bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–07–06
thirteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain



  1. Cell Death Dis. 2025 Jul 01. 16(1): 475
      Cadherin 17 (CDH17) plays a crucial role in the metastatic progression of colorectal cancer (CRC) through its interaction with α2β1 integrin and desmocollin 1. To further elucidate the molecular mechanisms involving CDH17 functions in CRC, we examined global expression alterations following CDH17 silencing in various metastatic cell lines. Loss of CDH17 resulted in a marked down-regulation of the intestinal cancer stem cell (CSC) marker LGR5, leading to the inhibition of Wnt/β-catenin signaling, suppression of pluripotency genes such as MYC, and a subsequent reduction in stemness properties. Treatment with CDH17/integrin blocking antibodies produced similar effects, decreasing both, LGR5 expression and Wnt signaling. CDH17 silencing also down-regulated various transporters associated with drug-resistance, including the glutamine-transporter SLC38A5. Consequently, the loss of CDH17 increased sensitivity to 5-FU, irinotecan, oxidative stress and anoikis in CRC cells. Notably, SLC38A5 silencing was necessary for CDH17-driven effects on drug resistance and survival. Pharmacological inhibition of SLC38A5 with amiloride, significantly increased cell sensitivity to 5-FU and irinotecan, and improved mouse survival in metastasis models. In conclusion, CDH17 plays a crucial role in maintaining colorectal cancer cell stemness and chemoresistance via LGR5/Wnt/MYC signaling and SLC38A5 expression. These findings underscore the therapeutic potential of CDH17 targeting in metastatic CRC, and support the use of amiloride for inhibiting liver metastasis.
    DOI:  https://doi.org/10.1038/s41419-025-07811-w
  2. Sci Rep. 2025 Jul 02. 15(1): 22886
      Cancer stem cells (CSCs) are present in small quantities in tumor populations. To permit various analyses of CSCs, we attempted to enrich and expand ornithine decarboxylase (ODC) degron-transduced colorectal cancer (CRC) cells, which retain low proteasome activity. ZsGreen fluorescence-positive (ZsGreen+) cells were collected by sorting the ODC degron-transduced HCT116, DLD1, and SW480 cells, which were defined as enriched ZsGreen+ cells. ZsGreen+ cells still maintained CSC properties. These cells had higher stem cell marker expression and increased resistance to chemotherapy with 5-fluorouracil and oxaliplatin. ZsGreen+ HCT116 and DLD1 cells had greater sphere-forming ability and enhanced tumorigenicity compared to ZsGreen- control cells. Time-lapse microscopy showed that a single enriched ZsGreen+ HCT116 cell had asymmetric cell division. Thus, cancer stem model cells were acquired in sufficient quantity. Using these cells, we performed a comprehensive microRNA analysis; miR-491-3p was a candidate to suppress cancer stemness. Finally, we found that up-regulated genes in the enriched HCT116 ZsGreen+ cells correlated with those up-regulated in human clinical spheroid samples established from patient-derived xenografts (PDXs) derived from CRC tissue samples, further supporting the acquisition of enriched model CSCs. These cells with the aid of clinical spheroid samples would be useful in identifying novel CSC markers and developing medicine for anti-CSC therapy.
    DOI:  https://doi.org/10.1038/s41598-025-04277-w
  3. Cell Res. 2025 Jul 04.
      Phenotypic plasticity is a hallmark feature driving cancer progression, metastasis, and therapy resistance. Fetal-like transcriptional programs have been increasingly implicated in promoting plastic cell states, yet their roles remain difficult to study due to limitations of existing culture models. Here, we establish a chemically defined patient-derived organoid system that enables long-term expansion of colorectal cancer (CRC) cells while preserving fetal-like features associated with phenotypic plasticity. Using this model, we identify an oncofetal state (OnFS) that is enriched in advanced tumors and linked to key features of plasticity, including epithelial-mesenchymal plasticity, as well as increased metastasis and treatment resistance. Mechanistically, we show that FGF2-AP-1 signaling maintains the OnFS program and associated phenotypic plasticity in CRC. This model offers a powerful platform for studying the fetal-like features underlying cancer cell plasticity and their role in tumor progression and treatment resistance in CRC.
