bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–09–14
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Aurora kinase A drives non-canonical YAP1/TAZ crosstalk to sustain primary resistance to anti-EGFR therapies in colorectal cancer.
  2. Endothelial F3-mediated autolysosome and lipid metabolism promote resistance to anti-VEGFA therapy in metastatic colorectal cancer.
  3. Deep visual proteomics reveals an in vivo-like phenotype of orthotopically transplanted human colon organoids.
  4. Host and microbiome lipid metabolism in colorectal cancer development and therapy.
  5. Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
  6. Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
  7. Defining the mucosal ecosystem: epithelial-mesenchymal interdependence in gastrointestinal health and disease.
  8. HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
  9. Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
  10. The role and mechanism of abnormal lipid metabolism in colorectal cancer.
  11. Targeting fatty acid-binding protein 4: A therapeutic intersection of obesity and cancer via lipid metabolism.
  1. Mol Ther Oncol. 2025 Sep 18. 33(3): 201032
    Aurora kinase A drives non-canonical YAP1/TAZ crosstalk to sustain primary resistance to anti-EGFR therapies in colorectal cancer.
    Anxo Rio-Vilariño, Ana Garcia-Bautista, Aiora Cenigaonandia-Campillo, Pedro A Mateos-Gomez, Laura Garcia-Garcia, Marina I Schlaepfer, Laura Garcia-Hernandez, Laura Del Puerto-Nevado, Oscar Aguilera, Natalia Baños, Pablo Minguez, Víctor Manuel Castellano, Jesús Garcia-Foncillas, Arancha Cebrian.
      Anti-epidermal growth factor receptor (EGFR) therapies are the most recommended first-line treatment for RAS/RAF wild-type unresectable metastatic colorectal cancer (CRC) according to the European Society for Medical Oncology guidelines. However, primary resistance renders this treatment ineffective for almost 40% of patients. Our previous work identified Aurora kinase A (AURKA) as a key resistance driver through non-canonical, Hippo-independent Yes-associated protein 1 (YAP1) activation. However, the role of the other main Hippo coactivator, transcriptional coactivator with PDZ-binding motif (TAZ), in this resistance mechanism remains unexplored. By integrating preclinical in vitro and in vivo models, including cell lines and patient-derived xenografts, with RNA sequencing, we investigated the impact of TAZ overexpression in cetuximab resistance driven by the AURKA/YAP1 axis. Our findings reveal that TAZ overexpression sustains YAP1-mediated resistance and stemness. Even under YAP1 suppression, TAZ-overexpressing cells remain unresponsive to anti-EGFR therapies, whereas dual YAP1/TAZ silencing restores sensitivity. Treatment with alisertib, a phase III AURKA inhibitor, simultaneously destabilizes YAP1 and TAZ, restoring anti-EGFR efficacy by suppressing stemness. Transcriptomic analyses further show that AURKA inhibition and dual YAP1/TAZ suppression disrupt stem-like traits and reveal transcriptional deregulations affecting nucleotide metabolism. These findings demonstrate that AURKA orchestrates YAP1/TAZ crosstalk, which is crucial for driving stemness and resistance to anti-EGFR therapies, highlighting AURKA inhibitors as a promising strategy to enhance anti-EGFR therapies in metastatic CRC.
    Keywords:  Aurora kinase A; TAZ; YAP1; anti-EGFR; cancer stem cells; cetuximab; drug resistance; metastatic colorectal cancer; non-canonical Hippo pathway
    DOI:  https://doi.org/10.1016/j.omton.2025.201032
  2. Autophagy. 2025 Sep 08. 1-20
    Endothelial F3-mediated autolysosome and lipid metabolism promote resistance to anti-VEGFA therapy in metastatic colorectal cancer.
    Nan Huang, Junxi Ren, Xinyue Deng, Qize Bao, Genjie Huang, Shimeng Zhi, Yuedan Li, Juan Li, Binghui Hu, Dongqiang Zeng, Huiying Sun, Wei Zeng, Min Shi, Wangjun Liao, Jianhua Wu, Na Huang.
