bims-instec 2025-10-26 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2025–10–26
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Intestinal LKB1 Loss Drives a Premalignant Program Along the Serrated Cancer Pathway.
Lipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics.
CANDiT: A machine learning framework for differentiation therapy in colorectal cancer.
Unraveling enteroendocrine cell lineage dynamics and associated gene regulatory networks during intestinal development.
Embryonic Signaling Pathways Shape Colorectal Cancer Subtypes: Linking Gut Development to Tumor Biology.
Non-canonical EGFR signaling promotes MAPK-dependent extrusion of epithelial cells.
A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.
Ex vivo modelling of human colorectal cancer liver metastasis by normothermic machine perfusion.
Metabolic regulation of behavior by the intestinal enzyme FMO-2.
Tissue and cellular spatiotemporal dynamics in colon aging.
Organellar pH as an emerging vulnerability to exploit in cancer.
Leveraging platinum-protein interactions to overcome chemoresistance.

Gastroenterology. 2025 Oct 23. pii: S0016-5085(25)05850-0. [Epub ahead of print]

Intestinal LKB1 Loss Drives a Premalignant Program Along the Serrated Cancer Pathway.

S F Plugge, H Ma, J Y van der Vaart, J Sprangers, F H M Morsink, D Xanthakis, C Jamieson, K B W Stroot, A R Keijzer, T Margaritis, T Candelli, R Straver, J de Ridder, F C P Holstege, W W J de Leng, G J A Offerhaus, A Merenda, M M Maurice.

   BACKGROUND & AIMS: Heterozygous inactivating mutations of Serine Threonine Kinase 11/Liver Kinase B1 (LKB1) are causative to the Peutz-Jeghers syndrome (PJS), a hereditary disease characterized by gastrointestinal hamartomatous polyposis and increased cancer susceptibility. Although LKB1 loss-induced polyp formation has been ascribed to nonepithelial tissues, how LKB1 deficiency increases cancer risk of patients by altering the phenotypical landscape and hierarchical organization of epithelial tissues remains poorly understood.
METHODS: Using CRISPR/Cas9, we generated heterozygous and homozygous Lkb1-deficient mouse small intestinal and human colon organoids. These organoids were characterized by an integrated approach that combines imaging, bulk and single-cell RNA sequencing, and growth factor dependency assays. Our findings were validated in human PJS-derived tissues using immunohistochemistry and linked to colorectal cancer profiles using the Cancer Genome Atlas (TCGA) cancer database.
RESULTS: Our results reveal that heterozygous Lkb1 loss is sufficient to push intestinal cells into a premalignant transcriptional program associated with serrated colorectal cancer, which is further amplified by loss of heterozygosity. This altered epithelial growth state associates with persistent features of regeneration and enhanced EGFR ligand and receptor expression, conferring niche-independent growth properties to Lkb1-deficient organoids. Moreover, our newly generated LKB1-mutant signature is enriched in sporadic serrated colorectal cancer, and synergistic cooperation of Lkb1 deficiency with mutant Kras was experimentally confirmed by assessing organoid growth properties and transcriptomes.
CONCLUSIONS: Heterozygous loss of LKB1 pushes intestinal cells into a chronic regenerative state, which is amplified on loss of heterozygosity. Lkb1 deficiency thereby generates fertile ground for serrated colorectal cancer formation in the intestine, potentially explaining the increased cancer risk observed in PJS.

Keywords:  Colorectal Cancer; LKB1; Organoids; Peutz-Jeghers Syndrome; Regeneration; Serrated Tumors

DOI:  https://doi.org/10.1053/j.gastro.2025.07.041
World J Gastrointest Oncol. 2025 Oct 15. 17(10): 109398

Lipid metabolic reprogramming in colorectal cancer: Insights to mechanisms and therapeutics.

Chen-Dong Wang, Bi-Xiang Zhang, Jia Song.

  Colorectal cancer (CRC) exhibits profound lipid metabolic reprogramming, a hallmark of malignant transformation that supports tumorigenesis, immune evasion, and therapeutic resistance. Dysregulated lipid metabolism in CRC involves altered fatty acid synthesis, uptake, oxidation, and cholesterol metabolism, which collectively drive cancer cell proliferation, metastasis, and interactions with the tumor microenvironment (TME). This review synthesizes current insights into lipid metabolic rewiring in CRC, its role in shaping immunosuppressive TME dynamics, and emerging therapeutic strategies targeting lipid pathways.

