bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–02–02
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Intestinal stem cells in intestinal homeostasis and colorectal tumorigenesis.
  2. Inhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids.
  3. Prostaglandin E2 and Akt promote stemness in Apc mutant Dclk1+ cells to give rise to colitis-associated cancer.
  4. Pioneering a New Frontier: Modeling the Epithelial-immune Cell Axis Using Human Intestinal Organoids.
  5. Beyond chemotherapy: Exploring 5-FU resistance and stemness in colorectal cancer.
  6. Merging metabolic modeling and imaging for screening therapeutic targets in colorectal cancer.
  7. A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity.
  8. Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis.
  9. Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer.
  10. Predicting patient outcomes with gene-expression biomarkers from colorectal cancer organoids and cell lines.
  11. HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1.
  12. Establishment of novel colorectal cancer organoid model based on tumor microenvironment analysis.
  1. Life Med. 2024 Oct;3(5): lnae042
    Intestinal stem cells in intestinal homeostasis and colorectal tumorigenesis.
    Gaoli Shi, Yang Li, Haihong Shen, Qiankun He, Pingping Zhu.
      Colorectal cancer (CRC), one of the most common tumors in the world, is generally proposed to be generated from intestinal stem cells (ISCs). Leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive ISCs are located at the bottom of the crypt and harbor self-renewal and differentiation capacities, serving as the resource of all intestinal epithelial cells and CRC cells as well. Here we review recent progress in ISCs both in non-tumoral and tumoral contexts. We summarize the molecular mechanisms of ISC self-renewal, differentiation, and plasticity for intestinal homeostasis and regeneration. We also discuss the function of ISCs in colorectal tumorigenesis as cancer stem cells and summarize fate dynamic, competition, niche regulation, and remote environmental regulation of ISCs for CRC initiation and propagation.
    Keywords:  cancer stem cells; differentiation; intestinal stem cells; niche; self-renewal
    DOI:  https://doi.org/10.1093/lifemedi/lnae042
  2. BMC Cancer. 2025 Jan 23. 25(1): 136
    Inhibition of BRD4 attenuated IFNγ-induced apoptosis in colorectal cancer organoids.
    Akimi Yonezawa, Kana Shimomura, Koji Okamoto, Haruna Takeda.
       BACKGROUND: This study aimed to analyze the functional role of Brd4 in colorectal cancer (CRC) organoids. Brd4 was identified as a CRC-related gene by our previous Sleeping Beauty mutagenesis transposon screening in mice. Brd4 is a transcriptional regulator that recognizes acetylated histones and is known to be involved in inflammatory responses. The role of Brd4 in CRC development remains largely unknown.
    METHODS: We knocked out Brd4 in tumor organoids carrying mutations in Apc and Kras to generate Brd4KO organoids, and performed RNA-seq. The response of Brd4KO organoids to IFNγ was analyzed via a cell viability assay, an apoptosis assay, and RNAseq. The results were validated by pharmacological inhibition experiments with JQ1 in human CRC organoids.
    RESULTS: In Brd4KO organoids, the IFNγ signaling genes Il33 and Myc target genes were downregulated. The addition of IFNγ to the colon organoids induced apoptosis, but IFNγ-induced apoptosis was attenuated in the Brd4KO organoids compared with the control organoids (two-sided t-test, P < 0.05). Similar results were obtained from pharmacological inhibition with JQ1 in human CRC organoids; IL33 expression was decreased, and IFNγ-induced apoptosis was attenuated in the presence of JQ1.
    CONCLUSIONS: Our results showed that the inhibition of Brd4 suppressed IFNγ-induced cytotoxicity by modulating the Jak-Stat pathway. These data suggested that the inhibition of Brd4 could increase cell viability in the cancer microenvironment where IFNγ is abundant, revealing a new aspect of the molecular mechanism of CRC development. Our results may help in evaluating the application of Bet inhibitors in treating CRC. Additionally, our RNA-seq data sets will be helpful for clarifying the relationship between Brd4 and immunomodulators, such as Il33, or for studying the responses of colonic epithelial cells to IFNγ.