      Patients with metastatic colorectal cancer (mCRC) to the liver exhibit poor survival rates. Chemotherapy combined with anti-vascular therapy has emerged as the standard treatment, but resistance to anti-VEGFA therapy inevitably develops. The metabolic reprogramming of tumor vascular endothelial cells (TECs) plays a crucial, yet still poorly understood, role in the development of therapeutic resistance. We identified lipid-rich and fatty acid oxidation (FAO)-activated proliferating TECs in fatty colorectal cancer liver metastasis (CRLM) that mediate resistance to anti-VEGFA treatment. The TEC-specific F3 protein inhibited the macroautophagy/autophagy-lysosome pathway through the MAPK/JNK-MAPK/ERK-TP53/p53 signaling axis, thereby prevented CPT1A protein degradation and enhanced FAO. F3 was also involved in promoting lipid uptake and lipophagy. This process promoted cellular FAO under conditions of fatty acids and anti-VEGFA stimulation. Targeting FAO proved effective in overcoming resistance to anti-VEGFA treatment. Our findings elucidated the role of lipid metabolism in therapy-resistant TECs in fatty CRLM and provided a theoretical foundation for further research on anti-VEGFA therapy resistance. Moreover, we underscored the potential of combining FAO inhibitors to enhance the efficacy of anti-angiogenic therapy.
    Keywords:  Anti-angiogenic therapy; CD142; CPT1A; autophagy-lysosome; lipid-rich tumor microenvironment; lipophagy
    DOI:  https://doi.org/10.1080/15548627.2025.2551720
  3. Cell Syst. 2025 Sep 10. pii: S2405-4712(25)00229-7. [Epub ahead of print] 101396
    Deep visual proteomics reveals an in vivo-like phenotype of orthotopically transplanted human colon organoids.
    Frederik Post, Annika Hausmann, Sonja Kabatnik, Sophia Steigerwald, Alexandra Brand, Ditte L Clement, Jonathan Skov, Kadi Lõhmussaar, Hjalte L Larsen, Martti Maimets, Theresa L Boye, Gabriela Jez, Toshiro Sato, Casper Steenholdt, Florian Rosenberger, Andreas Mund, Ole H Nielsen, Kim B Jensen, Matthias Mann.
      Intestinal epithelial damage predisposes to disorders like inflammatory bowel disease (IBD), with organoid transplantation emerging as a potential treatment. However, it is not known how well organoids recapitulate in vivo intestinal epithelial cells (IECs). We employed deep visual proteomics (DVP), integrating AI-guided cell classification, laser microdissection, and ultra-high-sensitivity proteomics at the single-cell level to generate an in-depth proteome resource of IECs directly isolated from the human colon and organoids. While in vitro organoids display high proliferation and low functional signatures, xenotransplantation induces a remarkable shift toward an in vivo-like phenotype. We recapitulated this transition by modifying culture conditions. Our data provide a comprehensive spatial proteomics resource and validate xenotransplanted organoids as suitable models for studying human IEC behavior with unprecedented molecular detail and demonstrate their clinical potential for patients with IBD and other intestinal disorders. A record of this paper's transparent peer review process is included in the supplemental information.
    Keywords:  IBD; colon; mass spectrometry; organoids; proteomics; spatial proteomics
    DOI:  https://doi.org/10.1016/j.cels.2025.101396
  4. Trends Cancer. 2025 Sep 10. pii: S2405-8033(25)00203-1. [Epub ahead of print]
    Host and microbiome lipid metabolism in colorectal cancer development and therapy.
    Gabriel Medina Evora, Madita Brauer, Elisabeth Letellier.
