bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–08–03
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism.
  2. Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype.
  3. Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.
  4. ACADS Suppresses Proliferation of Colorectal Cancer Cells via ROS-Triggered Autophagy and Degradation of CDK2.
  5. Protocol for automated graph-based clustering of single-cell RNA-seq data with application in mouse intestinal stem cells.
  6. ATRX loss induces lineage plasticity and squamous-like phenotype to promote colorectal cancer metastasis.
  7. Crosstalk between hippo and Wnt pathways in intestinal stem cells regeneration.
  8. Metabolic adaptations in cancer progression.
  9. Valproic acid improves the efficacy of oxaliplatin/fluoropyrimidine-based chemotherapy by targeting cancer stem cell via β-Catenin modulation in colorectal cancer.
  10. Development of a bispecific CDH17-GUCY2C ADC bearing the ferroptosis inducer RSL3 for the treatment of colorectal cancer.
  11. Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription.
  12. Epigenetic regulation of cancer stemness.
  13. Ferreting Out Ferroptosis: Extending the Mechanism of Action of RSL3 to the Selenoproteome in Colorectal Cancer.
  14. Anoikis and NETosis in colorectal cancer liver metastasis: the relationship and perspectives.
  1. Oncogene. 2025 Jul 25.
    Liquid-liquid phase separation of GPS2-LATS1 promotes colorectal cancer progression by reprogramming lipid metabolism.
    Yuliang Ren, Junjie Chen, Xiangrong Zhan, Songran Sheng, Yifan Zhong, Manxiang Gu, Xuewen Liu, Liang Zhang, Lei Bao, Yuan Si, Ying Liu.
      Aberrant lipid metabolism is a hallmark of colorectal cancer (CRC), yet the underlying regulatory mechanisms remain incompletely understood. Here, we identified G protein pathway suppressor 2 (GPS2) as a pivotal oncogenic driver that orchestrates lipid metabolic reprogramming to fuel CRC progression. Clinically, GPS2 is overexpressed in CRC and is correlated with aggressive phenotypes. Functionally, GPS2 depletion inhibits tumor growth in vitro and in vivo, whereas its overexpression accelerates malignancy. Mechanistically, GPS2 dual-regulates lipid metabolism by facilitating the nuclear translocation of sterol regulatory element-binding protein 1 (SREBP1) to activate lipid synthesis and by increasing peroxisome proliferator-activated receptor α (PPARα) transcription to promote fatty acid oxidation. Crucially, we revealed that GPS2 undergoes liquid-liquid phase separation (LLPS) in CRC cells, where it forms biomolecular condensates that promote oncogenic signaling. Through its coiled-coil domain, phase-separated GPS2 directly interacts with the C-terminal kinase domain of large tumor suppressor 1 (LATS1), a core kinase of the Hippo pathway, inducing LLPS of LATS1 and suppressing its activity. This inactivation releases YAP, which in turn amplifies SREBP1/PPARα-driven lipid metabolism. Rescue experiments confirmed that YAP reconstitution restores SREBP1 nuclear translocation and PPARα transcription upon GPS2 loss, establishing the LATS1-YAP axis as the central effector of GPS2-mediated lipid metabolic programming. Our study delineates a novel phase separation-dependent mechanism whereby GPS2 spatially reorganizes LATS1-YAP signaling to reprogram lipid metabolism and promote CRC progression, suggesting potential therapeutic targets for metabolic intervention in CRC.
    DOI:  https://doi.org/10.1038/s41388-025-03498-7
  2. Adv Sci (Weinh). 2025 Jul 29. e05436
    Acidosis Forces Fatty Acid Uptake and Metabolism in Cancer Cells Regardless of Genotype.
    Sébastien Ibanez, Maria Virginia Giolito, Sultan Al-Siyabi, Kristian Serafimov, Florine Laloux, Emeline Dierge, Léo Aubert, Céline Guilbaud, Selena Kaye, Paula Varon, Dorothée Marchand, Hanne Vlieghe, Emmanuel Hermans, Caroline Bouzin, Davide Brusa, Christiani Andrade Amorim, Barabara Pachikian, Yvan Larondelle, Cyril Corbet, Chantal Dessy, Olivier Feron.
