bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–07–26
eighteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Histone Acetyltransferase HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation.
  2. Mapping mesenchymal diversity in the human small intestine and organoids.
  3. Setdb1 safeguards proper differentiation of adult intestinal stem cells by controlling chromatin accessibility and transcriptome variability.
  4. A self-amplifying nerve-fibroblast circuit drives colorectal cancer progression.
  5. ACSS2 is required for colorectal cancer progression and a druggable target for colorectal cancer treatment.
  6. Gene expression adaptation of metastases to their host tissue.
  7. E3 ubiquitin-ligase Hakai regulates LRP4 stability and Wnt/β-catenin signalling in colorectal cancer cells.
  8. IGF2BP3 is essential for the growth heterogeneity of colorectal adenoma cells by regulating MYC.
  9. RHOA at the intersection of inflammation-driven and sporadic colorectal cancer.
  10. DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.
  11. Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
  12. Patterns of progression and survival in patients with mismatch repair deficient/ microsatellite instability- high metastatic colorectal cancer treated with immunotherapy.
  13. Prophylactic inhibition of LATS1/2 before high-dose irradiation promotes the regeneration of the damaged intestinal epithelium.
  14. Evidence of endothelial anergy and T-cell exclusion in microsatellite stable colorectal liver metastases revealed through human hemi-liver perfusion and spatial transcriptomics.
  15. Clonal drift in the aging gut: Mapping the fate of stem cells over time.
  16. A bibliometric analysis of arachidonic acid metabolism in colorectal cancer with a focus on COX inhibitors-related clinical trials landscape.
  17. Crosstalk Between Schwann Cells and CD4+ T Cells Promotes Perineural Invasion in Colorectal Cancer.
  18. Immune-epithelial crosstalk governs immune checkpoint inhibitor efficacy in colorectal cancer.
  1. J Biol Chem. 2026 Jul 24. pii: S0021-9258(26)02240-4. [Epub ahead of print] 113368
    Histone Acetyltransferase HAT1 Regulates Intestinal Stem Cell Proliferation and Differentiation.
    Prabakaran Nagarajan, Caden J Martin, Andrea R Keller, Kübra B Akkaya-Colak, Maria H Festing, Maria M Mihaylova, Mark R Parthun.
      Stem cells are critical for the development and maintenance of tissue integrity. An important example is intestinal stem cells (ISCs) that generate all epithelial cell types necessary for formation of the intestinal lining. HAT1 is a histone acetyltransferase that acetylates newly synthesized histone H4 molecules on lysine residues 5 and 12 during replication-coupled chromatin assembly. Within the intestine, HAT1 is specifically expressed in intestinal stem and progenitor cells. We generated an inducible deletion of the HAT1 gene in intestinal epithelial cells. Following loss of HAT1, intestinal crypts became elongated, with an increase in stem and progenitor cell proliferation and an increase in the population of OLFM+ cells. Loss of HAT1 also resulted in alterations in intestinal stem cell differentiation, including an increase in the number of Goblet cells and the mislocalization of Paneth cells into villi. HAT1 is specifically responsible for the acetylation of histone H4 lysine 5 (H4K5ac) in intestinal stem cells. Genome-wide characterization of HAT1-dependent H4K5ac in intestinal crypt cells indicates that the most significant loss of H4K5ac occurs regions of the genome that correspond to in lamina-associated domains (LADs), as defined in mouse embryonic fibroblasts. Loss of H4K5ac is accompanied by an increase in histone H3 K9 tri-methylation, indicating that HAT1 regulates genome-wide histone modification patterns in intestinal crypt cells. A direct role for HAT1 in intestinal stem cell function was demonstrated using organoids in culture. HAT1 is required for differentiation in organoids and for the maintenance of Lgr5+ stem cells. These results indicate that HAT1 is required for the proper regulation of intestinal stem cell renewal and differentiation.
    DOI:  https://doi.org/10.1016/j.jbc.2026.113368
  2. Nat Cell Biol. 2026 Jul 22.
    Mapping mesenchymal diversity in the human small intestine and organoids.
    Kelli F Johnson, Xiangning Dong, Yu-Hwai Tsai, Angeline Wu, Sydney G Clark, Abigail Vallie, Sha Huang, Charlie J Childs, Rachel K Zwick, Ian Glass, Katherine D Walton, Ophir D Klein, Jason R Spence.
