bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–09–21
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models.
  2. The Microbial Bile Acid Metabolite 3-oxo-LCA Inhibits Colorectal Cancer Progression.
  3. Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD.
  4. Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.
  5. SUNRISE-CRC: a randomized phase II study of high-dose intermittent sunitinib versus trifluridine/tipiracil in metastatic colorectal carcinoma.
  6. Small but mighty: inulin promotes small intestinal bacterial fructose feeding.
  7. Interactions Between Dietary Metabolites and Regulatory Risk Variants for Human Colon Cancer.
  8. Multi-drug pharmacotyping improves therapy prediction in pancreatic cancer organoids.
  9. Covariation MS uncovers a protein that controls cysteine catabolism.
  10. A comprehensive analysis of supermere, exomere, and extracellular vesicle isolation and cargo in colorectal cancer.
  11. Cancer-associated fibroblasts shape the formation of budding cancer cells at the invasive front of human colorectal cancer.
  12. Restraint of cancer cell plasticity by spatial homotypic clustering.
  1. Cell Rep Med. 2025 Sep 18. pii: S2666-3791(25)00436-7. [Epub ahead of print] 102363
    Cetuximab increases LGR5 expression and augments LGR5-targeting antibody-drug conjugate efficacy in patient-derived colorectal cancer models.
    Peyton C High, Zhengdong Liang, Cara Guernsey-Biddle, Shraddha Subramanian, Yueh-Ming Shyu, Adela M Aldana, Yukimatsu Toh, Kendra S Carmon.
      Colorectal cancer (CRC) remains the second-leading cause of cancer-associated deaths, indicating an urgent need for improved therapeutic options. We previously generated antibody-drug conjugates (ADCs) targeting the cancer stem-like cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5). However, tumor relapse due to LGR5 downregulation and suboptimal payload selection warrants strategies to improve ADC efficacy. Here, we report that cetuximab, an epidermal growth factor receptor (EGFR)-targeting monoclonal antibody indicated for RASWT metastatic CRC, augments LGR5 expression independent of RAS/PIK3CA mutation status and promotes EGFR-LGR5 interactions. Furthermore, we describe the development of LGR5 ADCs incorporating a camptothecin-derived payload that is well tolerated and significantly inhibits tumor growth. Importantly, cetuximab in combination with LGR5 ADCs results in enhanced tumor inhibition or regression versus single-agent treatment and extends survival in RASMUT patient-derived xenografts. These findings support growing evidence that ADC combination therapies may be more effective than monotherapies and suggest a broader clinical use for cetuximab in treating RASMUT CRC.
    Keywords:  EGFR; LGR5; antibody-drug conjugate; cetuximab; colorectal cancer; combination treatment
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102363
  2. Cancer Res. 2025 Sep 16.
    The Microbial Bile Acid Metabolite 3-oxo-LCA Inhibits Colorectal Cancer Progression.
    Fei Sun, Ke Wang, Xingchen Dong, Henry Secaira-Morocho, Alisa Hui, Chunmiao Cai, Jonathan J Sze, Brian Low, Shirsa Udgata, Cheri A Pasch, Tao Huan, Dustin A Deming, Qiyun Zhu, Jiaoyang Jiang, Ting Fu.
      Bile acids (BAs) not only influence the gut microbiome composition but are also metabolized by gut bacteria to form various microbial BAs. Among these, 3-oxo-lithocholic acid (3-oxo-LCA) and isoallo-LCA have been reported to modulate host immunity, suppress intestinal pathogens, and provide anti-aging benefits, suggesting that they could also affect intestinal epithelial cells and colorectal cancer (CRC) progression. To investigate the impact of 3-oxo-LCA on intestinal tumorigenesis, we evaluated its activity in vitro on mouse and human CRC cell lines, as well as primary mouse intestinal organoids and patient-derived CRC organoids (PDCOs), and in vivo using a genetically engineered mouse model (GEMM), cell line-derived syngeneic and xenograft tumors, and patient-derived xenografts. 3-oxo-LCA functioned as a potent FXR agonist that restored FXR signaling both in vitro and in vivo. Activation of FXR signaling reduced the growth of CRC cell lines and suppressed the proliferation of intestinal stem cells in both mouse organoids and PDCOs. In the APCMin/+ GEMM, 3-oxo-LCA reduced BA levels, enhanced gut barrier function, decreased tumor burden, and suppressed tumor initiation. Furthermore, 3-oxo-LCA significantly inhibited tumor progression in syngeneic and xenograft mouse models and promoted apoptosis within the tumors. Together, these results underscore the function of 3-oxo-LCA as an FXR agonist with the ability to inhibit CRC tumorigenesis and progression by modulating epithelial cell growth and death.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-3898
  3. Nat Metab. 2025 Sep 19.
    Fructose and glucose from sugary drinks enhance colorectal cancer metastasis via SORD.