Keywords:  Colorectal cancer; High-fat diet; Lipid metabolism reprogramming; Targeted drugs; Tumor microenvironment

DOI:  https://doi.org/10.4251/wjgo.v17.i10.109398
Cell Rep Med. 2025 Oct 20. pii: S2666-3791(25)00494-X. [Epub ahead of print] 102421

CANDiT: A machine learning framework for differentiation therapy in colorectal cancer.

Saptarshi Sinha, Joshua Alcantara, Kevin Perry, Vanessa Castillo, Annelies K Ondersma, Satarupa Banerjee, Ella McLaren, Celia R Espinoza, Sahar Taheri, Eleadah Vidales, Courtney Tindle, Adel Adel, Siamak Amirfakhri, Joseph R Sawires, Jerry Yang, Michael Bouvet, Pradipta Ghosh.

  Reactivating lineage commitment to differentiate, and hence eliminate, cancer stem cells (CSCs) remains a therapeutic challenge. Here, we present CANDiT (cancer-associated nodes for differentiation targeting), a machine learning framework that identifies transcriptomic vulnerabilities for differentiation therapy in colorectal cancer (CRC). Centering on CDX2-a master intestinal lineage factor lost in high-risk, poorly differentiated CRCs-we identify PRKAB1, a stress polarity sensor, as a top therapeutic target. A clinical-grade PRKAB1 agonist reactivates lineage programs, dismantles Wnt/YAP-driven stemness, and selectively eliminates CDX2-low CSCs across CRC cell lines, xenografts, and patient-derived organoids (PDOs). Multivariate analysis reveals a strong therapeutic index tied to the CDX2-low state. A 50-gene response signature, derived from integrated modeling across all platforms, predicts ∼50% reduction in recurrence and mortality risk. Like immunotherapy, CANDiT resurrects a physiologic program-differentiation-to selectively eliminate CSCs, offering a scalable, precision framework for lineage restoration in solid tumors.

Keywords:  CCDC88A; CDX2 restoration; SPS; cancer stem cell; differentiation therapy; stress-polarity pathway

DOI:  https://doi.org/10.1016/j.xcrm.2025.102421
Biol Open. 2025 Oct 15. pii: bio062083. [Epub ahead of print]14(10):

Unraveling enteroendocrine cell lineage dynamics and associated gene regulatory networks during intestinal development.

Sara Jiménez, Florence Blot, Aline Meunier, Rishabh Kapoor, Valérie Schreiber, Colette Giethlen, Sabitri Ghimire, Maxime M Mahe, Nacho Molina, Adèle De Arcangelis, Gérard Gradwohl.

  Enteroendocrine cells (EECs) are rare intestinal epithelial cells producing multiple hormones that regulate essential aspects of digestion and energy. EEC subtypes, their hormone repertoire and differentiation mechanisms from intestinal stem cells have been characterized in the adult intestine. Although EECs must be functional from birth because their absence leads to severe intestinal malabsorption in newborns, the processes that determine their subtype specification during development remain largely unknown. We used mouse embryos, human pluripotent stem cell-derived intestinal organoid models and single-cell transcriptomics to characterize EEC lineages and dynamics during development. Our findings demonstrate that in both mice and humans, the majority of EECs are specified during development through similar differentiation trajectories to those observed in the adult intestine. This suggests that EEC subtype specification occurs independently of fully organized crypt-villus structures and stimulation by diet or microbiota. However, the emergence of certain EEC subtypes depends on tissue maturation. Finally, our integrative approach infers lineage-specific regulators dynamically, identifying new candidates controlling EEC differentiation in the developing human gut.

Keywords:  Cell fate; Enteroendocrine; Gene regulatory networks; Hormone; Organoid; Stem cell

DOI:  https://doi.org/10.1242/bio.062083
Pathophysiology. 2025 Oct 01. pii: 52. [Epub ahead of print]32(4):

Embryonic Signaling Pathways Shape Colorectal Cancer Subtypes: Linking Gut Development to Tumor Biology.

Kitty P Toews, Finn Morgan Auld, Terence N Moyana.