      The organization of diverse mesenchymal populations during human small intestinal development is critical for tissue architecture and function yet remains poorly defined. Here, to construct a comprehensive, tissue-scale map of the developing human small intestine at single cell resolution, we leveraged single-cell RNA-sequencing data to build a Xenium spatial transcriptomics gene panel covering the cell diversity of the human small intestine. We defined five subpopulations occupying discrete anatomical locations within the lamina propria and submucosa-the subepithelial cells, lamina propria fibroblasts, submucosal fibroblasts, smooth muscle cells and CXCL13+ fibroblasts. Our data establish molecular markers to distinguish these populations in both sequencing and imaging data. We leverage this high-resolution atlas to interrogate cell-cell signalling, benchmark pluripotent stem cell-derived human intestinal organoids and to demonstrate how this resource can incorporate relative spatial organization into tissue analysis, with broad implications for modelling development, regeneration and disease.
    DOI:  https://doi.org/10.1038/s41556-026-02027-2
  3. iScience. 2026 Aug 21. 29(8): 116731
    Setdb1 safeguards proper differentiation of adult intestinal stem cells by controlling chromatin accessibility and transcriptome variability.
    Ioanna Peraki, Liwei Zhang, Dimitris Botskaris, Marianna Stagaki, Ioannis K Deligiannis, Haroula Kontaki, Elena Deligianni, Ioannis Giannoulakis, Orsalia Hazapis, Matthieu D Lavigne, Celia P Martinez-Jimenez, Iannis Talianidis.
      The histone methylase Setdb1 plays a pivotal role in embryonic stem cell maintenance and developmental lineage specification. However, its function in adult stem cells remains elusive. Here we show that the conditional inactivation of Setdb1 in Lgr5+ intestinal stem cells alters the transcriptional programs of the progeny cell types and results in increased cell-to-cell transcriptional variability. Loss of Setdb1 blocked differentiation toward the absorptive enterocyte lineage, while the secretory cell types were only marginally affected due to the activation of alternative developmental trajectories. Setdb1 inactivation did not affect global H3K9 methylation at large heterochromatin domains but led to altered distribution of transposase-accessible chromatin regions, aberrant exposure of transcription factor binding sites, and premature activation of differentiation-specific genes. The results demonstrate that Setdb1 regulates intestinal stem cell differentiation by fine-tuning chromatin accessibility in open euchromatin regions, thereby controlling transcriptional variability between cells.
    Keywords:  Setdb1; differentiation; gene regulatory networks; heterochromatin; intestinal stem cells; transcriptome variability; virtual knock-out
    DOI:  https://doi.org/10.1016/j.isci.2026.116731
  4. Cancer Cell. 2026 Jul 24. pii: S1535-6108(26)00305-3. [Epub ahead of print]
    A self-amplifying nerve-fibroblast circuit drives colorectal cancer progression.
    Hiroki Kobayashi, Tadashi Iida, Yosuke Ochiai, Akihiro Sakai, Ruth A White, Yi Zeng, Xiaofei Zhi, Jin Qian, Feijing Wu, Biyun Zheng, Junya Arai, Masahiro Hata, Hualong Zheng, Puran Zhang, Shuang Li, Quin T Waterbury, Jonathan S LaBella, Harry Nagendra, Leah B Zamechek, Atsushi Ogura, Mitsuro Kanda, Holger K Eltzschig, Susan L Woods, Daniel L Worthley, Atsushi Enomoto, Timothy C Wang.
      Nerves and cancer-associated fibroblasts (CAFs) have each been shown to regulate cancer progression directly. However, whether these cells interact to control tumor progression remains largely unknown. We show that in colorectal cancer (CRC), cholinergic stimulation induces CHRM3/Gq-dependent NTN1 secretion from CAFs, which in turn enhances intratumor cholinergic innervation. Within this feedforward loop, cholinergic stimulation promotes CRC growth directly through tumoral CHRM3/Gq-mediated YAP activation, while CAF-derived NTN1 promotes CRC growth and epithelial-to-mesenchymal transition-like programs via UNC5B-PI3K/AKT signaling. Chemogenetic activation of cholinergic neurons or fibroblast activation of the M3 receptor/Gq promotes tumoral YAP and AKT signaling and CRC progression. Conversely, blocking CHRM3 or NTN1 suppresses these pathways and improves mouse survival. In human CRC, high NTN1 expression is associated with a mesenchymal-like subtype and poor patient outcomes. These findings suggest that the neuro-mesenchymal interaction is central to CRC progression and could be therapeutically targeted with a CHRM3 antagonist or NTN1-blocking antibody.