    Tianshi Feng, Qin Luo, Yanlin Liu, Zeyu Jin, David Skwarchuk, Rumi Lee, Miso Nam, John M Asara, Daya R Adye, Philip L Lorenzi, Lin Tan, Guangsheng Pei, Zhongming Zhao, Neda Zarrin-Khameh, Adriana Paulucci-Holthauzen, Brian W Simons, Ju-Seog Lee, Scott Kopetz, Jihye Yun.
      The consumption of sugar-sweetened beverages (SSBs), which contain high levels of fructose and glucose, has been causally and mechanistically linked to an increased risk of colorectal cancer (CRC). However, the effects of SSB consumption on advanced stages of disease progression, including metastasis, remain poorly understood. Here we show that exposure of CRC cells to a glucose and fructose formulation-reflecting the composition of both high-fructose corn syrup and sucrose found in SSBs-enhances cellular motility and metastatic potential compared to glucose alone. Given that CRC cells grow poorly in fructose alone, and cells in vivo are not physiologically exposed to fructose without glucose, we excluded the fructose-only condition from our studies unless needed as a control. Mechanistically, the combination of glucose and fructose elevates the NAD⁺/NADH ratio by activation of the reverse reaction of sorbitol dehydrogenase in the polyol pathway. This redox shift relieves NAD⁺ limitations and accelerates glycolytic activity, which in turn fuels activation of the mevalonate pathway, ultimately promoting CRC cell motility and metastasis. Our findings highlight the detrimental impact of SSBs on CRC progression and suggest potential dietary and therapeutic strategies to mitigate metastasis in patients with CRC.
    DOI:  https://doi.org/10.1038/s42255-025-01368-w
  4. Nature. 2025 Sep 17.
    Basal cell of origin resolves neuroendocrine-tuft lineage plasticity in cancer.
    Abbie S Ireland, Daniel A Xie, Sarah B Hawgood, Margaret W Barbier, Lisa Y Zuo, Benjamin E Hanna, Scarlett Lucas-Randolph, Darren R Tyson, Benjamin L Witt, Ramaswamy Govindan, Afshin Dowlati, Justin C Moser, Anish Thomas, Sonam Puri, Charles M Rudin, Joseph M Chan, Andrew Elliott, Trudy G Oliver.
      Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes1-9. The mechanisms driving neuroendocrine-tuft tumour heterogeneity and the origins of tuft-like cancers are unknown. Using multiple genetically engineered animal models of SCLC, we demonstrate that a basal cell of origin (but not the accepted neuroendocrine origin) generates neuroendocrine-tuft-like tumours that highly recapitulate human SCLC. Single-cell clonal analyses of basal-derived SCLC further uncovered unexpected transcriptional states, including an Atoh1+ state, and lineage trajectories underlying neuroendocrine-tuft plasticity. Uniquely in basal cells, the introduction of genetic alterations enriched in human tuft-like SCLC, including high MYC, PTEN loss and ASCL1 suppression, cooperates to promote tuft-like tumours. Transcriptomics of 944 human SCLCs revealed a basal-like subset and a tuft-ionocyte-like state that altogether demonstrate notable conservation between cancer states and normal basal cell injury response mechanisms10-13. Together, these data indicate that the basal cell is a probable origin for SCLC and other neuroendocrine-tuft cancers that can explain neuroendocrine-tuft heterogeneity, offering new insights for targeting lineage plasticity.
    DOI:  https://doi.org/10.1038/s41586-025-09503-z
  5. Oncologist. 2025 Sep 18. pii: oyaf288. [Epub ahead of print]
    SUNRISE-CRC: a randomized phase II study of high-dose intermittent sunitinib versus trifluridine/tipiracil in metastatic colorectal carcinoma.
    Jorien B E Janssen, Kirti K Iyer, Sophie L Gerritse, Eline Janssen, Elske C Gootjes, Mariette Labots, Tineke E Buffart, Miriam L Wumkes, Joeri A J Douma, Mirte M Streppel, Laurien M Buffart, Marianne A Jonker, Erik van den Hombergh, Nielka P van Erp, Jan Paul Medema, Daniele V F Tauriello, Dennis Poel, Henk M W Verheul.
       BACKGROUND: Patients with metastatic colorectal cancer often have poor or short responses to currently available therapies. Drug repurposing with alternative dosing schedules may offer unexpected clinical benefit, even for agents that previously failed for this indication.