    Keywords:  Apoptosis; Brd4; Colorectal cancer; IFNγ; IL33; JQ1; Organoid
    DOI:  https://doi.org/10.1186/s12885-025-13544-y
  3. Cell Mol Gastroenterol Hepatol. 2025 Jan 28. pii: S2352-345X(25)00010-4. [Epub ahead of print] 101469
    Prostaglandin E2 and Akt promote stemness in Apc mutant Dclk1+ cells to give rise to colitis-associated cancer.
    Hayley J Good, Frederikke Larsen, Alice E Shin, Liyue Zhang, Mathieu Derouet, David Meriwether, Daniel Worthley, Srinivasa T Reddy, Timothy C Wang, Samuel Asfaha.
       BACKGROUND AND AIMS: Loss of the tumor suppressor gene Apc in Lgr5+ intestinal stem cells results in aberrant Wnt signaling and colonic tumorigenesis. In the setting of injury, however, we and others have also shown that non-stem cells can also give rise to colonic tumors. The mechanism by which inflammation leads to cellular plasticity and cancer, however, remains largely unknown.
    METHODS: RNA expression analysis of Wnt, COX and Akt signaling was assessed in patients with quiescent or active UC and patients with UC-associated neoplasia using available datasets. The role of COX signaling in colonic tumorigenesis was examined using epithelial and Dclk1+ cell specific conditional COX-1 knockout mice and pharmacologic treatment with different NSAIDs.
    RESULTS: In this study, we show that prostaglandins and phospho-Akt are key inflammatory mediators that promote stemness in Apc mutant Dclk1+ cells that give rise to colorectal cancer. Moreover, prostaglandin E2 (PGE2) and Akt are increased in colitis in both mice and humans, leading to inflammation-associated dysplasia upon activation of Wnt signaling. Importantly, inhibition of epithelial derived COX-1 by Aspirin or conditional knockout in Dclk1+ cells reduced PGE2 levels and prevented the development of inflammation-associated colorectal cancer.
    CONCLUSIONS: Our data shows that epithelial and Dclk1+ cell derived COX-1 plays an important role in inflammation-associated tumorigenesis. Importantly, low dose Aspirin was effective in chemo-prevention through inhibition of COX-1 that reduced colitis-associated cancer.
    Keywords:  Aspirin; Dclk1; colitis; colon cancer; stem cells
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101469
  4. Cell Mol Gastroenterol Hepatol. 2025 Jan 23. pii: S2352-345X(25)00002-5. [Epub ahead of print] 101461
    Pioneering a New Frontier: Modeling the Epithelial-immune Cell Axis Using Human Intestinal Organoids.
    Scott T Magness.
      
    DOI:  https://doi.org/10.1016/j.jcmgh.2025.101461
  5. Eur J Pharmacol. 2025 Jan 23. pii: S0014-2999(25)00047-0. [Epub ahead of print]991 177294
    Beyond chemotherapy: Exploring 5-FU resistance and stemness in colorectal cancer.
    Ursheeta Singh, Rekha Rani Kokkanti, Srinivas Patnaik.
      Colorectal cancer (CRC) remains a significant global health challenge, demanding continuous advancements in treatment strategies. This review explores the complexities of targeting colorectal cancer stem cells (CSCs) and the mechanisms contributing to resistance to 5-fluorouracil (5-FU). The efficacy of 5-FU is enhanced by combination therapies such as FOLFOXIRI and targeted treatments like bevacizumab, cetuximab, and panitumumab, particularly in KRAS wild-type tumors, despite associated toxicity. Biomarkers like thymidylate synthase (TYMS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD) are crucial for predicting 5-FU efficacy and resistance. Targeting CRC-CSCs remains challenging due to their inherent resistance to conventional therapies, marker variability, and the protective influence of the tumor microenvironment which promotes stemness and survival. Personalized treatment strategies are increasingly essential to address CRC's genetic and phenotypic diversity. Advances in immunotherapy, including immune checkpoint inhibitors and cancer vaccines, along with nanomedicine-based therapies, offer promising targeted drug delivery systems that enhance specificity, reduce toxicity, and provide novel approaches for overcoming resistance mechanisms. Integrating these innovative strategies with traditional therapies may enhance the effectiveness of CRC therapy by addressing the underlying causes of 5-FU resistance in CSCs.