    Keywords:  EMT; Netrin-1; Netrin-1 antibody NP137; acetylcholine; cancer neuroscience; cholinergic nerves; colorectal cancer; epithelial-to-mesenchymal transition; fibroblasts; muscarinic receptor 3; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.ccell.2026.06.018
  5. iScience. 2026 Aug 21. 29(8): 116860
    ACSS2 is required for colorectal cancer progression and a druggable target for colorectal cancer treatment.
    Lei Wang, Urszula Dougherty, Wenliang He, Lu Gao, Caleb Muefong, Rajesh Sarkar, Jie Du, Ardaman Shergill, Hening Lin, Marc Bissonnette, Yan Chun Li.
      Acyl-CoA synthetase short chain family member 2 (ACSS2) catalyzes the conversion of acetate to acetyl-CoA. Here we show that ACSS2 expression is markedly elevated in all stages of human colorectal cancer (CRC), and Acss2 silencing or genetic ablation leads to a marked reduction in CRC tumor load in allograft and xenograft models and CRC models induced by epithelial Apc deletion or azoxymethane/dextran sodium sulfate treatment. Tumors with ACSS2 depletion exhibit robust DNA damage, excessive apoptosis, and increased recruitment of macrophages and CD8+ T cells to the tumor microenvironment. Treatment with a small-molecule ACSS2 inhibitor markedly suppresses tumor growth in allograft/xenograft and Apc-mutant CRC models. ACSS2 promotes tumor cell growth by blocking DNA damage and apoptosis under nutritional stress. Collectively, these data indicate that the conversion of acetate to acetyl-CoA by ACSS2 is required for CRC progression and ACSS2 is a potential druggable target for CRC management.
    Keywords:  ACSS2; ACSS2 inhibitor; acetate; acetyl-CoA; colorectal cancer
    DOI:  https://doi.org/10.1016/j.isci.2026.116860
  6. iScience. 2026 Aug 21. 29(8): 116744
    Gene expression adaptation of metastases to their host tissue.
    Luise Nagel, Marten Wenzel, Sascha Hoppe, Mohammad Karimpour, Patrick S Plum, Abdossamad Hamoudi, Israt Jahan, Sarah Schmitt, Marek Franitza, Roger Wahba, Marc Bludau, Christiane J Bruns, Alexander Quaas, Andreas Beyer, Axel M Hillmer.
      Adaptation of metastatic cells to their host tissue determines the pathogenicity of cancer. Yet, it remains elusive to what extent the host environment drives gene expression programs in metastatic cells. We present a new concept to identify adaptive mechanisms that enable metastases to establish themselves in a novel tissue context. We generated quadruple-paired single-cell RNA-sequencing data from malignant and benign tissues from untreated donors with colorectal adenocarcinoma and liver metastasis. Utilizing a computational approach, we deduce tissue-adaptive expression patterns by identifying genes that consistently adapt to the host tissue. Expression changes in metastases are reminiscent of benign liver epithelial cells, including basic cellular functions such as energy metabolism, as well as tissue-specific pathways such as the regulation of lipid metabolism by peroxisome proliferator-activated receptor alpha (PPAR-α). This approach identifies the molecular adaptation of cancers to the host environment, which potentially increases the pathogenicity of metastatic cells, proposing a new therapeutic strategy to target adaptive processes.
    Keywords:  adaptation; colorectal cancer; liver metastasis; single cell sequencing
    DOI:  https://doi.org/10.1016/j.isci.2026.116744
  7. iScience. 2026 Aug 21. 29(8): 116743
    E3 ubiquitin-ligase Hakai regulates LRP4 stability and Wnt/β-catenin signalling in colorectal cancer cells.
    Andrea Rodríguez-Alonso, Lía Jove, Gloria Alfonsín, Marta Tasende, Ingrid Jordens, Madelon Maurice, Angélica Figueroa.
      The epithelial-mesenchymal transition is associated with the acquisition of cancer stem cell (CSC) traits that promote metastasis and therapy resistance. Here, we investigated the role of the E3 ubiquitin-ligase Hakai in regulating CSC-associated properties in colorectal cancer. Using tumoursphere models, loss-of-function approaches, proteomics, bioinformatics, and Wnt/β-catenin pathway studies, we found that Hakai depletion reduced tumoursphere formation, CSC marker expression, and Wnt target gene activation. Mechanistically, our findings support that Hakai regulates LRP4 stability, a negative regulator of Wnt signaling, consistent with ubiquitin-dependent mechanism. Consequently, Hakai enhances β-catenin/TCF transcriptional activity, nuclear accumulation of β-catenin, and attenuation of LRP4-mediated inhibition of Wnt signaling. Pharmacological inhibition of Hakai with Hakin-1, a selective inhibitor of its HYB domain responsible for E3 ubiquitin-ligase activity, reduced tumoursphere formation and promoted differentiation-associated features. Furthermore, these findings highlight Hakai inhibition as a potential CSC-directed therapeutic strategy in colorectal cancer.