    METHODS: We explored a high-dose treatment strategy for sunitinib, assessing its potential for both cancer cell killing and inducing immunogenic cell death in patient-derived tumour organoids (PDTOs) of metastatic colorectal cancer (mCRC). In a randomized clinical trial, we studied the efficacy of high-dose intermittent sunitinib (700 mg once every 2 weeks) in patients with advanced CRC compared to standard therapy with trifluridine/tipiracil. The primary outcome measure was progression-free survival (PFS); secondary outcomes included overall survival, safety and tolerability, quality of life, and exploratory biomarker analyses.
    RESULTS: While high, intermittent dosing was found to effectively kill PDTOs in vitro, no support for immunogenic cell death was found. In our clinical trial, among a total of 63 evaluable patients, median PFS was 2.8 months (95% CI 0.9-4.7) for the investigation arm compared to 1.9 months (95% CI 1.6-2.3) for the trifluridine/tipiracil group (p = 0.78, HR 1.22; 95% CI 0.73-2.04). The trial was halted prematurely due to toxicities: in particular, hemorrhage, fever and gastrointestinal adverse events.
    CONCLUSION: High-dose intermittent sunitinib treatment did not improve PFS for patients with heavily pretreated mCRC compared to standard 3rd or 4th-line treatment with trifluridine/tipiracil, whereas significant toxicity was observed. In addition, this approach provoked no relevant immunological responses in vitro, discouraging further research for potential combinations with immunotherapeutics.
    IDENTIFIER: NCT03909724.
    Keywords:  Tyrosine kinase inhibitors; high-dose; metastatic colorectal cancer; patient-derived tumour organoids
    DOI:  https://doi.org/10.1093/oncolo/oyaf288
  6. Nat Metab. 2025 Sep 15.
    Small but mighty: inulin promotes small intestinal bacterial fructose feeding.
    Hallie R Wachsmuth, Frank A Duca.
      
    DOI:  https://doi.org/10.1038/s42255-025-01374-y
  7. bioRxiv. 2025 Sep 08. pii: 2025.09.05.674475. [Epub ahead of print]
    Interactions Between Dietary Metabolites and Regulatory Risk Variants for Human Colon Cancer.
    Tania N Fabo, Robin M Meyers, Evin Padhi, Laura N Kellman, Yang Zhao, Soumya Kundu, David L Reynolds, Ziwei Chen, Xue Yang, Lisa Ko, Ibtihal Elfaki, Stephen B Montgomery, Paul A Khavari.
      Interactions between genetic variants and environmental factors influence malignancy risk, including for colorectal cancer (CRC). Prevalent CRC susceptibility loci reside predominantly in noncoding regulatory DNA where they may interact with dietary influences to dysregulate expression of specific genes predisposing to neoplasia. The impacts of CRC protective and risk dietary metabolites, butyrate and deoxycholic acid, were thus studied on the transcription-directing activity of 3703 regulatory CRC-associated variants via massively parallel reporter assays (MPRA) in human colonic cells. 1595 variant-dietary metabolite interactions were identified, pointing to dysregulation of MED13L, NKD2, and several modulators of Wnt/β-catenin signaling in potential CRC gene-environment interactions (GxE). Opposing impacts of butyrate and deoxycholic acid were also uncovered, indicating dietary influences may converge on common CRC risk loci and nominating FOSL1 and SP1 as mediators of these opposing responses. Coupling MPRA to relevant environmental factors offers an approach to extend insight into GxE in common human cancers.
    DOI:  https://doi.org/10.1101/2025.09.05.674475
  8. Cancer Cell Int. 2025 Sep 13. 25(1): 321
    Multi-drug pharmacotyping improves therapy prediction in pancreatic cancer organoids.
    Katharina Wansch, Uwe Pelzer, François Schneider, Florian Dölvers, Anna Kühn, Mihnea P Dragomir, Jana Ihlow, Georg Hilfenhaus, Loredana Vecchione, Matthäus Felsenstein, Dou Ma, Markus Lerchbaumer, Christian Jürgensen, Marcus Bahra, Adrian E Granada, Gregor Duwe, Sebastian Stintzing, Ulrich Keilholz, Christopher C M Neumann.