      Colorectal cancer (CRC) remains one of the most prevalent cancers, with treatment largely dependent on surgery and chemotherapy, underscoring the need for novel or adjunct therapies. Cancer cells reprogram their lipid metabolism to support proliferation, invasiveness, and chemoresistance, making it a promising therapeutic target. Although several inhibitors of lipogenesis, lipases, lipid uptake, and lipid storage are under investigation in CRC, none have yet shown sufficient efficacy. Importantly, the tumor microenvironment (TME) and the microbiome influence CRC lipid metabolism by supplying compensatory lipids and engaging in crosstalk that affects the efficacy of lipid-targeting therapies. This review describes the role of lipids in CRC and explores how the TME and the gut/tumor microbiome may contribute to current challenges in the development of effective lipid-targeting therapies.
    Keywords:  colorectal cancer; diet; inhibitors; lipid metabolism; microbiome; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.trecan.2025.08.005
  5. J Biol Chem. 2025 Sep 08. pii: S0021-9258(25)02545-1. [Epub ahead of print] 110693
    Defined media reveals the essential role of lipid scavenging in supporting cancer cell proliferation.
    Oliver J Newsom, Eric Zheng, Lucas B Sullivan.
      Fetal bovine serum (FBS) is an undefined additive that is ubiquitous to mammalian cell culture media and whose functional contributions to promoting cell proliferation remain poorly understood. Efforts to replace serum supplementation in culture media have been hindered by an incomplete understanding of the environmental requirements fulfilled by FBS. Here, we use a combination of live-cell imaging and quantitative lipidomics to elucidate the role of serum in supporting proliferation. We show that serum provides consumed factors that enable proliferation, with serum metal and lipid components serving as crucial metabolic resources. Despite access to a wide range of lipid classes available in serum, we find albumin-bound lipids are the primary species consumed by cancer cells. Furthermore, we find that supplementing with additives that contain necessary metals and any of the albumin-associated lipid classes can obviate the FBS requirement for cancer cell proliferation. Using this defined system, we investigated cancer cell lipid consumption dynamics, finding that albumin-associated lipids are primarily consumed through a mass-action mechanism with minimal competition within or amongst lipid classes. We also find that lipid scavenging is a dominant lipid acquisition route and is necessary for cancer cell proliferation. This work therefore identifies metabolic contributions of serum and provides a framework for building defined culture systems that sustain cell proliferation without the undefined contributions of serum.
    DOI:  https://doi.org/10.1016/j.jbc.2025.110693
  6. Mol Cell. 2025 Sep 03. pii: S1097-2765(25)00708-7. [Epub ahead of print]
    Protection against ferroptosis through maintaining homeostasis of docosahexaenoate-containing phospholipids.
    Yaqin Deng, Goncalo Vale, Yonggang Liang, Shaojie Cui, Shimeng Xu, Jeffrey G McDonald, Jin Ye.
      Although polyunsaturated phospholipids are vital for cellular functions, their overaccumulation renders cells vulnerable to ferroptosis. It remains unclear how cells exposed to excess polyunsaturated fatty acids (PUFAs) prevent their over-incorporation into phospholipids. Here, we identified a mechanism by which ubiquitin regulatory X domain-containing protein 8 (UBXD8), a fatty acid (FA)-interacting protein, prevents overaccumulation of phospholipids containing docosahexaenoate (DHA), one of the most abundant PUFAs in mammalian cells. UBXD8 binds to and activates 1-acylglycerol-3-phosphate O-acyltransferase 3 (AGPAT3), which specifically incorporates DHA into phospholipids. Thus, cultured cells and mouse livers deficient in UBXD8 were resistant to ferroptosis because of reduced production of DHA-containing phospholipids. Excess unsaturated FAs, including DHA, through their interaction with UBXD8, disrupt the UBXD8/AGPAT3 complex, thereby inhibiting AGPAT3-catalyzed synthesis of DHA-containing phospholipids. This FA-sensing mechanism prevents overaccumulation of DHA-containing phospholipids in cells exposed to excess DHA, thus reducing the ferroptotic potency of DHA, a property that might contribute to the health benefits of this ω-3 PUFA.
    Keywords:  AA; AGPAT3; DHA; UBXD8; ferroptosis; phospholipids; polyunsaturated fatty acids
    DOI:  https://doi.org/10.1016/j.molcel.2025.08.023
  7. Nat Rev Gastroenterol Hepatol. 2025 Sep 11.
    Defining the mucosal ecosystem: epithelial-mesenchymal interdependence in gastrointestinal health and disease.