  The morphogenesis of the primordial gut relies on signaling pathways such as Wnt, FGF, Notch, Hedgehog, and Hippo. Reciprocal crosstalk between the endoderm and mesoderm is integrated into the signaling pathways, resulting in craniocaudal patterning. These pathways are also involved in adult intestinal homeostasis including cell proliferation and specification of cell fate. Perturbations in this process can cause growth disturbances manifesting as adenomas, serrated lesions, and cancer. Significant differences have been observed between right and left colon cancers in the hindgut, and between the jejunoileum, appendix, and right colon in the midgut. The question is to what extent the embryology of the mid- and hindgut contributes to differences in the underlying tumor biology. This review examines the precursor lesions and consensus molecular subtypes (CMS) of colorectal cancer (CRC) to highlight the significance of embryology and tumor microenvironment (TME) in CRC. The three main precursor lesions, i.e., adenomas, serrated lesions, and inflammatory bowel disease-associated dysplasia, are linked to the CMS classification, which is based on transcriptomic profiling and clinical features. Both embryologic and micro-environmental underpinnings of the mid- and hindgut contribute to the differences in the tumors arising from them, and they may do so by recapitulating embryonic signaling cascades. This manifests in the range of CRC CMS and histologic cancer subtypes and in tumors that show multidirectional differentiation, the so-called stem cell carcinomas. Emerging evidence shows the limitations of CMS particularly in patients on systemic therapy who develop drug resistance. The focus is thus transitioning from CMS to specific components of the TME.

Keywords:  colorectal cancer; consensus molecular subtypes; drug resistance; embryologic development; mid- and hindgut; pathogenesis; precursor lesions; right and left colon; signaling pathways; tumor micro-environment

DOI:  https://doi.org/10.3390/pathophysiology32040052
J Cell Sci. 2025 Oct 24. pii: jcs.264173. [Epub ahead of print]

Non-canonical EGFR signaling promotes MAPK-dependent extrusion of epithelial cells.

Paola Molina, Mikiyas Daniel, Tung Hoang, Jason Wang, Ian Macara.

  Individual epithelial cells that express oncogenes are often extruded from monolayers of wildtype cells but the extrusion mechanism is not fully understood. We examined extrusion of mammary epithelial cells caused by induction of oncogenic Ras(Q61L). Ras-dependent extrusion requires ERK but not AKT activation. Unexpectedly, however, extrusion was suppressed by Erlotinib, an inhibitor of Epidermal growth factor receptor (EGFR), and by deletion of EGFR. In pancreatic and lung cancers, EGFR is required for full activation of Ras. However, EGFR inhibition or deletion had no impact on Ras(Q61L)-GTP levels or ERK phosphorylation. EGFR expression was not required in surrounding WT cells but was needed by the Ras(Q61L) cells for extrusion, yet deletion of Ras exchange factors Sos1/2 did not block extrusion. Moreover, expression of constitutively active MEK instead of Ras was sufficient to drive extrusion, and EGFR inhibition in these cells reduced extrusion. Notably, expression of Ras triggered internalization of E-cadherin, which was partially blocked by EGFR inhibition. Together, these data demonstrate an unanticipated requirement for noncanonical EGFR signaling in cancer cell extrusion, which may act in part by promoting E-cadherin endocytosis.

Keywords:  Cancer; Cell competition; Cell extrusion; Epithelia; Signaling; Tyrosine kinases

DOI:  https://doi.org/10.1242/jcs.264173
Cancer Discov. 2025 Oct 21.

A plastic EMP1⁺ to LGR5⁺ cell state conversion as a bypass to KRAS-G12D pharmacological inhibition in metastatic colorectal cancer.

Alessia Centonze, Adrià-Jaume Roura, Meritxell Novillo-Font, Cristina Giordano, Xavier Hernando-Momblona, Montserrat Llanses, Paula Prats, Marta Sevillano, Débora Cabot, Mireia Novell, Gabriel Pabst, Florian Andersch, Adrià Cañellas-Socias, Chong Zhang, Nikolaos-Nikiforos Giakoumakis, Hugh Sparks, Chris Dunsby, Julien Colombelli, Asunción Fernández-Barral, Elena Sancho, Camille Stephan-Otto Attolini, Alberto Muñoz, Antonio Barbachano, Héctor G Palmer, Jordi Martínez-Quintanilla, Johannes Zuber, Cristina Blaj, Elsa Quintana, Carme Cortina, Marc A Marti-Renom, Eduard Batlle.