      While proteins facilitate fatty acid (FA) partitioning into plasma membranes, movement between membrane leaflets occurs through a "flip-flop" mechanism. This study provides evidence that biological acidosis, as encountered in tumors and ischemic diseases, promotes FA protonation, thereby enhancing neutral, non-ionized FA uptake. This positions the altered lipid metabolism in acid-exposed cells as a consequence, rather than a cause, of preferential FA uptake. Cancer cell vulnerability, independent of their genetic background, directly stems from this paradigm shift, as detoxifying the overload of very long-chain FA (VLCFA) becomes highly dependent on peroxisomal activity. Inhibition of peroxisomal function in acid-exposed cancer cells leads to the rerouting of these fatty acids into triglycerides within lipid droplets, but also into phospholipids, contributing to membrane alterations, triggering ER stress, and ultimately supporting cytotoxicity. Using patient-derived tumor organoids and sera from human volunteers supplemented with polyunsaturated FA (PUFA), it is shown that inhibiting peroxisomal ACOX1 selectively kills acid-exposed cancer cells, an effect exacerbated by pharmacological stimulation of glycolysis. Similar acid-driven FA uptake is observed in endothelial cells and cardiac myocytes, opening new therapeutic avenues not only cancer but also cardiovascular diseases.
    Keywords:  acidosis; cancer; fatty acid; lipid metabolism; peroxisome
    DOI:  https://doi.org/10.1002/advs.202505436
  3. Cell Rep Med. 2025 Jul 22. pii: S2666-3791(25)00326-X. [Epub ahead of print] 102253
    Therapeutic targeting of syndecan-1 axis overcomes acquired resistance to KRAS-targeted therapy in gastrointestinal cancers.
    Madelaine S Theardy, Mitsunobu Takeda, Alexey Sorokin, Shuaitong Chen, Zecheng Yang, Xiaofei Wang, Preeti Kanikarla, Oluwadara Coker, Phuoc Nguyen, Yongkun Wei, Jun Yao, Liang Yan, Yanqing Jin, Yiming Cai, Masakatsu Paku, Ziheng Chen, Kara Z Li, Francesca Citron, Hideo Tomihara, Sisi Gao, Angela K Deem, Jun Zhao, Huamin Wang, Samir Hanash, Ronald A DePinho, Anirban Maitra, Giulio F Draetta, Haoqiang Ying, Scott Kopetz, Wantong Yao.
      The therapeutic benefit of recently developed mutant KRAS (KRAS∗) inhibitors remains limited by the rapid onset of resistance. Here, we aim to delineate mechanisms underlying acquired resistance and identify actionable targets for overcoming this clinical challenge. Previously, we identified syndecan-1 (SDC1) as a key effector for pancreatic cancer progression whose surface expression is driven by KRAS∗. By leveraging both pancreatic and colorectal cancer models, we show that surface SDC1 expression initially diminishes upon KRAS∗ inhibition but recovers in tumor cells that bypass KRAS∗ dependency. Mechanistically, we reveal that YAP1 activation drives the recovery of SDC1 surface localization to enhance macropinocytosis-mediated nutrient salvaging and activation of multiple receptor tyrosine kinases for tumor maintenance, promoting resistance to KRAS∗-targeted therapy. Overall, our study provides a strong rationale for targeting the YAP-SDC1 axis to overcome resistance to KRAS∗ inhibition, thereby revealing promising therapeutic opportunities for improving the clinical outcome of patients with KRAS∗-mutated cancers.
    Keywords:  KRAS inhibitor; colorectal cancer; macropinocytosis; pancreatic cancer; syndecan; therapy resistance
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102253
  4. FASEB J. 2025 Jul 31. 39(14): e70878
    ACADS Suppresses Proliferation of Colorectal Cancer Cells via ROS-Triggered Autophagy and Degradation of CDK2.
    Yimeng Ma, Meiting Tong, Baiwang Zhu, Lunan Chen, Chenhui Xu, Gaojie Cao, Junyu Wang, Zixuan Xue, Qipeng Xie, Xiaodong Zhang, Chuanshu Huang, Lingling Zhao, Haishan Huang.