      Patient-Derived Organoids (PDOs) represent a promising technology for therapy prediction in pancreatic cancer, with the potential of enhancing treatment outcomes and allowing more effective, personalized treatment choices. However, classification approaches into sensitive and resistant models remain very variable and are based on single-agent testing only, neglecting interactive effects of multi-drug combinations. Here, we established 13 PDOs and performed both single-agent and multi-drug testing. By comparing different clustering approaches of drug-response metrics and establishing a new classification approach based on pharmacokinetic modelling, we were able to evaluate which score best predicts the clinical response of patients. Our newly developed score considered the Area Under The Curve (AUC) of cell viability curves and reached a prediction accuracy of 85%. Our data supports previous findings for PDOs to constitute an effective platform for translational drug testing. Furthermore, our results suggest that the AUC is a more accurate drug-response metric than the half maximal inhibitory concentration (IC50), and that multi-drug testing yields a higher accuracy than single-agent testing. The methodology and outcomes presented in this study are of critical relevance for future PDO-based translational trials as they allow a new physiology-based approach towards multi-drug testing and classification of organoid response, which improves PDO prediction accuracy.
    Keywords:  Multi-Drug response metrics ; Pancreatic adenocarcinoma; Patient-derived organoids; Pharmacokinetic modelling
    DOI:  https://doi.org/10.1186/s12935-025-03969-7
  9. Nature. 2025 Sep 17.
    Covariation MS uncovers a protein that controls cysteine catabolism.
    Haopeng Xiao, Martha Ordonez, Emma C Fink, Taylor A Covington, Hilina B Woldemichael, Junyi Chen, Mika Sarkin Jain, Milan H Rohatgi, Shelley M Wei, Nils Burger, Muneeb A Sharif, Julius Jan, Yaoyu Wang, Jonathan J Petrocelli, Katherine Blackmore, Amanda L Smythers, Bingsen Zhang, Matthew Gilbert, Hakyung Cheong, Sumeet A Khetarpal, Arianne Smith, Dina Bogoslavski, Yu Lei, Laura Pontano Vaites, Fiona E McAllister, Nick Van Bruggen, Katherine A Donovan, Edward L Huttlin, Evanna L Mills, Eric S Fischer, Edward T Chouchani.
      The regulation of metabolic processes by proteins is fundamental to biology and yet is incompletely understood. Here we develop a mass spectrometry (MS)-based approach that leverages genetic diversity to nominate functional relationships between 285 metabolites and 11,868 proteins in living tissues. This method recapitulates protein-metabolite functional relationships mediated by direct physical interactions and local metabolic pathway regulation while nominating 3,542 previously undescribed relationships. With this foundation, we identify a mechanism of regulation over liver cysteine utilization and cholesterol handling, regulated by the poorly characterized protein LRRC58. We show that LRRC58 is the substrate adaptor of an E3 ubiquitin ligase that mediates proteasomal degradation of CDO1, the rate-limiting enzyme of the catabolic shunt of cysteine to taurine1. Cysteine abundance regulates LRRC58-mediated CDO1 degradation, and depletion of LRRC58 is sufficient to stabilize CDO1 to drive consumption of cysteine to produce taurine. Taurine has a central role in cholesterol handling, promoting its excretion from the liver2, and we show that depletion of LRRC58 in hepatocytes increases cysteine flux to taurine and lowers hepatic cholesterol in mice. Uncovering the mechanism of LRRC58 control over cysteine catabolism exemplifies the utility of covariation MS to identify modes of protein regulation of metabolic processes.
    DOI:  https://doi.org/10.1038/s41586-025-09535-5
  10. Cell Rep. 2025 Sep 17. pii: S2211-1247(25)01058-7. [Epub ahead of print]44(10): 116287
    A comprehensive analysis of supermere, exomere, and extracellular vesicle isolation and cargo in colorectal cancer.
    Oleg S Tutanov, Clark Massick, Marisol Ramirez, James N Higginbotham, Lizandra Jimenez, Mark Castleberry, Zheng Cao, Eliana John, Maxwell S Hamilton, Qin Zhang, Dennis K Jeppesen, Danielle L Michell, Sarah E Glass, Purvi Patel, Kristie L Rose, Evan Krystofiak, Hua-Chang Chen, Quanhu Sheng, Qi Liu, James G Patton, Alissa M Weaver, Jeffrey L Franklin, Kasey C Vickers, Robert J Coffey.
      Biofluids contain a heterogeneous mixture of extracellular vesicles and non-vesicular nanoparticles (including exomeres and supermeres) that transport a diverse array of proteins, RNA, and lipids. Our previous efforts to characterize the contents of these carriers in colorectal cancer relied on 2D culture systems requiring large-scale setups and time-consuming ultracentrifugation-based isolation. To streamline this process, we have combined 3D hollow-fiber bioreactor production and fast-protein liquid chromatography-based size-exclusion chromatography. Here, we compare the impact of culture methods and purification strategies on small extracellular vesicle, exomere, and supermere cargo. Proteomic analyses show consistently distinct profiles for extracellular vesicles, exomeres, and supermeres regardless of culture conditions or isolation method. In contrast, these two variables influence small RNAs, their base modifications, and lipidomic profiles. We present an online tool to query these and future secretome datasets (https://superomics.shinyapps.io/browse).