    Keywords:  E3 ubiquitin-ligase Hakai; LRP4; Wnt/β-catenin pathway; cancer stem cell; colon cancer
    DOI:  https://doi.org/10.1016/j.isci.2026.116743
  8. iScience. 2026 Jul 17. 29(7): 116535
    IGF2BP3 is essential for the growth heterogeneity of colorectal adenoma cells by regulating MYC.
    Tomohiko Sunami, Roberto Coppo, Kunishige Onuma, Jumpei Kondo, Hiroyuki Uematsu, Daisuke Hoshi, Yoshihiro Yamamoto, Osamu Kikuchi, Shinya Ohashi, Yasuhide Takeuchi, Kazuto Kugou, Yoshinori Hasegawa, Yoshiro Itatani, Kazutaka Obama, Yoshitaka Hippo, Manabu Muto, Atsushi Yamada, Masahiro Inoue.
      Colorectal adenoma is a major precancerous lesion of colorectal cancer (CRC). The adenoma-carcinoma sequence is a multistep progression to CRC caused by the accumulation of genetic mutations. However, the non-genetic mechanisms underlying this process remain largely unknown. In this study, organoids were established from colorectal adenomas patients. Some organoids showed heterogeneity in the proliferative potential of single cells, which is regulated by non-genetic mechanisms. IGF2BP3 was identified as a differentially expressed gene associated with different growth patterns. IGF2BP3 modulated MYC expression levels in positive and negative directions, enabling high proliferative capacity and preventing MYC-induced cell death. IGF2BP3 affected tumorigenicity of mouse adenomas in vivo. Intratumoral heterogeneity in the growth potential is acquired at the precancerous stage of colorectal carcinogenesis, and IGF2BP3 is important for regulating MYC levels. These findings suggested a gatekeeping mechanism in the early stages of carcinogenesis.
    Keywords:  Heterogeneity; IGF2BP3; MYC; adenoma-carcinoma sequence
    DOI:  https://doi.org/10.1016/j.isci.2026.116535
  9. Front Immunol. 2026 ;17 1844372
    RHOA at the intersection of inflammation-driven and sporadic colorectal cancer.
    Sofia Elena Muccioli, Laura Hidalgo-García, Phuong A Ngo, Markus F Neurath, Rocío López-Posadas.
      In the last decades, colorectal cancer (CRC) has emerged as a global problem, representing approximately 10% of all malignant tumors and the second leading cause of cancer-related death. Colitis-associated cancer (CAC) arises from chronic unresolved inflammation and is typically characterised by poor prognosis. Among key cellular regulators, the small GTPase RHOA controls cytoskeleton dynamics in various cell types and, thereby, key biological processes. Although it has been linked to various diseases, the role of RHOA in cancer remains controversial. RHOA has been proposed as a biomarker in cancer including CRC, but recent evidence shows that RHOA inactivation increases Wnt signalling and tumour risk in the murine intestinal epithelium. This review summarises the mechanisms of RHOA function and regulation and analyses the oncogenic pathways in which it is involved, with a focus on sporadic CRC and CAC. We discuss whether the RHOA pathway serves the same function in the two types of intestinal cancer and how the inflammatory context can modulate RHOA outcome following activation or inhibition, which still remains an open question. Finally, we address opportunities for therapeutic targeting of RHOA and related proteins. The understanding of the function of RHOA specifically in CRC may help identify limitations that might have hampered the development of novel targets for optimized treatment and/or diagnostic strategies.
    Keywords:  Cytoskeleton; Inflammation; RHOA; colitis-associated cancer (CAC); colorectal cancer (CRC)
    DOI:  https://doi.org/10.3389/fimmu.2026.1844372
  10. Cell Rep. 2026 Jul 24. pii: S2211-1247(26)00797-7. [Epub ahead of print]45(8): 117719
    DHODH is a synthetic lethal target in PIK3CA-mutant colorectal cancer.
    Jun Liang, Xi Liu, Ziyun Ni, Sen Zhang, Xiangli He, Lili Wang, Yukun Huang, Zhaomin Xu, Zhongyu Xu, Jiayi Qian, Lixue Lu, Naijipu Abuduaini, Jing Tian, Minghua Zeng, Qi Wang, Jing Sun, Qiong Xie, Yonghui Wang, Weiqiang Lu, Bo Feng, Bo Han, Jin Huang.