      Autophagy is a survival mechanism by which cells adapt to the changes of the microenvironment. It may play two completely opposite roles in promoting or inhibiting the progression of cancer, depending on specific cellular conditions, including ROS levels, metabolic stress status, and other microenvironmental factors. However, the mechanism underlying autophagy regulation of cancer development remains poorly understood. Acyl-CoA dehydrogenase short chain (ACADS), an enzyme essential for mitochondrial short-chain fatty acid β-oxidation, plays a crucial role in fatty acid metabolism. Here, we present evidence that ACADS is downregulated significantly in colorectal cancer (CRC) tissues and that this downregulation correlates with poor patient prognosis. Using in vitro and in vivo models, we demonstrate that ACADS inhibits the proliferation of CRC cells, suggesting a potential role as a tumor suppressor. Mechanistically, we show that ACADS induces autophagy by increasing reactive oxygen species levels, leading to autophagy-mediated degradation of CDK2 and subsequent cell cycle arrest at the G0/G1 phase. These findings establish ACADS-autophagy as a negative axis of CRC progression and highlight its potential as a therapeutic target for CRC.
    Keywords:  ACADS; CDK2; autophagy; cell proliferation; colorectal cancer
    DOI:  https://doi.org/10.1096/fj.202500185R
  5. STAR Protoc. 2025 Jul 31. pii: S2666-1667(25)00406-X. [Epub ahead of print]6(3): 104000
    Protocol for automated graph-based clustering of single-cell RNA-seq data with application in mouse intestinal stem cells.
    Alexander L E Wang, Luca Zanella, Yosuke Ochiai, Leonardo Golinelli, Andrea Califano, Ermanno Malagola, Alessandro Vasciaveo.
      We present a protocol for isolating highly purified crypt epithelial cells from the mouse intestine for single-cell RNA sequencing (scRNA-seq). Optimized for the mouse jejunum, it can be adapted to all intestinal tracts, including the colon. The pipeline incorporates automated community detection of cell populations (ACDC), a time- and memory-efficient Python package for automated graph-based optimal clustering of large scRNA-seq datasets. We demonstrate its usage to identify cellular populations in an intestinal stem cell dataset and generate publication-ready figures. For complete details on the use and execution of this protocol, please refer to Malagola et al.1.
    Keywords:  Bioinformatics; Cell Biology; Cell Differentiation; Cell isolation; Flow Cytometry; Genomics; Molecular Biology; RNA-seq; Sequence analysis; Single Cell; Stem Cells
    DOI:  https://doi.org/10.1016/j.xpro.2025.104000
  6. Trends Cell Biol. 2025 Jul 24. pii: S0962-8924(25)00155-2. [Epub ahead of print]
    ATRX loss induces lineage plasticity and squamous-like phenotype to promote colorectal cancer metastasis.
    Yali Chen, Gaili Ji, Peishan Hu, Rong Xiang.
      Colorectal cancer (CRC) metastasis is driven by phenotypic plasticity beyond classic epithelial-mesenchymal transition (EMT), including non-canonical lineages such as squamous-like phenotypes. Their regulatory mechanisms and clinical significance remain unclear. In the current issue of Nature, Cammareri et al. identified ATRX loss as a driver of multilineage plasticity, including squamous-like characteristics, linked to increased metastasis and poor clinical outcomes in CRC.
    Keywords:  ATRX; CRC; metastasis; multilineage plasticity; squamous-like phenotype
    DOI:  https://doi.org/10.1016/j.tcb.2025.07.003
  7. Cell Signal. 2025 Jul 24. pii: S0898-6568(25)00438-3. [Epub ahead of print]135 112023
    Crosstalk between hippo and Wnt pathways in intestinal stem cells regeneration.
    Yanqiu Li, Yujun Hou, Yue He, Kexin Cheng, Ying Chen, Ying Li, Siyuan Zhou.