    Frances J England, Manqiang Lin, Michael Sigal, Simon J Leedham.
      The crypt-villus architecture of the intestinal mucosa is underpinned by dynamic interactions between distinct populations of epithelial, stromal and immune cells. Although the epithelial compartment has attracted substantial attention, there is a growing appreciation for the critical role of mesenchymal cells in shaping epithelial stem cell function and dictating lineage specification. In this Review, we outline how the epithelial and mesenchymal compartments of the developing gut evolve in a mutually dependent manner to establish dynamic reciprocal signalling gradients that maintain adult tissue homeostasis. We discuss how perturbations to this delicate ecosystem result in rapid adaptive cellular responses that act to restore tissue function. Furthermore, we explore how the intricate nature of cell fate interdependence also renders the mucosa susceptible to pathological disruption. Drawing on the latest studies, we highlight the crosstalk networks between the epithelial and stromal compartments that underlie these processes and consider how these insights are informing future research directions and therapeutic strategies. In doing so, we advocate for a shift away from the conventional epithelial-centric paradigm toward a more integrated framework that considers the full spectrum of intercellular interactions maintaining intestinal tissue integrity and shaping disease progression.
    DOI:  https://doi.org/10.1038/s41575-025-01113-4
  8. Cell. 2025 Sep 02. pii: S0092-8674(25)00929-8. [Epub ahead of print]
    HT SpaceM: A high-throughput and reproducible method for small-molecule single-cell metabolomics.
    Jeany Delafiori, Mohammed Shahraz, Andreas Eisenbarth, Volker Hilsenstein, Bernhard Drotleff, Alberto Bailoni, Bishoy Wadie, Måns Ekelöf, Alexander Mattausch, Theodore Alexandrov.
      Single-cell metabolomics (SCM) promises to reveal metabolism in its complexity and heterogeneity, yet current methods struggle with detecting small-molecule metabolites, throughput, and reproducibility. Addressing these gaps, we developed HT SpaceM, a high-throughput SCM method combining cell preparation on custom glass slides, small-molecule matrix-assisted laser desorption ionization (MALDI) imaging mass spectrometry (MS), and batch processing. We propose a unified framework covering quality control, characterization, structural validation, and differential and functional analyses. Profiling HeLa and NIH3T3 cells, we detected 73 small-molecule metabolites validated by bulk liquid chromatography tandem MS (LC-MS/MS), achieving high reproducibility and single-cell resolution. Interrogating nine NCI-60 cancer cell lines and HeLa, we identified cell-type markers in subpopulations and metabolic hubs. Upon inhibiting glycolysis in HeLa cells, we observed emerging glucose-centered metabolic coordination and intra-condition heterogeneity. Overall, we demonstrate how HT SpaceM enables robust, large-scale SCM across over 140,000 cells from 132 samples and provide guidance on how to interpret metabolic insights beyond population averages.
    Keywords:  LC-MS/MS; MALDI-imaging mass spectrometry; NCI-60; SpaceM; co-abundance; heterogeneity; high-throughput; reproducibility; single-cell metabolomics; small-molecule metabolites
    DOI:  https://doi.org/10.1016/j.cell.2025.08.015
  9. Nat Rev Cancer. 2025 Sep 08.
    Unravelling the genetics and epigenetics of the ageing tumour microenvironment in cancer.
    Hariharan Easwaran, Ashani T Weeraratna.