      Cancer cells acquire distinct metabolic and signaling dependencies driven by oncogenic mutations. Defining these mutation-specific liabilities can uncover therapeutic opportunities. Here, we identify dihydroorotate dehydrogenase (DHODH) as a selective metabolic dependency in PIK3CA-mutant colorectal cancer (CRC). DHODH sustains WDR77 O-GlcNAcylation and protein stability by promoting the generation of uridine diphosphate (UDP)-N-acetylglucosamine (UDP-GlcNAc), thereby maintaining PI3K-AKT signaling. Genetic or pharmacological inhibition of DHODH reduces WDR77 protein abundance, decreases phosphorylated AKT, and impairs cancer cell self-renewal and tumor initiation. Uridine supplementation restores WDR77 and AKT signaling, whereas O-GlcNAc transferase (OGT) depletion abrogates this rescue, establishing a UDP-dependent mechanism linking pyrimidine metabolism to signaling maintenance. Treatment with the DHODH inhibitor HL6 recapitulates the genetic phenotypes and suppresses tumor growth in xenograft, orthotopic, and patient-derived CRC models. This study demonstrates that the metabolic regulation of protein stability represents a critical mechanism underlying oncogene-specific dependencies in CRC.
    Keywords:  CP: cancer; DHODH; O-GlcNAcylation; PIK3CA mutation; cancer stemness; colorectal cancer
    DOI:  https://doi.org/10.1016/j.celrep.2026.117719
  11. Nat Metab. 2026 Jul 23.
    Mitochondrial metabolism determines chemotherapy sensitivity in colorectal cancer.
    Deborah Y Moss, Connor N Brown, Andrew M Shaw, Christopher McCann, Nikita Lewis, Matilda Downs, Rebecca Wurelly, Ciara Cunningham, Aaron Philips, Niamh Doherty, Sarah Gallagher, William J McDaid, Andrew Roe, Aisling Y Coughlan, Brenton Cavanagh, Callum Ormsby, Fiammetta Falcone, Rachel McCole, Scott Monteith, Emily Rogan, Sudhir B Malla, Alexandra J Emerson, Letitia Mohammed-Smith, Shaun Sharkey, Aoife Leonard, Peter F Gallagher, Arindam Banerjee, Sandra Van Schaeybroeck, Sufyan Pandor, Brian Quinn, Brett Greer, Christopher Elliott, Sarah Maguire, Aideen E Ryan, Philip D Dunne, Mary Mallon, Stephanie Craig, Omar Aftab, Laura C Greaves, Bryan P Marzullo, Daniel A Tennant, Vicky Coyle, Ian G Mills, Owen Sansom, Tríona Ní Chonghaile, Daniel B Longley, Simon S McDade, Melissa J LaBonte, Emma M Kerr.
      Therapy resistance is attributed to over 80% of cancer deaths per year, emphasizing the urgent need to overcome this challenge for improved patient outcomes. Despite its widespread use in colorectal cancer (CRC) treatment, resistance to 5-fluorouracil (5FU) remains poorly understood. As an antimetabolite, 5FU imposes substantial metabolic stress, forcing cells that survive treatment to rapidly adapt. We explored acute 5FU-driven changes in mitochondria, the organelle critical for coordinating metabolic stress responses. Here we demonstrate in a range of CRC models that 5FU treatment promotes mitochondrial biogenesis and increases mitochondrial function in surviving cells. Furthermore, we show that targeting mitochondrial metabolism, particularly by inhibiting Complex I, sensitizes CRC cells to 5FU, resulting in delayed tumour growth and prolonged survival in preclinical models. Additionally, analysis of patient data suggests that oxidative metabolism signatures may predict responses to 5FU-based chemotherapy. These findings shed light on mechanisms underlying 5FU resistance and propose a rational strategy for combination therapy in CRC, emphasizing the potential clinical benefit of targeting mitochondrial metabolism to overcome resistance and enhance patient outcomes.
    DOI:  https://doi.org/10.1038/s42255-026-01578-w
  12. Oncologist. 2026 Jul 08. pii: oyag235. [Epub ahead of print]31(8):
    Patterns of progression and survival in patients with mismatch repair deficient/ microsatellite instability- high metastatic colorectal cancer treated with immunotherapy.