      Intestinal stem cell (ISC) regeneration is the key to maintaining intestinal homeostasis. The proliferation and differentiation of ISCs are regulated by the specific cells in the stem cell niche, and these cells mainly regulate ISC activity through secreting related ligands of various pathways, among which the Wnt pathway is the primary pathway regulating ISC regeneration, and the Hippo pathway plays an important role in controlling organ size and repairing injury. Accumulating evidence has identified that these two pathways closely cooperate to regulate the self-renewal and regeneration of ISCs, which has important significance in the maintenance of intestinal homeostasis and the treatment of intestinal disorders. Therefore, we provide an overview of the interaction of the Wnt and Hippo pathways in ISC regeneration and intestinal diseases, which not only sheds light on the mechanisms of maintaining intestinal homeostasis but also paves the way for novel therapeutic strategies for intestinal diseases.
    Keywords:  Crosstalk; Hippo pathway; Intestinal stem cell regeneration; Wnt pathway
    DOI:  https://doi.org/10.1016/j.cellsig.2025.112023
  8. Physiol Rev. 2025 Jul 28.
    Metabolic adaptations in cancer progression.
    Yiming Peng-Winkler, Sarah-Maria Fendt.
      Cancer cells reprogram their metabolism as they travel to distant organs to establish metastases, the leading cause of cancer-related mortality. While the metabolic state of primary tumors has been extensively studied, the specific metabolic alterations associated with metastases have only recently garnered significant attention. The metabolic dependencies that arise during the metastatic cascade, along with the adaptive metabolic shifts required for growth in a new microenvironment, present promising therapeutic targets. In this review, we provide an overview of cancer metabolism, followed by a detailed exploration of the metabolic changes occurring at each stage of metastasis and within common organs of metastatic spread. Lastly, we examine the potential and challenges of targeting metabolic pathways in cancer therapy.
    Keywords:  Cancer; Metabolism; Metabolism-based therapy; Metastasis; Organ microenvironment
    DOI:  https://doi.org/10.1152/physrev.00037.2024
  9. Cell Death Dis. 2025 Aug 01. 16(1): 583
    Valproic acid improves the efficacy of oxaliplatin/fluoropyrimidine-based chemotherapy by targeting cancer stem cell via β-Catenin modulation in colorectal cancer.
    Maria Serena Roca, Rita Lombardi, Cristina Testa, Federica Iannelli, Laura Grumetti, Tania Moccia, Veronica Barile, Laura Addi, Domenico Memoli, Alessandra Leone, Simone Di Franco, Giorgio Stassi, Antonio Avallone, Francesca Bruzzese, Biagio Pucci, Alfredo Budillon, Elena Di Gennaro.
      Despite advances in systemic therapeutic approaches, metastatic colorectal cancer (mCRC) patients harboring BRAF or RAS mutations have poor outcomes. Cancer stem cells (CSCs) play central roles in drug resistance and CRC recurrence. Therefore, targeting the epigenetic mechanisms that sustain CSC properties is a promising therapeutic approach. In this study, we report the efficacy of a treatment strategy with the potential to overcome chemotherapy resistance that involves administering the well-known antiepileptic drug and epigenetic agent valproic acid (VPA) and the standard chemotherapy regimen of oxaliplatin/fluoropyrimidine to wild-type CSCs and CSCs with BRAF and RAS mutations in enriched primary spheroid cultures. Notably, we demonstrated that VPA plus chemotherapy was more effective than other epigenetic drug-chemotherapy combinations by inhibiting cell proliferation and clonogenic growth and by inducing apoptosis and DNA damage. Mechanistically, proteomic analysis demonstrated that VPA induced CSC differentiation through the critical target of VPA, β-Catenin. Indeed, VPA promoted the proteasome-dependent degradation of β-Catenin by enhancing its binding to the E2 ubiquitin-conjugating enzyme UBE2a, leading to marked reductions in nuclear and cytoplasmic β-Catenin levels and subsequently decreasing β-Catenin/TCF-LEF target promoter activation. These effects were confirmed in three in vivo CRC xenograft models, including a syngeneic CT26 immunocompetent mouse model, where VPA combined with oxaliplatin/capecitabine chemotherapy and anti-VEGF therapy, a standard first-line treatment for mCRC, significantly suppressed tumor growth and prolonged survival with minimal toxicity. Proteomic analysis of tumor tissues from in vivo CRC models confirmed the VPA-mediated downregulation of CSC markers and β-Catenin.