    Keywords:  5-Fluorouracil; Cancer stem cells; Colorectal cancer; Drug resistance; Targeted therapy
    DOI:  https://doi.org/10.1016/j.ejphar.2025.177294
  6. NPJ Syst Biol Appl. 2025 Jan 28. 11(1): 12
    Merging metabolic modeling and imaging for screening therapeutic targets in colorectal cancer.
    Niki Tavakoli, Emma J Fong, Abigail Coleman, Yu-Kai Huang, Mathias Bigger, Michael E Doche, Seungil Kim, Heinz-Josef Lenz, Nicholas A Graham, Paul Macklin, Stacey D Finley, Shannon M Mumenthaler.
      Cancer-associated fibroblasts (CAFs) play a key role in metabolic reprogramming and are well-established contributors to drug resistance in colorectal cancer (CRC). To exploit this metabolic crosstalk, we integrated a systems biology approach that identified key metabolic targets in a data-driven method and validated them experimentally. This process involved a novel machine learning-based method to computationally screen, in a high-throughput manner, the effects of enzyme perturbations predicted by a computational model of CRC metabolism. This approach reveals the network-wide effects of metabolic perturbations. Our results highlighted hexokinase (HK) as a crucial target, which subsequently became our focus for experimental validation using patient-derived tumor organoids (PDTOs). Through metabolic imaging and viability assays, we found that PDTOs cultured in CAF-conditioned media exhibited increased sensitivity to HK inhibition, confirming the model predictions. Our approach emphasizes the critical role of integrating computational and experimental techniques in exploring and exploiting CRC-CAF crosstalk.
    DOI:  https://doi.org/10.1038/s41540-025-00494-1
  7. Cancer Res. 2025 Jan 31.
    A 3D Self-Assembly Platform Integrating Decellularized Matrix Recapitulates In Vivo Tumor Phenotypes and Heterogeneity.
    Michael J Buckenmeyer, Elizabeth A Brooks, Madison S Taylor, Ireolu K Orenuga, Liping Yang, Ronald J Holewinski, Thomas J Meyer, Melissa Galloux, Marcial Garmendia-Cedillos, Thomas J Pohida, Thorkell Andresson, Brad St Croix, Matthew T Wolf.
      Three-dimensional (3D) in vitro cell culture models are invaluable tools for investigating the tumor microenvironment (TME). However, analyzing the impact of critical stromal elements, such as extracellular matrix (ECM), remains a challenge. Here, we developed a hydrogel-free self-assembly platform to establish ECM-rich 3D "MatriSpheres" to deconvolute cancer cell-ECM interactions. Mouse and human colorectal cancer (CRC) MatriSpheres actively incorporated microgram quantities of decellularized small intestine submucosa ECM, which proteomically-mimicked CRC tumor ECM compared to traditional formulations like Matrigel. Solubilized ECM, at sub-gelation concentrations, was organized by CRC cells into intercellular stroma-like regions within 5 days, displaying morphological similarity to CRC clinical pathology. MatriSpheres featured ECM-dependent transcriptional and cytokine profiles associated with malignancy, lipid metabolism, and immunoregulation. Model benchmarking with scRNA sequencing demonstrated that MatriSpheres enhanced correlation with in vivo tumor cells over traditional ECM-poor spheroids. This facile approach enables tumor-specific tissue morphogenesis, promoting cell-ECM communication to improve fidelity for disease modeling applications.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-1954
  8. Cell Death Discov. 2025 Jan 25. 11(1): 21
    Autophagic flux-lipid droplet biogenesis cascade sustains mitochondrial fitness in colorectal cancer cells adapted to acidosis.
    Xiaojie Liu, Xue Sun, Wenqing Mu, Yanan Li, Wenqing Bu, Tingting Yang, Jia Zhang, Rui Liu, Jiayu Ren, Jin Zhou, Peishan Li, Yufang Shi, Changshun Shao.