    Michael LaPelusa, Preksha Shah, Deepak Bhamidipati, Naishu Kui, Alisha Bent, Arvind Dasari, Ryan Huey, Bryan Kee, Scott Kopetz, Phat Le, Kaysia Ludford, Maria Pia Morelli, Van K Morris, Christine Parseghian, Kanwal Raghav, Jason Willis, Robert Wolff, Dan Zhao, Michael J Overman, Victoria S Higbie.
       BACKGROUND: Immunotherapy has shown to be efficacious in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer (CRC). Unfortunately, there is still a population of patients who either do not respond or progress after prior response. Understanding the progression dynamics and outcomes based on the nature of disease progression (PD) is critical in this patient population.
    METHODS: We performed a retrospective analysis of 166 patients with advanced dMMR/MSI-H CRC who received immunotherapy. PD patterns were classified as intrinsic (progression at first restaging scan) or adaptive (progression after initial stable/responding disease) and as single organ or systemic.
    RESULTS: Progression was seen in 64 patients (38.6%) with single organ progression in 31 (48.4%) and systemic progression in 33 (51.5%). Intrinsic progression was seen in 32 patients (50%) and adaptive progression in 32 (50%). Patients with single organ progression had a longer median TTP (mTTP) and median OS (mOS) compared to patients with systemic progression (mTTP: 8.8 vs 4.0 months, P = .005; mOS: 65.9 vs 18.7 months, P = .023). Patients with adaptive PD had a longer mTTP and mOS compared to patients with intrinsic PD (mTTP: 11.6 vs 1.9 months, P = <.01; mOS: 65.9 months vs 17.0 months, P = .001).
    CONCLUSION: This analysis identifies significant differences in outcomes of patients with dMMR/MSI-H CRC based on the pattern and extent of progression, underscoring the need for tailored therapeutic strategies depending on the nature of PD-1-based progression.
    Keywords:  MSI-H/dMMR; colorectal cancer; immune checkpoint blockade; immunotherapy
    DOI:  https://doi.org/10.1093/oncolo/oyag235
  13. NPJ Regen Med. 2026 Jul 20.
    Prophylactic inhibition of LATS1/2 before high-dose irradiation promotes the regeneration of the damaged intestinal epithelium.
    Lucy M Driver, Frances Anne Tosto, Bridget S Scherer, Lixia Luo, Katy Harbaugh, Olivia White, Ayra Charania, Jordan Tran, Rebecca Bacon, Patrick J Morris, Michele Ceribelli, Damien Y Duveau, Lale Evsen, Scott B Hoyt, Keerthana Kurapati, Koravit Poysungnoen, John W Hickey, Jatin Roper, Christine E Eyler, Craig J Thomas, Chang-Lung Lee.
      Following radiation injury, intestinal epithelial cells adapt through cellular plasticity to regenerate and repopulate the damaged epithelium by activating Yap, a key effector protein of the Hippo signaling pathway. However, the impact of pharmacologically targeting the Hippo pathway on the regeneration of the irradiated intestinal epithelium remains poorly understood. Here, we investigated this question using NCGC-023, a selective and potent small-molecule inhibitor of Yap's upstream regulators LATS1/2. NCGC-023 treatment significantly increased active Yap protein expression in human enteroids and protected them against ionizing radiation (IR) in vitro. In mice, transient treatment with NCGC-023 before IR reduced radiation-induced DNA damage, suppressed premitotic apoptosis and aberrant mitosis in intestinal crypt cells, facilitated regenerative reprogramming of the damaged intestinal epithelium, and improved survival of mice subjected to IR doses that precipitate gastrointestinal acute radiation syndrome (GI-ARS). Mechanistically, NCGC-023 treatment before IR upregulated key signaling pathways controlled by LATS1/2, including Yap-dependent regenerative responses involving Il-33 and Yap-independent cellular responses to heavy metals mediated by metallothioneins. Moreover, NCGC-023 treatment did not exacerbate delayed injury in multiple organs of mice that survived 4 months post-irradiation. Together, these results demonstrate that transient NCGC-023 treatment before high-dose IR promotes the regeneration of the damaged intestinal epithelium. This proof-of-concept study supports further development of LATS1/2 inhibitors as prophylactic medical countermeasures for GI-ARS.
    DOI:  https://doi.org/10.1038/s41536-026-00496-5
  14. Mol Cancer. 2026 Jul 20.
    Evidence of endothelial anergy and T-cell exclusion in microsatellite stable colorectal liver metastases revealed through human hemi-liver perfusion and spatial transcriptomics.