    DOI:  https://doi.org/10.1038/s41422-025-01139-y
  4. Signal Transduct Target Ther. 2025 Jun 30. 10(1): 206
      Cancer stem cells (CSCs) are responsible for colorectal cancer (CRC) chemoresistance, recurrence, and metastasis. Therefore, identifying molecular stemness targets that are involved in tumor growth is crucial for effective treatment. Here, we performed an extensive in vitro and in vivo molecular and functional characterization, revealing the pivotal role of the lysine methyltransferase SET and MYND Domain Containing 3 (SMYD3) in colorectal cancer stem cell (CRC-SC) biology. Specifically, we showed that SMYD3 interacts with and methylates c-MYC at K158 and K163, thereby modulating its transcriptional activity, which is implicated in stemness and colorectal malignancy. Our in vitro data suggest that SMYD3 pharmacological inhibition or its stable genetic ablation affects the clonogenic and self-renewal potential of patient-derived CRC-SCs and organoids by altering their molecular signature. Moreover, we found that SMYD3 stable knock-out or pharmacological inhibition drastically reduces CRC tumorigenicity in vivo and CRC-SC metastatic potential. Overall, our findings identify SMYD3 as a promising therapeutic target acting directly on c-MYC, with potential implications for countering CRC-SC proliferation and metastatic dissemination.
    DOI:  https://doi.org/10.1038/s41392-025-02290-z
  5. Nat Commun. 2025 Jul 01. 16(1): 5461
      The intestinal epithelium undergoes fast turnover, and the villus length in the small intestine gradually decreases from the duodenum to the ileum. However, the underlying mechanisms remain poorly understood. In this study, we investigate the regulatory mechanism underlying the regional disparity of villus length. A progressive strengthening of BMP signaling from the duodenum to the jejunum and ileum establishes a signaling gradient, resulting in differences in the rates of cell proliferation and apoptosis. We show that BMP signaling regulates the survival of the small intestine epithelial cells by inhibiting integrin expression and thereby inducing cell apoptosis. Combined with mathematical modeling, our data reveal that BMP signaling provides positional cues and antagonizes Wnt signaling to control villus growth, while Wnt signaling promotes BMP signaling to counteract excessive proliferation, thus maintaining villus length. Our findings provide insights into the signaling dynamics governing epithelial turnover and villus length in the small intestine.
    DOI:  https://doi.org/10.1038/s41467-025-60643-2
  6. J Exp Clin Cancer Res. 2025 Jul 03. 44(1): 186
      Emerging evidence demonstrates that the metabolic and non-metabolic functions of metabolic enzymes play a key role in tumorigenesis and progression. 6-phosphogluconate dehydrogenase (6PGD) is a key metabolic enzyme in the pentose phosphate pathway (PPP), which displays aberrant expressions and functions in cancer. However, whether 6PGD serves non-metabolic functions in regulating cancer progression and drug response has not been reported. Here, we found that highly expressed 6PGD contributes to colorectal cancer (CRC) tumor growth and tumor metastasis. Mechanistically, 6PGD binds to ALKBH5 and inhibits its activity through the non-metabolic activity of 6PGD; this increases m6A modification levels and the stability of MDM2 mRNA and decreases the p53 protein stability, subsequently activating the expression of CCNA2 and HMGA2, which are responses to CRC tumor growth and tumor metastasis. Collectively, these findings reveal the multi-functionality of 6PGD in promoting CRC tumor growth, tumor metastasis, and drug responses through its non-metabolic activity.
    Keywords:  6-phosphogluconate dehydrogenase (6PGD); Colorectal cancer (CRC); Metastasis; Non-metabolic activity; Proliferation
    DOI:  https://doi.org/10.1186/s13046-025-03450-3
  7. Adv Sci (Weinh). 2025 Jul 02. e00019
      Ferroptosis is a specific type of lipid peroxide-mediated cell death which is crucial in tumor suppression. While the mitochondrial carrier homolog 2 (MTCH2) is implicated in lipid homeostasis and mitochondrial metabolism, its role in ferroptosis and colorectal cancer (CRC) remains uncharacterized. Here, MTCH2 is identified as a crucial regulator of ferroptosis in CRC progression. Clinically, high expression of MTCH2 in CRC tissues predicts poor prognosis. Functionally, loss of MTCH2 inhibits azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colorectal tumorigenesis in MTCH2cKO mice and leads to accumulation of ferrous ion and enhances ferroptosis of CRC in vitro and in vivo. Mechanistically, MTCH2 deficiency promotes the proteasome-dependent ubiquitination of E2F4 and attenuates transcriptional inhibition of transferrin receptor (TFRC) by E2F4, ultimately facilitating TFRC-mediated ferroptosis in CRC cells. Moreover, MTCH2 depletion combined with sorafenib treatment synergistically triggers ferroptosis, suppresses liver metastasis, and effectively eradicates tumors in liver metastasis foci. Taken together, This study reveals the mechanism of MTCH2 deficiency-induced ferroptosis to inhibit the progression of CRC and supports a potential therapeutic strategy targeting the MTCH2/E2F4/TFRC signaling axis in CRC patients with liver metastasis.