      Cancer development is associated with adaptation to various stressful conditions, such as extracellular acidosis. The adverse tumor microenvironment also selects for increased malignancy. Mitochondria are integral in stress sensing to allow for tumor cells to adapt to stressful conditions. Here, we show that colorectal cancer cells adapted to acidic microenvironment (CRC-AA) are more reliant on oxidative phosphorylation than their parental cells, and the acetyl-CoA in CRC-AA cells are generated from fatty acids and glutamine, but not from glucose. Consistently, CRC-AA cells exhibit increased mitochondrial mass and fitness that depends on an upregulated autophagic flux-lipid droplet axis. Lipid droplets (LDs) function as a buffering system to store the fatty acids derived from autophagy and to protect mitochondria from lipotoxicity in CRC-AA cells. Blockade of LD biogenesis causes mitochondrial dysfunction that can be rescued by inhibiting carnitine palmitoyltransferase 1 α (CPT1α). High level of mitochondrial superoxide is essential for the AMPK activation, resistance to apoptosis, high autophagic flux and mitochondrial function in CRC-AA cells. Thus, our results demonstrate that the cascade of autophagic flux and LD formation plays an essential role in sustaining mitochondrial fitness to promote cancer cell survival under chronic acidosis. Our findings provide insight into the pro-survival metabolic plasticity in cancer cells under microenvironmental or therapeutic stress and imply that this pro-survival cascade may potentially be targeted in cancer therapy.
    DOI:  https://doi.org/10.1038/s41420-025-02301-6
  9. Mol Oncol. 2025 Jan 28.
    Molecular and functional profiling unravels targetable vulnerabilities in colorectal cancer.
    Efstathios-Iason Vlachavas, Konstantinos Voutetakis, Vivian Kosmidou, Spyridon Tsikalakis, Spyridon Roditis, Konstantinos Pateas, Ryangguk Kim, Kymberleigh Pagel, Stephan Wolf, Gregor Warsow, Antonia Dimitrakopoulou-Strauss, Georgios N Zografos, Alexander Pintzas, Johannes Betge, Olga Papadodima, Stefan Wiemann.
      Colorectal cancer (CRC) patients with microsatellite-stable (MSS) tumors are mostly treated with chemotherapy. Clinical benefits of targeted therapies depend on mutational states and tumor location. Many tumors carry mutations in KRAS proto-oncogene, GTPase (KRAS) or B-Raf proto-oncogene, serine/threonine kinase (BRAF), rendering them more resistant to therapies. We performed whole-exome sequencing and RNA-Sequencing of 28 tumors of the Athens Comprehensive Cancer Center CRC cohort, and molecularly characterized CRC patients based on their microsatellite instability (MSI) status, single-nucleotide variations (SNVs)/copy number alterations (CNAs), and pathway/transcription factor activities at the individual patient level. Variants were classified using a computational score for integrative cancer variant annotation and prioritization. Complementing this with public multi-omics datasets, we identified activation of transforming growth factor beta (TGFβ) signaling to be more strongly activated in MSS patients, whereas Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) molecular cascades were activated specifically in MSI tumors. We unraveled mechanisms consistently perturbed in the transcriptional and mutational circuits and identified Runt-related transcription factors (RUNX transcription factors) as putative biomarkers in CRC, given their role in the regulation of pathways involved in tumor progression and immune evasion. Assessing the immunogenicity of CRC tumors in the context of RAS/RAF mutations and MSI/MSS status revealed a critical impact that KRAS mutations have on immunogenicity, particularly in the MSS patient subgroup, with implications for diagnosis and treatment.
    Keywords:  CRC; MSI status; RAS/RAF; SNVs/CNAs; WES/RNA‐sequencing; pathway/TF activity
    DOI:  https://doi.org/10.1002/1878-0261.13814
  10. Front Mol Biosci. 2025 ;12 1531175
    Predicting patient outcomes with gene-expression biomarkers from colorectal cancer organoids and cell lines.
    Alexandra Razumovskaya, Mariia Silkina, Andrey Poloznikov, Timur Kulagin, Maria Raigorodskaya, Nina Gorban, Anna Kudryavtseva, Maria Fedorova, Boris Alekseev, Alexander Tonevitsky, Sergey Nikulin.
       Introduction: Colorectal cancer (CRC) is characterized by an extremely high mortality rate, mainly caused by the high metastatic potential of this type of cancer. To date, chemotherapy remains the backbone of the treatment of metastatic colorectal cancer. Three main chemotherapeutic drugs used for the treatment of metastatic colorectal cancer are 5-fluorouracil, oxaliplatin and irinotecan which is metabolized to an active compound SN-38. The main goal of this study was to find the genes connected to the resistance to the aforementioned drugs and to construct a predictive gene expression-based classifier to separate responders and non-responders.