    Peter Kok-Ting Wan, Ranchu Cheng, David Johnson, Carl Lee, Shihong Wu, Areeb Mian, Ahmet Hazini, Sorayya Moradi, Kate Friesen, Flurin Caviezel, Syed Hussain Abbas, Brannon Nicholls, Hatem Sadik, Adil Lakha, Keaton Jones, Girishkumar Kumaran, Matthew J Bottomley, Rob Jones, Mark Coles, Rachael Bashford-Rogers, Constantin Coussios, Len Seymour, Robert Carlisle, Kerry Fisher, Alex Gordon-Weeks.
       BACKGROUND: Colorectal liver metastasis (CRLM) is the terminal stage of colorectal cancer and remains largely resistant to immunotherapeutics, yet the underlying immune escape mechanisms remain poorly understood. Through novel observational methods focused on human living and fixed tissue, we profiled the spatial and molecular features of microsatellite stable (MSS) CRLM and the surrounding liver microenvironment.
    METHODS: First, we re-purposed normothermic hepatic machine perfusion as a preclinical model of MSS CRLM, enabling delivery of labelled T-cells through physiological vascular routes into living, tumour-bearing human livers. Second, to dissect the liver microenvironment, we spatially map the transcriptomes of MSS CRLM and adjacent liver at single-cell resolution across ~ 1.9 million cells, and perform multiplexed immunofluorescence applying a19-marker panel to a validation cohort.
    RESULTS: Whilst T-cells readily extravasated within the peri-tumoural liver, they failed to extravasate into MSS CRLM. Spatial analyses revealed a progressive shift in endothelial phenotypes across regions: from a non-inflamed state in normal liver, to a highly inflamed, peri-tumoural endothelium, and finally to an anergic, angiogenic endothelial population within CRLM characterised by reduced expression of adhesion molecules required for T-cell extravasation. CD4 T-cells that extravasate in the peri-tumoural liver are TCR-reactive yet exhausted, whereas CD4 T-cells within CRLM show stress responses, impaired cytokine gene expression and reduced TCR reactivity, residing within hypoxic niches. These divergent CD4 phenotypes are associated with distinct fibroblast-myeloid niches across peri-tumoural and tumour regions.
    CONCLUSION: Based on these observations, MSS CRLM impair T-cell extravasation and simultaneously drive intra-tumoural endothelial anergy, peri-tumoural T-cell exhaustion and an intra-tumoural T-cell stress response. Further mechanistic work is needed to validate these findings and guide the development of novel immunotherapeutics.
    Keywords:  Colorectal cancer liver metastasis; Eendothelial anergy; Human cancer models; Liver perfusion; Multiplexed imaging; Spatial transcriptomics; T cell exhaustion
    DOI:  https://doi.org/10.1186/s12943-026-02732-4
  15. PLoS Biol. 2026 Jul;24(7): e3003928
    Clonal drift in the aging gut: Mapping the fate of stem cells over time.
    Tzu-Chiao Lu, Hongjie Li.
      Aging tissues gradually lose cellular diversity due to stem cell exhaustion. A new PLOS Biology study utilizes advanced lineage tracing to track intestinal stem cell lineages across the life span. The findings reveal clonal attrition happens in early ages.
    DOI:  https://doi.org/10.1371/journal.pbio.3003928
  16. Discov Oncol. 2026 Jul 21.
    A bibliometric analysis of arachidonic acid metabolism in colorectal cancer with a focus on COX inhibitors-related clinical trials landscape.
    Xingcan Fan, Tao Yu, Yulin Song, Qiuyu Liao, Gang Liu.
       BACKGROUND: Colorectal cancer (CRC) remains a global malignancy with high morbidity and mortality. Long-term uncontrolled intestinal inflammation drives CRC initiation and development. As a vital essential fatty acid and prostaglandin precursor, arachidonic acid (AA) participates in inflammatory and immune regulation, and its metabolic disorder is tightly linked to multiple inflammatory diseases and CRC. This study clarified the progress of research on AA metabolism and CRC through bibliometric analysis, and analyzed the clinical application prospects of COX inhibitors in CRC by integrating clinical trial data.
    METHODS: For bibliometric analysis, data were retrieved from WOSCC (1990-2025) using specific search terms, preprocessed, and analyzed via R Studio and LDA topic model to clarify publication trends and research hotspots. Meanwhile, relevant clinical trials of COX inhibitors for CRC and its precancerous lesions were collected from the Trialtrove database for multidimensional analysis.