      Somatic mutations in several genes, including key oncogenes and tumour suppressor genes, are present from early life and can accumulate as an individual ages, indicating that the potential for cancer is present and growing throughout life. However, the risk of developing cancer rises sharply after 50-60 years of age, suggesting that the ability of these mutations to undergo clonal expansion and drive cancer development is dependent on the progressive changes in the epigenome and microenvironment that occur during ageing. Epigenetic changes, including DNA methylation and histone modifications, can drive various hallmarks of ageing in precancerous cells, including induction of senescence, the senescence-associated secretory phenotype, genomic instability and reduction of nuclear integrity, metabolic and inflammatory stress responses, stem cell function and differentiation potential, and redox balance. This can also alter the normal immune and stromal cells in the tissue microenvironment, which cumulatively enhances the effects of cancer driver mutations, ultimately promoting cancer development and progression in aged individuals. Unravelling these mechanisms will provide novel preventive and therapeutic strategies to limit the burden and progression of cancer in aged individuals.
    DOI:  https://doi.org/10.1038/s41568-025-00868-x
  10. Sci Prog. 2025 Jul-Sep;108(3):108(3): 368504251368237
    The role and mechanism of abnormal lipid metabolism in colorectal cancer.
    Jinhui Zha, Pengxu Cang, Yonghao Zhong, Ruilin Liu, Gang Fan.
      Colorectal cancer ranks among the most prevalent and lethal malignant tumors globally. Historically, the incidence of colorectal cancer in China has been lower than that in developed European and American countries; however, recent trends indicate a rising incidence due to changes in dietary patterns and lifestyle. Lipids serve critical roles in human physiology, such as energy provision, cell membrane formation, signaling molecule function, and hormone synthesis. Dysregulation of lipid metabolism is strongly associated with various metabolic disorders, including cardiovascular disease, obesity, hepatic steatosis, and diabetes, as well as tumor initiation, progression, and metastasis. Lipid metabolism significantly contributes to cancer development by facilitating biofilm synthesis, supplying substrates for biomass production, and activating signaling pathways linked to cancer cell proliferation and migration. This narrative review summarizes recent advancements in understanding the regulation of lipid metabolism in colorectal cancer, evaluates potential molecular targets, and highlights relevant clinical trials. All relevant literature was retrieved through a comprehensive search of the PubMed database.
    Keywords:  Colorectal cancer; cholesterol; fatty acids; lipid droplets; lipid metabolism
    DOI:  https://doi.org/10.1177/00368504251368237
  11. Prog Lipid Res. 2025 Sep 09. pii: S0163-7827(25)00035-9. [Epub ahead of print] 101353
    Targeting fatty acid-binding protein 4: A therapeutic intersection of obesity and cancer via lipid metabolism.
    Katarzyna Smolińska, Aleksandra Szopa, Piotr Dobrowolski, Jacek Dziedzic, Norbert Nowak, Anna Serefko, Michał Mirecki, Jan Sobczyński, Timo Ylikomi, Matthias Nees.
      Fatty acid-binding protein 4 (FABP4) has emerged as a multifunctional regulator in cancer biology, linking dysregulated lipid metabolism, immune modulation, and tumor progression. Initially recognized for its role in fatty acid transport and lipid homeostasis, FABP4 is now understood as a secreted adipokine that influences diverse oncogenic processes, particularly in adipose-rich tumor microenvironments. It is upregulated in various cancers and secreted by both tumor and cancer-associated fibroblasts. FABP4 facilitates lipid transfer, promotes fatty acid oxidation, and reprograms cancer cell metabolism. It also contributes to the crosstalk between tumor-associated macrophages, T-cells, and dendritic cells. FABP4 also supports epithelial-mesenchymal transition, enhances tumor cell plasticity, promotes invasion and metastasis, and has an impact on therapeutic resistance. The inhibition of FABP4 using small-molecule inhibitors or monoclonal antibodies has shown promise in restoring therapeutic sensitivity and reducing metastasis in preclinical models. FABP4 has emerged as a potential diagnostic and prognostic biomarker that predicts poor outcomes in multiple cancer types, supporting risk stratification and noninvasive diagnostics. Together, these findings place FABP4 at the intersection of tumor metabolism, immune evasion, and therapy resistance, highlighting its potential as both a biomarker and a therapeutic target in precision oncology and personalized medicine.
    Keywords:  FABP4; Lipid metabolism; Obesity; cancer
    DOI:  https://doi.org/10.1016/j.plipres.2025.101353
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