    DOI:  https://doi.org/10.1038/s41419-025-07902-8
  10. Cell Death Discov. 2025 Jul 28. 11(1): 347
    Development of a bispecific CDH17-GUCY2C ADC bearing the ferroptosis inducer RSL3 for the treatment of colorectal cancer.
    Ying Zhang, Jing Du, Xiaohong Cui, Yuhang Ling, Chengwu Tang.
      Colorectal cancer is a malignant tumor of the colon or rectum, with approximately 150,000 new cases each year. Current treatment strategies, such as surgery, chemotherapy, radiotherapy, and immunotherapy, face challenges ranging from cancer recurrence, drug resistance to significant toxicity. Therefore, these patients urgently need more effective treatments. Ferroptosis, a novel form of cell death characterized by iron-dependent lipid peroxidation, has emerged as a promising new approach for treating colorectal cancer. Inactivation of phospholipid hydroperoxide glutathione peroxidase (GPX4) or the cysteine/glutamate antiporter SLC7A11 leads to the depletion of cellular glutathione (GSH), resulting in lipid peroxidation and subsequent ferroptosis. Here, we found that CDH17 and GUCY2C are co-overexpressed in colorectal cancer cells and developed a bispecific antibody-drug conjugate (BsADC) targeting CDH17 and GUCY2C, conjugated with the ferroptosis inducer RSL3 (a GPX4 inhibitor). Experimental results showed that, compared to monoclonal antibody ADCs, BsADC exhibits better binding and internalization activities, and could inhibit tumor cell proliferation more effectively. Moreover, the BsADC displayed an advantageous safety profile in mice. These findings suggest that the CDH17-GUCY2C BsADC, which induces ferroptosis in tumor cells, could be a promising new treatment for colorectal cancer.
    DOI:  https://doi.org/10.1038/s41420-025-02652-0
  11. Sci Adv. 2025 Jul 25. 11(30): eadw4974
    Hippo signaling regulates the nuclear behavior and DNA binding times of YAP and TEAD to control transcription.
    Benjamin Kroeger, Samuel A Manning, Varshini Mohan, Jieqiong Lou, Guizhi Sun, Sara Lamont, Alex J McCann, Mathias Francois, Jose M Polo, Elizabeth Hinde, Kieran F Harvey.
      Over the past two decades, genetic and proteomic screens have identified the Hippo pathway as a complex signaling network that controls tissue growth and human cancer. Despite these advances, our understanding of how Hippo signaling regulates transcription is less clear. To address this, we used live microscopy to study the nuclear behavior of the major Hippo pathway transcription effectors, YAP and TEADs. We reveal that TEADs are a major determinant of YAP DNA binding and nuclear mobility, while YAP minorly influences TEADs. YAP and TEAD1 associate with DNA for longer periods in cells with intrinsically low Hippo pathway activity and upon acute Hippo pathway perturbation. TEAD1 binds the genome on a broad range of timescales, and this is extended substantially in nuclear condensates. Last, a cancer-associated YAP fusion protein exhibits substantially different biophysical behavior than either YAP or TEAD1. Thus, we reveal that Hippo signaling regulates transcription, in part, by influencing the DNA binding times of YAP and TEADs.
    DOI:  https://doi.org/10.1126/sciadv.adw4974
  12. Signal Transduct Target Ther. 2025 Aug 01. 10(1): 243
    Epigenetic regulation of cancer stemness.
    Claudia Galassi, Gwenola Manic, Manel Esteller, Lorenzo Galluzzi, Ilio Vitale.
      Gene expression is finely controlled by the abundance and activation status of transcription factors and their regulators, as well as by a number of reversible modifications of DNA and histones that are commonly referred to as epigenetic marks. Such alterations (i.e., methylation, acetylation, and ubiquitination) are catalyzed by an array of dedicated enzymes with antagonistic activity, including methyltransferases and demethylases, acetyltransferases and deacetylases, as well as ubiquitin ligases and deubiquitinating enzymes. The epigenetic control of transcription is critical not only for embryonic and postembryonic development but also for the preservation of homeostasis in all adult tissues. In line with this notion, epigenetic defects have been associated with a variety of human disorders, including (but not limited to) congenital conditions as well as multiple hematological and solid tumors. Here, we provide an in-depth discussion of the impact of epigenetic alterations on cancer stemness, i.e., the ability of a small population of poorly differentiated malignant cells to (1) self-renew while generating a more differentiated progeny, and (2) exhibit superior tumor initiating/repopulating potential along with exceptional plasticity and improved resistance to environmental and therapy-elicited stress. Moreover, we critically evaluate the potential and limitations of targeting epigenetic modifiers as a means to eradicate cancer stem cells for therapeutic purposes.