    RESULTS: This bibliometric analysis highlights the significant growth in research on AA metabolism in colorectal cancer, identifying key authors, countries, and research hotspots. The field has transitioned from a focus on COX-2 and PGE2 to a more integrated understanding that includes gut microbiota and immune modulation. For clinical trial analysis, among the 61 included trials, aspirin and celecoxib monotherapies were dominant, and combination regimens have drawn rising attention. Regarding trial status, less than one-third of trials were completed, while plenty remained active or terminated early.
    CONCLUSION: By synthesizing the results of bibliometric and clinical trial landscape studies, we summarized drugs targeting the AA pathway that inhibit inflammatory cancer transformation.
    Keywords:  Arachidonic acid (AA); Bibliometric analysis; Clinical trials; Colitis-associated colorectal cancer (CAC); Colorectal cancer (CRC)
    DOI:  https://doi.org/10.1007/s12672-026-05516-w
  17. Cancer Res. 2026 Jul 23.
    Crosstalk Between Schwann Cells and CD4+ T Cells Promotes Perineural Invasion in Colorectal Cancer.
    Huayuan Liu, Yiqiao Deng, Yi Yang, Junshuai Xue, Nuersimanguli Maimaitiming, Bingzhi Wang, Yujing Xin, Jinxue Zhou, Xiaomeng Liu, Chengyao Guo, Lang Yang, Zhen Huang, Haitao Zhou, Jianqiang Cai, Hong Zhao.
      Perineural invasion (PNI) is a common pathological feature associated with poor prognosis of colorectal cancer (CRC). A better understanding of the mechanisms underlying PNI formation could help identify potential strategies to inhibit tumor progression. Here, we revealed an integral role of CD4+ T cells in the development and progression of PNI in CRC. Single-cell RNA sequencing, spatial transcriptomics, and multiplex immunohistochemistry profiling uncovered a distinct HSPA6+CD4+ T cell subset expressing T stress (Tstr) cell markers in CRC PNI tissues. Schwann cells (SCs) colocalized with the HSPA6+CD4+ Tstr cells in PNI, and functional studies showed that SCs promoted Tstr cell differentiation while Tstr cells enhanced SC migration. Interaction between SCs and CD4+ T cells activated the MAPK pathway in SCs and the JAK-STAT pathway in Tstr cells, and inhibition of MAPK and STAT signaling suppressed nerve invasion of CRC cells in vivo. Moreover, SCs in contact with tumor cells possessed the ability to recruit CD4+ T cells; tumor-derived TNF-α stimulated SCs to secrete CCL4, thereby recruiting CD4+ T cells toward SCs. The anti-TNF-α monoclonal antibody infliximab reversed the pro-invasive and pro-migratory effects of SCs on CRC cells and reduced intratumoral CD4+ Tstr cells, and the combination of infliximab with anti-PD-1 treatment produced a combinatorial tumor suppressive effect. Together, this study suggests that SCs near CRC tissues recruit CD4+ T cells and promote their conversion to CD4+ Tstr cells to establish an immunosuppressive microenvironment and simultaneously enhance the migration and tumor-promoting capabilities of SCs, thereby accelerating PNI development.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5781
  18. iScience. 2026 Jul 17. 29(7): 116544
    Immune-epithelial crosstalk governs immune checkpoint inhibitor efficacy in colorectal cancer.
    Sheah Lin Lee, Adrian C Bateman, Margaret Ashton-Key, John N Primrose, Alex Mirnezami, Aymen Al-Shamkhani, Stephen M Thirdborough.
      Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) elicits a CD8+ T cell response. However, the magnitude and composition of this response vary among patients, influencing the efficacy of immune checkpoint inhibitors (ICIs). To investigate this heterogeneity, we integrated bulk transcriptomics with immune repertoire sequencing in dMMR CRC. We identified co-regulated gene modules associated with T- and B cell clonal expansion, immune-metabolic interactions, and therapeutic response. Key transcriptional programs linked to T cell clonality and ICI responsiveness were validated using spatial transcriptomics and the TCGA-CRC cohort. We observed an inverse relationship between immune activation and oxidative metabolism and identified immune-epithelial crosstalk as a determinant of ICI efficacy. These findings may inform biomarker development and patient stratification in both dMMR and mismatch repair-proficient CRC. Transcriptional programs linked to T cell clonality in dMMR CRC also define a subset of immunologically active microsatellite-stable tumors, supporting the rationale for extending ICI-based therapies to these patients.
    Keywords:  T and B cell clonality; checkpoint inhibitor; immune-epithelial crosstalk; mismatch repair-deficient colorectal cancer; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2026.116544
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