Inhibitors of the oncogene KRAS hold promise for treating metastatic CRC (mCRC). Here we show that a selective, covalent small molecule inhibitor of the active (ON) conformation of RAS-G12D, RMC-9945, exerts durable disease control in preclinical CRC models of early liver metastasis, but its therapeutic activity was diminished in the advanced metastatic disease. RMC-9945-treated metastases underwent a transition from a poor-prognosis-associated Emp1⁺ transcriptional state to a WNT-driven Lgr5⁺ stem cell-like state that withstands the absence of RAS-G12D activity. This cell state change occurred within hours of RAS(ON) inhibitor treatment through a shift in transcription factor usage that involved limited chromatin remodeling. Forced conversion of metastatic cells to the Lgr5⁺ state through RAS-G12D inhibition, followed by genetic ablation of this population, reduced metastatic burden and prolonged survival in a mouse mCRC model. Overall, these preclinical findings demonstrate a central role for oncogenic KRAS in governing cellular plasticity in mCRC.

DOI: https://doi.org/10.1158/2159-8290.CD-25-0679
Mol Cancer. 2025 Oct 21. 24(1): 264

Ex vivo modelling of human colorectal cancer liver metastasis by normothermic machine perfusion.

Manuel Trebo, Thomas Maurer, Felix J Krendl, Stefan Salcher, Agnieszka Martowicz, Theresa Hautz, Sieghart Sopper, Arno Amann, Benno Cardini, Lukas H Poelsler, Anna Mair, Julia Hofmann, Andras T Meszaros, Martin Hermann, Michael Günther, Steffen Ormanns, Zlatko Trajanoski, Stefan Schneeberger, Dominik Wolf, Rupert Oberhuber, Andreas Pircher.

   BACKGROUND: Colorectal cancer liver metastasis (CRLM) is associated with poor survival, primarily due to acquired therapy resistance. While novel therapies arise, translation is limited by the lack of tumor models accurately representing dynamic microenvironmental interplay. Here, we show that ex vivo normothermic machine perfusion (NMP) offers a novel preclinical framework to study the intratumoral dynamics of CRLM biology.
METHODS: Six resected metastatic human livers were preserved for two days and subjected to multi-omic profiling of serially sampled adjacent liver and metastatic tissue using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST). Tissue integrity was assessed and cross-validated by immunofluorescence (IF), high-resolution respirometry (HRR) and flow-cytometry.
RESULTS: NMP was successfuly applied to metastatic livers with minimal surgical adaptations, preserving both intrinsic hepatic properties and tissue viability over an extended duration. Single-cell and spatial mapping confirmed preservation of CRLM phenotypic properties and demonstrated high clinical translatability by applicability of the intrinsic epithelial consensus molecular subtypes to metastasis. Spatially deconvoluted pathway activities reflected functional tissue-microenvironments. Transcriptomic profiles - including those of tumor-associated myeloid cells - were preserved during NMP. Finally, we demonstrate tumor-associated myeloid cell persistence as a driver of disease progression and poor survival in colorectal cancer.
CONCLUSION: Our findings represent the basis for future innovative applications adopting NMP in the context of CRLM, providing a new preclinical tumor model avenue.

Keywords:   Ex vivo ; Colorectal cancer metastasis; Human cancer model; Liver transplantation; Normothermic machine perfusion; Single-cell mapping; Spatial transcriptomics.

DOI:  https://doi.org/10.1186/s12943-025-02430-7
Sci Adv. 2025 Oct 24. 11(43): eadx3018

Metabolic regulation of behavior by the intestinal enzyme FMO-2.

Elizabeth S Kitto, Safa Beydoun, Ella Henry, Megan L Schaller, Mira Bhandari, Sarah A Easow, Angela M Tuckowski, Marshall B Howington, Ajay Bhat, Aditya Sridhar, Eugene Chung, Charles R Evans, Scott F Leiser.

Many elements of an organism's behavior are intertwined with the organism's health. Over a long period of time, health status is also indicative of life span, with improved health correlating with a longer life. However, the relationship between longevity and behavior remains relatively unexplored. Here, we report that modification of a single longevity gene downstream of dietary restriction and hypoxia markedly alters behavior in Caenorhabditis elegans. We found that modified expression of flavin-containing monooxygenase (fmo-2) leads to altered sensory perception and decision-making in a variety of behavioral paradigms. This cell nonautonomous signaling pathway is linked to changes in tryptophan metabolism, where loss of fmo-2 requires the tryptophan metabolite serotonin and overexpressed fmo-2 requires the tryptophan metabolite quinolinic acid to change behavior. These results suggest a unique mechanism for gut metabolism to communicate positive satiety signals and negative depressive signals to the organism by modifying an essential amino acid. They also demonstrate the importance of examining pleiotropic effects in promising longevity interventions.

