression caused ferroptosis in colorectal cancer cells, restoring tumor cell sensitivity to oxaliplatin. Mechanistically, this is due to RBMS1 inducing prion protein translation, resulting in ferroptosis resistance in tumor cells. Validation of clinical specimens revealed that RBMS1 is similarly linked to tumor development and a poor prognosis. Overall, RBMS1 is a potential therapeutic target with clinical translational potential, particularly for oxaliplatin chemoresistance in colorectal cancer.
    Keywords:  RNA-binding motif single-stranded interacting protein 1; colorectal cancer; ferroptosis; oxaliplatin resistance
    DOI:  https://doi.org/10.1002/mc.23647
  4. Nat Metab. 2023 Oct 19.
    The cellular states and fates of shed intestinal cells.
    Keren Bahar Halpern, Yael Korem Kohanim, Adi Biram, Yotam Harnik, Adi Egozi, Oran Yakubovsky, Ziv Shulman, Shalev Itzkovitz.
      The intestinal epithelium is replaced every few days1. Enterocytes are shed into the gut lumen predominantly from the tips of villi2,3 and have been believed to rapidly die upon their dissociation from the tissue4,5. However, technical limitations prohibited studying the cellular states and fates of shed intestinal cells. Here we show that shed epithelial cells remain viable and upregulate distinct anti-microbial programmes upon shedding, using bulk and single-cell RNA sequencing of male mouse intestinal faecal washes. We further identify abundant shedding of immune cells, which is elevated in mice with dextran sulfate sodium-induced colitis. We find that faecal host transcriptomics reflect changes in the intestinal tissue following perturbations. Our study suggests potential functions of shed cells in the intestinal lumen and demonstrates that host cell transcriptomes in intestinal washes can be used to probe tissue states.
    DOI:  https://doi.org/10.1038/s42255-023-00905-9
  5. Cancer Metab. 2023 Oct 19. 11(1): 18
    Aspirin reprogrammes colorectal cancer cell metabolism and sensitises to glutaminase inhibition.
    Amy K Holt, Arafath K Najumudeen, Tracey J Collard, Hao Li, Laura M Millett, Ashley J Hoskin, Danny N Legge, Eleanor M H Mortensson, Dustin J Flanagan, Nicholas Jones, Madhu Kollareddy, Penny Timms, Matthew D Hitchings, James Cronin, Owen J Sansom, Ann C Williams, Emma E Vincent.
       BACKGROUND: To support proliferation and survival within a challenging microenvironment, cancer cells must reprogramme their metabolism. As such, targeting cancer cell metabolism is a promising therapeutic avenue. However, identifying tractable nodes of metabolic vulnerability in cancer cells is challenging due to their metabolic plasticity. Identification of effective treatment combinations to counter this is an active area of research. Aspirin has a well-established role in cancer prevention, particularly in colorectal cancer (CRC), although the mechanisms are not fully understood.
    METHODS: We generated a model to investigate the impact of long-term (52 weeks) aspirin exposure on CRC cells, which has allowed us comprehensively characterise the metabolic impact of long-term aspirin exposure (2-4mM for 52 weeks) using proteomics, Seahorse Extracellular Flux Analysis and Stable Isotope Labelling (SIL). Using this information, we were able to identify nodes of metabolic vulnerability for further targeting, investigating the impact of combining aspirin with metabolic inhibitors in vitro and in vivo.
    RESULTS: We show that aspirin regulates several enzymes and transporters of central carbon metabolism and results in a reduction in glutaminolysis and a concomitant increase in glucose metabolism, demonstrating reprogramming of nutrient utilisation. We show that aspirin causes likely compensatory changes that render the cells sensitive to the glutaminase 1 (GLS1) inhibitor-CB-839. Of note given the clinical interest, treatment with CB-839 alone had little effect on CRC cell growth or survival. However, in combination with aspirin, CB-839 inhibited CRC cell proliferation and induced apoptosis in vitro and, importantly, reduced crypt proliferation in Apcfl/fl mice in vivo.