    Keywords:  MTCH2; colorectal cancer; ferroptosis; liver metastasis; sorafenib
    DOI:  https://doi.org/10.1002/advs.202500019
  8. Cancer Res. 2025 Jul 03.
      The pronounced desmoplastic response in pancreatic ductal adenocarcinoma (PDAC) contributes to the development of a microenvironment depleted of oxygen and nutrients. To survive in this hostile environment, PDAC cells employ various adaptive mechanisms that may represent therapeutic targets. Here, we showed that nutrient starvation and microenvironmental signals commonly present in PDAC tumors activate PPAR-δ to rewire cellular metabolism and promote invasive and metastatic properties both in vitro and in vivo. Mild mitochondrial inhibition induced by low-dose etomoxir or signals from tumor-associated macrophages altered the lipidome and triggered the downstream transcriptional program of PPAR-δ. Specifically, PPAR-δ reduced mitochondrial oxygen consumption and boosted the glycolytic capacity by altering the ratio of MYC and PGC1A expression, two key regulators of pancreatic cancer metabolism. Notably, genetic or pharmacological inhibition of PPAR-δ prevented this metabolic rewiring and suppressed both invasiveness in vitro and metastasis in vivo. These findings establish PPAR-δ as a central driver of metabolic reprogramming in response to starvation and tumor microenvironmental cues that promotes a pro-metastatic phenotype in PDAC, suggesting that PPAR-δ inhibition could serve as a therapeutic strategy to combat PDAC progression.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3475
  9. Genes Immun. 2025 Jul 03.
      Folic acid plays a crucial role in cellular regulation and metabolism, commonly included in dietary supplements. Despite this, its involvement in colorectal cancer (CRC), particularly in metabolic pathways and immune evasion, remains poorly understood. We developed the FMRG_score system using machine learning algorithms on TCGA and GEO data to assess modification patterns influencing clinical outcomes and immune characteristics in CRC. The system's reliability was validated across multiple external immunotherapy cohorts. We examined associations between FMRG-related features and clinical traits, mutation profiles, biological functions, immune infiltration, therapy responses, and drug sensitivities. By integrating in vitro and in vivo experiments with bioinformatics, we built a nine-gene risk model linked to folate metabolism for CRC prognosis. Notably, CYP26A1, a key gene in the model, was upregulated in CRC tissues, promoting cell proliferation, migration, invasion, and contributing to an immunosuppressive tumor microenvironment. Significant differences in clinical traits, immune infiltration, checkpoint expression, therapy response, and drug sensitivity were observed between risk groups. This folate-based scoring system provides a novel tool for evaluating CRC prognosis, tumor microenvironment, and response to immunotherapy. We also propose CYP26A1 as a potential oncogene in CRC, offering new therapeutic insights.
    DOI:  https://doi.org/10.1038/s41435-025-00342-6
  10. Nat Aging. 2025 Jun 30.
      Diapause is a long-lived state of resilience that allows organisms to outlast adversity. Caenorhabditis elegans can endure months in a fasting-induced adult reproductive diapause (ARD) and, upon refeeding, regenerate and reproduce. Here we find that mutants of ARD master regulator hlh-30/TFEB arrest in a senescence-like state during ARD and refeeding, in which germline stem cells are characterized by DNA damage, nucleolar expansion, cell cycle arrest and mitochondrial dysfunction, alongside dysregulated immune and growth metabolic signatures, elevated senescence-associated β-galactosidase and premature aging at the organismal level. Forward genetic screens reveal a TFEB-TGFβ signaling axis that systemically controls diapause, stem cell longevity and senescence, aligning nutrient supply to proper metabolism and growth signaling. Notably, TFEB's vital role is conserved in mouse embryonic and human cancer diapause. Thus, ARD offers a powerful model to study stem cell longevity and senescence in vivo, directly relevant to mammals.