    Methods: In this study, we analyzed gene expression profiles of seven patient-derived CRC organoids and performed correlation analyses between gene expression and IC50 values for the three standard-of-care chemotherapeutic drugs. We also included in the study publicly available datasets of colorectal cancer cell lines, thus combining two different in vitro models relevant to cancer research. Logistic regression was used to build gene expression-based classifiers for metastatic Stage IV and non-metastatic Stage II/III CRC patients. Prognostic performance was evaluated through Kaplan-Meier survival analysis and log-rank tests, while independent prognostic significance was assessed using multivariate Cox proportional hazards modeling.
    Results: A small set of genes showed consistent correlation with resistance to chemotherapy across different datasets. While some genes were previously implicated in cancer prognosis and drug response, several were linked to drug resistance for the first time. The resulting gene expression signatures successfully stratified Stage II/III and Stage IV CRC patients, with potential clinical utility for improving treatment outcomes after further validation.
    Discussion: This study highlights the advantages of integrating diverse experimental models, such as organoids and cell lines, to identify novel prognostic biomarkers and enhance the understanding of chemotherapy resistance in CRC.
    Keywords:  chemotherapy; colorectal cancer; drug resistance; organoids; response prediction; transcriptomic gene signature
    DOI:  https://doi.org/10.3389/fmolb.2025.1531175
  11. Cell Signal. 2025 Jan 26. pii: S0898-6568(25)00040-3. [Epub ahead of print] 111627
    HDAC2 promotes colorectal tumorigenesis by triggering dysregulation of lipid metabolism through YAP1.
    Zhanghan Chen, Weifeng Hong, Bing Li, Dongli He, Zhong Ren, Mingyan Cai, Yirong Cheng, Jingyi Liu, Enpan Xu, Yanyun Du, Yuelun Dong, Shilun Cai, Qiang Shi, Zhipeng Qi, Yunshi Zhong.
      Dysfunction of lipid metabolism is important for the development and progression of colorectal cancer, but the underlying mechanisms remain unclear. Here, HDAC2 was identified as highly expressed in both adenoma and colorectal cancer. We aimed to explore the roles and mechanisms of HDAC2 in lipid metabolism in colorectal cancer. HDAC2 expression in adenoma and colorectal cancer tissues was measured using tissue arrays. The function of HDAC2/YAP1 was identified using in vitro and in vivo experiments. Coimmunoprecipitation experiments, DNA pull-down assays, luciferase analyses, and ChIP-qPCR (Chromatin Immunoprecipitation-quantitative real-time polymerase chain reaction) assays were used to identify the potential mechanisms of HDAC2. We found that HDAC2 can disrupt lipid metabolism in colorectal cancer by mediating the deacetylation of YAP1. Mechanistically, HDAC2 can bind to YAP1 and mediate deacetylation of the K280 site of YAP1. Furthermore, the deacetylation of YAP1 reduces the efficiency of its binding to the ZMYND11 promoter region, exacerbating lipid metabolism disorders, which in turn reduce lipid accumulation and increase lipid catabolism in colorectal cancer cells. Our study identified a novel regulatory mechanism of lipid metabolism in colorectal cancer in which HDAC2 increases lipid catabolism by regulating the deacetylation of the K280 site of YAP1, revealing that HDAC2 promotes tumor progression through the regulation of lipid metabolism.
    Keywords:  Colorectal cancer; HDAC2; Lipid metabolism; YAP1
    DOI:  https://doi.org/10.1016/j.cellsig.2025.111627
  12. Life Med. 2024 Aug;3(4): lnae027
    Establishment of novel colorectal cancer organoid model based on tumor microenvironment analysis.
    Zhidong Xu, Shengwen Meng, Ran Xu, De Ma, Emmanuel Enoch Dzakah, Hailun Zheng, Tingjing Yao, Chao Ni, Bing Zhao.
      
    DOI:  https://doi.org/10.1093/lifemedi/lnae027
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