    Keywords:  CP: Cancer; CP: Genomics; EV; FPLC; NVEP; RNA-seq; SEC; exomeres; exosomes; extracellular RNA; extracellular vesicles; hollow fiber bioreactor; lipidomics; non-vesicular extracellular nanoparticles; proteomics; sEV; secreted RNAs; supermeres
    DOI:  https://doi.org/10.1016/j.celrep.2025.116287
  11. Commun Biol. 2025 Sep 16. 8(1): 1345
    Cancer-associated fibroblasts shape the formation of budding cancer cells at the invasive front of human colorectal cancer.
    Juan L García-Rodríguez, Ulrik Korsgaard, Stine M Vissing, Thea Petersen Paasch, Mariana Semenova, Simon L Vendelbo, Eva F Jensby, Hannah L Williams, Paul Vinu Salachan, Camilla Blunk Brandt, Jacob Hanimann, Lin Lin, Inti Zlobec, Karina D Sørensen, Jørgen Kjems, Henrik Hager, Lasse S Kristensen.
      The formation of budding cancer cells at the invasive front of solid tumors is one of the first steps of metastasis. However, this process is still incompletely elucidated. Here, we used spatial molecular imaging to disentangle the complex interactions between cancer cells and the tumor microenvironment at the invasive front of colorectal tumors. Employing a 1000-plex gene panel, we defined all major cell types in tumors and adjacent normal tissue with accurate spatial information. Individual cancer cell clusters were located together, consistent with an expected mutation- and epigenetic-driven clonal evolution. However, cancer cell clusters encompassing budding cells exhibited a markedly different spatial distribution as they also contained cells that were scattered around the periphery of the main cancer cell masses. Moreover, these cells were frequently in contact with cancer-associated fibroblasts (CAFs) and underwent broad gene expression changes, mainly related to epithelial-mesenchymal transition (EMT), remodeling of the extracellular matrix (ECM), and migration. In addition, we defined an 11-gene signature (TYK2, IL2RG, KRT17, HLA-B, NPPC, WIF1, IL32, B2M, CCND1, CRIP1, ITGB1), which characterizes cancer cells en route to metastasis and is associated with inferior outcomes. Collectively, our findings suggest that CAFs induce pro-invasive gene expression changes involved in EMT, ECM remodeling, and migration.
    DOI:  https://doi.org/10.1038/s42003-025-08799-x
  12. Cancer Cell. 2025 Sep 18. pii: S1535-6108(25)00366-6. [Epub ahead of print]
    Restraint of cancer cell plasticity by spatial homotypic clustering.
    Simona Migliozzi, Bruno Adabbo, Luciano Garofano, Fan Wu, Pedro Davila, Ricardo J Komotar, Michael E Ivan, Ashish H Shah, Benjamin B Currall, Sion Williams, Daniel Bilbao Cortes, Melinda Minucci Boone, Macarena I de la Fuente, Sakir H Gultekin, Michele Ceccarelli, Antonio Iavarone, Anna Lasorella.
      Tumor heterogeneity fueled by plasticity of cancer cells is a key to therapy failure. Here, we define the role of proximal communications of malignant cells in glioblastoma plasticity. We find that tumor cell state coherence is maximal in cells organized in homotypic clusters with defined relationships with non-malignant cells, whereas randomly dispersed cells downregulate the original state, acquire alternative phenotypes and exhibit changes in the microenvironment. We demonstrate the intrinsic propensity of glioblastoma cells to develop into clustered and dispersed spatial patterns in orthotopic mouse models and experimentally validate the cell state-specific mechanisms of cell-cell adhesion that prevent phenotype deviation with pharmacologic perturbations in patients-derived glioblastoma models. We establish the generality of "homotypic clustered cell identity" in circulating clustered and single breast cancer cells and show that the glioblastoma glycolytic-plurimetabolic dispersed cellular state uniquely confers shorter survival, thus assigning clinical significance to the spatial patterning of cancer cells in human tumors.
    Keywords:  cancer cell plasticity; glioblastoma; intratumor heterogeneity; single-cell spatial proteomics; single-cell spatial transciptomic; tumor ecosystem
    DOI:  https://doi.org/10.1016/j.ccell.2025.08.009
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