    CONCLUSIONS: Together, these results show that aspirin leads to significant metabolic reprogramming in colorectal cancer cells and raises the possibility that aspirin could significantly increase the efficacy of metabolic cancer therapies in CRC.
    Keywords:  Aspirin; CB-839; Colorectal cancer; Glutaminase; Metabolic reprogramming; Metabolism
    DOI:  https://doi.org/10.1186/s40170-023-00318-y
  6. Nat Commun. 2023 Oct 16. 14(1): 6514
    Sleeping Beauty transposon mutagenesis identified genes and pathways involved in inflammation-associated colon tumor development.
    Kana Shimomura, Naoko Hattori, Naoko Iida, Yukari Muranaka, Kotomi Sato, Yuichi Shiraishi, Yasuhito Arai, Natsuko Hama, Tatsuhiro Shibata, Daichi Narushima, Mamoru Kato, Hiroyuki Takamaru, Koji Okamoto, Haruna Takeda.
      Chronic inflammation promotes development and progression of colorectal cancer (CRC). To comprehensively understand the molecular mechanisms underlying the development and progression of inflamed CRC, we perform in vivo screening and identify 142 genes that are frequently mutated in inflammation-associated colon tumors. These genes include senescence and TGFβ-activin signaling genes. We find that TNFα can induce stemness and activate senescence signaling by enhancing cell plasticity in colonic epithelial cells, which could act as a selective pressure to mutate senescence-related genes in inflammation-associated colonic tumors. Furthermore, we show the efficacy of the Cdk4/6 inhibitor in vivo for inflammation-associated colonic tumors. Finally, we functionally validate that Arhgap5 and Mecom are tumor suppressor genes, providing possible therapeutic targets for CRC. Thus, we demonstrate the importance of the inactivation of senescence pathways in CRC development and progression in an inflammatory microenvironment, which can help progress toward precision medicine.
    DOI:  https://doi.org/10.1038/s41467-023-42228-z
  7. Cancer Res. 2023 Oct 17.
    Delineating a role for methionine metabolism in colorectal cancer.
    Shiyu Liu, Jason W Locasale.
      Advances in mass spectrometry allow for broader applications of metabolomics in research and clinical applications. In a recent issue of Nature Metabolism, Voorde and colleagues utilized metabolite profiling to investigate the metabolism of colorectal cancer (CRC) in mouse models, organoids and patients. This study underscores the utility of metabolomics in distinguishing CRC, offering potential for its use in precision medicine. It also revealed a pivotal role for adenosylhomocysteinase in the methionine cycle and highlighted its potential as a therapeutic target.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-3169
  8. Eur J Med Chem. 2023 Oct 13. pii: S0223-5234(23)00844-9. [Epub ahead of print]261 115877
    ATP ion channel P2X7 receptor as a regulatory molecule in the progression of colorectal cancer.
    Cheng Zuo, Yong-Sheng Xu, Peng-Fei He, Wen-Jun Zhang.
      Large amounts of adenosine triphosphate (ATP), a natural P2X7 receptor activator, are released during colorectal carcinogenesis. P2X7 receptor activation regulates the activity of colorectal cancer (CRC) cells by mediating intracellular signal transduction. Importantly, the opening and activation of membrane pores of P2X7 receptor are different, which can play a dual role in promoting or inhibiting the progression of CRC. These can also depend on P2X7 receptor to regulate the activities of immune cells in the microenvironment, play the functions of immune regulation, immune escape and immune monitoring. While the use of P2X7 receptor antagonists (such as BBG, A438079 and A740003) can play a certain inhibitory pharmacological role on the activity of CRC. Therefore, in this paper, the mechanism and immunomodulatory function of P2X7 receptor involved in the progression of CRC were discussed. Moreover, we discussed the effect of antagonizing the activity of P2X7 receptor on the progression of CRC. So P2X7 receptor may be a new pharmacological molecular target for the treatment of CRC.
    Keywords:  Antagonists; Colorectal cancer (CRC); Immune escape; P2X7 receptor; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ejmech.2023.115877
  9. Nat Metab. 2023 Oct 20.
    Dissecting the cellular states and fates of shed mouse intestinal cells.