    DOI:  https://doi.org/10.1038/s43587-025-00911-4
  11. BMC Gastroenterol. 2025 Jul 01. 25(1): 480
       BACKGROUND: Colorectal cancer (CRC) is a common cause of cancer-related mortality and is mainly influenced by metabolic dysfunction. The β-alanine metabolic pathway plays an important role in altering the aggressiveness and metabolic characteristics of the cancer cells. This study aimed to investigate the genetic role of the β-alanine metabolic pathway in CRC patient survival.
    METHODS: Using a Cox regression model, we assessed the impact of 27 single-nucleotide polymorphisms (SNPs) from 31 genes in the β-alanine metabolic pathway on overall survival (OS) and progression-free survival (PFS) in 287 patients with CRC. Additional methods, including differential expression analysis, expression quantitative trait loci analysis, dual-luciferase reporter assay, and cell phenotype assay, were used to evaluate the genetic function of candidate SNPs in tumor progression.
    RESULTS: We identified that SNP rs2811182 A > G allele located in DPYD was significantly associated with poorer prognosis of CRC, with hazard ratio (HR) of 0.63 for OS [95% confidence interval (CI) = 0.45-0.88, P = 7.12 × 10-3] and 0.68 for PFS (95% CI = 0.52-0.89, P = 5.01 × 10-3). Mechanistically, the G allele of rs2811182 increased DPYD transcriptional activity and expression by mediating the binding affinity of the transcription factor POU1F1. Importantly, the overexpression of DPYD reduced the malignant cell phenotypes of proliferation, migration, and invasion.
    CONCLUSIONS: This study indicates a pivotal genetic role for the β-alanine metabolic pathway, particularly rs2811182 in DPYD, in influencing CRC prognosis. These findings offer new perspectives for personalized treatment strategies and enhance our understanding of CRC pathogenesis.
    Keywords:  Beta-alanine metabolism; Colorectal cancer; Prognosis; Single-nucleotide polymorphisms
    DOI:  https://doi.org/10.1186/s12876-025-04051-2
  12. Sci Rep. 2025 Jul 02. 15(1): 22717
      Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. Increasing evidence has shown that ferroptosis plays a significant regulatory role in the occurrence and progression of cancer. However, new biomarkers associated with ferroptosis and new ferroptosis-related subtypes in CRC remain to be identified. We collected a colon adenocarcinoma (COAD) dataset from the cancer genome atlas (TCGA) database in UCSC Xena. Ferroptosis-related genes (FRGs) were extracted from the dataset, and we conducted gene expression profiling interactive analysis (GEPIA), cBioPortal analysis, and immune cell infiltration analysis. Additionally, we used the "ConsensusClusterPlus" R package to identify ferroptosis-related subtypes of CRC. Based on these subtypes, we analyzed their prognostic features, gene co-expression networks, and the ferroptosis landscape. We identified 21 FRGs in COAD. The genes RBMS1, NOX4, FABP4, CYB5R1, CPEB1, and ATM were significantly and positively correlated with immune cell infiltration and poor prognosis. Furthermore, we identified two COAD subtypes related to prognosis and ferroptosis (ferroptosis subtype 1 [FS1] and ferroptosis subtype 2 [FS2]). These subtypes were associated with tumor mutation burden (TMB), mutation status, immunogenic cell death (ICD), and immune checkpoint (ICP) regulatory genes. Finally, we established a ferroptosis landscape of COAD. We identified key ferroptosis-related genes and defined two distinct ferroptosis-associated subtypes in CRC that differ significantly in prognosis and immune infiltration. These findings provide new insights into the interaction between ferroptosis and the tumor immune microenvironment, offering potential biomarkers and therapeutic targets for improved diagnosis and personalized treatment of colorectal cancer.
    Keywords:  Colorectal cancer; Consensus cluster; Ferroptosis; TCGA
    DOI:  https://doi.org/10.1038/s41598-025-08901-7