    DOI:  https://doi.org/10.1038/s41392-025-02340-6
  13. Cancer Res. 2025 Aug 01. 85(15): 2775-2777
    Ferreting Out Ferroptosis: Extending the Mechanism of Action of RSL3 to the Selenoproteome in Colorectal Cancer.
    Sarah P Short.
      Although colorectal cancer is the second leading cause of cancer-related mortality in the United States, there has been limited progress in recent years in identifying new therapeutic options. However, cancer cells have been shown to be sensitive to ferroptosis, an iron-dependent lipid peroxide-induced form of cell death. In this issue of Cancer Research, DeAngelo and colleagues aimed to better understand the mechanisms underlying ferroptosis in colorectal cancer. However, using the ferroptosis-inducing small molecule RAS-selective lethal 3 (RSL3), they observed effects on colorectal cancer cells independent of RSL3's presumed target, glutathione peroxidase 4. Investigating further, they found that RSL3 inhibits multiple antioxidant proteins in the peroxidase and selenoprotein families to more broadly affect reactive oxygen species and lipid peroxidation than previously assumed. Loss of ALKBH8, a tRNA methyltransferase responsible for modifying the selenocysteine-specific tRNA, broadly decreased selenoprotein activity and induced ferroptosis in colorectal cancer. This work identifies the selenoproteome as a therapeutic target in colorectal cancer via induction of reactive oxygen species, lipid peroxidation, and ferroptosis and adds to a growing body of literature on the potential utility of pro-oxidant mechanisms in cancer therapy. See related article by DeAngelo et al., p. 2788.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1273
  14. Biochim Biophys Acta Rev Cancer. 2025 Jul 29. pii: S0304-419X(25)00143-X. [Epub ahead of print] 189401
    Anoikis and NETosis in colorectal cancer liver metastasis: the relationship and perspectives.
    Ruoyu Zhang, Yunfei Tan, Dedi Jiang, Dewei Kong, Mei Liu, Jianwei Liang, Aiwen Wu, Liming Wang.
      Colorectal cancer (CRC) is a leading cause of cancer-related mortality, with metastatic spread being the primary reason for fatalities. Anoikis, a form of programmed cell death triggered by cell detachment from the extracellular matrix (ECM), and NETosis, a neutrophil cell death mode releasing extracellular traps (NETs), play critical roles in CRC liver metastasis (CRCLM). This review explores the mechanisms of anoikis and NETosis, their interplay, and genetic underpinnings in CRCLM. Anoikis resistance in CRC cells allows survival during metastasis in the initial stage, while NETs promote tumor progression by facilitating immune evasion, ECM remodeling, and angiogenesis. Meanwhile, through bioinformatics analysis and summary, we elaborated on the relationship between anoikis and NETosis as well as the potential interaction mechanisms, exploring the connecting links between them. The crosstalk between these processes is analyzed, highlighting shared signaling pathways (e.g., PI3K/AKT, MAPK, EMT) and potential biomarkers (e.g., MUC13, GLI2, SIRT6, FASN). Therapeutic strategies targeting anoikis and NETosis, including inhibitors of integrins, EGFR, and NET components (e.g., DNase I, CXCR2 antagonists), inhibitors of autophagy (e.g., CQ, HCQ, azithromycin) are discussed. This comprehensive analysis advances understanding of CRCLM pathogenesis and provides novel perspectives for targeted interventions.
    Keywords:  Anoikis; Colorectal cancer liver metastasis; Extracellular matrix; NETosis
    DOI:  https://doi.org/10.1016/j.bbcan.2025.189401
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