      
    DOI:  https://doi.org/10.1038/s42255-023-00907-7
  10. Cancer Treat Res Commun. 2023 Sep 16. pii: S2468-2942(23)00085-0. [Epub ahead of print]37 100763
    Current and potential treatment of colorectal cancer metastasis to bone.
    Lauren Holladay, Jennie Luu, Vyshnavy Balendra, Kevin Kmetz.
       BACKGROUND: Colorectal cancer (CRC) with subsequent bone metastasis is associated with a poor prognosis compared with patients who do not develop bone metastasis. However, metastasis in bone is rare, contrasted with more common locations such as the liver and lungs. As a result, the treatment methods targeting CRC bone lesions are limited. This review aims to compile information regarding current and potential medical and surgical treatment methods for colorectal cancer with specific regard to bone metastasis.
    METHODS: A computer-based literature review of animal- and human-based studies was conducted using multiple database searches. Case reports were excluded.
    RESULTS: Preliminary findings demonstrate that treatments specifically targeting bone metastasis due to colorectal cancer are categorized by local vs. systemic treatment. The primary goals are the alleviation of skeletal-related events and improvement in quality of life. Current options include: chemotherapy, radiation, monoclonal antibodies, and surgery. Emerging options include intratumoral mellitin, MRgFUS, and bone microenvironment targeting.
    CONCLUSION: Treatment of CRC metastasis to bone is necessary to slow down metastatic progression, alleviate symptoms, and improve quality of life. With a possible rise in bone metastasis due to increased overall CRC survival rates, more clinical trials should be performed to address this growing concern.
    Keywords:  Bone metastasis; Chemotherapy; Colorectal cancer; Radiation; Surgery; Treatment
    DOI:  https://doi.org/10.1016/j.ctarc.2023.100763
  11. Cancer Drug Resist. 2023 ;6(6): 468-480
    The multidrug resistance transporter P-glycoprotein confers resistance to ferroptosis inducers.
    William J E Frye, Lyn M Huff, José M González Dalmasy, Paula Salazar, Rachel M Carter, Ryan T Gensler, Dominic Esposito, Robert W Robey, Suresh V Ambudkar, Michael M Gottesman.
      Aim: Ferroptosis is a non-apoptotic form of cell death caused by lethal lipid peroxidation. Several small molecule ferroptosis inducers (FINs) have been reported, yet little information is available regarding their interaction with the ATP-binding cassette (ABC) transporters P-glycoprotein (P-gp, ABCB1) and ABCG2. We thus sought to characterize the interactions of FINs with P-gp and ABCG2, which may provide information regarding oral bioavailability and brain penetration and predict drug-drug interactions. Methods: Cytotoxicity assays with ferroptosis-sensitive A673 cells transfected to express P-gp or ABCG2 were used to determine the ability of the transporters to confer resistance to FINs; confirmatory studies were performed in OVCAR8 and NCI/ADR-RES cells. The ability of FINs to inhibit P-gp or ABCG2 was determined using the fluorescent substrates rhodamine 123 or purpuin-18, respectively. Results: P-gp overexpression conferred resistance to FIN56 and the erastin derivatives imidazole ketone erastin and piperazine erastin. P-gp-mediated resistance to imidazole ketone erastin and piperazine erastin was also reversed in UO-31 renal cancer cells by CRISPR-mediated knockout of ABCB1. The FINs ML-162, GPX inhibitor 26a, and PACMA31 at 10 µM were able to increase intracellular rhodamine 123 fluorescence over 10-fold in P-gp-expressing MDR-19 cells. GPX inhibitor 26a was able to increase intracellular purpurin-18 fluorescence over 4-fold in ABCG2-expressing R-5 cells. Conclusion: Expression of P-gp may reduce the efficacy of these FINs in cancers that express the transporter and may prevent access to sanctuary sites such as the brain. The ability of some FINs to inhibit P-gp and ABCG2 suggests potential drug-drug interactions.
    Keywords:  ABCG2; Ferroptosis; P-glycoprotein; drug resistance
    DOI:  https://doi.org/10.20517/cdr.2023.29
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