DOI: https://doi.org/10.1126/sciadv.adx3018
Nat Biotechnol. 2025 Oct 22.

Tissue and cellular spatiotemporal dynamics in colon aging.

Aidan C Daly, Francesco Cambuli, Tarmo Äijö, Britta Lötstedt, Nemanja Despot Marjanovic, Sara Fernandez, Olena Kuksenko, Matthew Smith-Erb, Daniel Domovic, Nicholas Van Wittenberghe, Eugene Drokhlyansky, Gabriel K Griffin, Hemali Phatnani, Richard Bonneau, Aviv Regev, Sanja Vickovic.

Tissue structure and molecular circuitry in the colon can be profoundly impacted by systemic age-related effects but many of the underlying molecular cues remain unclear. Here, we build a cellular and spatial atlas of the colon across three anatomical regions and 11 age groups, encompassing ~1,500 mouse gut tissues profiled by spatial transcriptomics and ~400,000 single nucleus RNA-sequencing profiles. We develop a computational framework, cSplotch, which learns a hierarchical Bayesian model of spatially resolved cellular expression associated with age, tissue region and sex by leveraging histological features to share information across tissue samples and data modalities. Using this model, we identify cellular and molecular gradients along the adult colonic tract and across the main crypt axis and multicellular programs associated with aging in the large intestine. Our multimodal framework for the investigation of cell and tissue organization can aid in the understanding of cellular roles in tissue-level pathology.

DOI: https://doi.org/10.1038/s41587-025-02830-6
Trends Cancer. 2025 Oct 23. pii: S2405-8033(25)00234-1. [Epub ahead of print]

Organellar pH as an emerging vulnerability to exploit in cancer.

Cheska Marie Galapate, Cosimo Commisso.

  Cancer cells undergo metabolic reprogramming to sustain their energy demands, and favor glycolysis despite the presence of functional mitochondria. This metabolic shift leads to the rapid production of lactate and protons. If not managed, this accumulation of acidic byproducts would lower the intracellular pH (pHi). To counteract this, cancer cells employ diverse mechanisms to extrude excess protons through membrane transporters, and also sequester them within acidic organelles. Consequently, an alkaline pHi provides cancer cells with a survival advantage by promoting their proliferation, migration, and resistance to cell death. Given the role of organellar acidification in sustaining this altered pH balance, targeting this process represents a potential therapeutic vulnerability in cancer. We explore the mechanisms by which cancer cells maintain pH homeostasis, with a particular focus on organellar pH and its impact on tumor progression. In addition, we assess inhibitors of the key transporters involved in organellar acidification and discuss their therapeutic potential in cancer.

Keywords:  cancer metabolism; organelle acidification; pH homeostasis

DOI:  https://doi.org/10.1016/j.trecan.2025.09.006
Nat Commun. 2025 Oct 20. 16(1): 9263

Leveraging platinum-protein interactions to overcome chemoresistance.

Fang Wang, Jonathan Braverman, George Eng, Ozen Leylek, Nicholas L Petrone, Daniel S Honeycutt, Shinya Imada, Brian Pallares, Daiyao Zhang, Jason M Mrosla, Camellia S Huang, Anna A Griadunova, William K McCarthy, Jacob M Goldberg, Michael T Hemann, Stephen J Lippard, Ömer H Yilmaz.

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, enabling the removal of cytotoxic agents, such as anthracycline drugs. However, platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, we design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone. These drug conjugates retain the anticancer activity of anthracyclines and exhibit the ability to both circumvent drug efflux and delay the acquisition of drug resistance. In vivo experiments demonstrate that such drug conjugates extend survival in a preclinical organoid-based model of metastatic colon cancer in mice. Mechanistic studies indicate that these drug conjugates overcome resistance through covalent platinum-protein interactions, leading to significantly improved drug retention and alteration of subcellular drug distribution. This application of platinum offers many opportunities to confront issues related to chemoresistance and alternative pathways for augmenting conventional chemotherapeutics.

DOI: https://doi.org/10.1038/s41467-025-64295-0