bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–06–21
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. From mice to humans-divergent strategies for intestinal homeostasis and regeneration.
  2. Regulation of EIF5A and hypusination by p53 determines colorectal cancer cell fitness.
  3. Targeting CCDC90B restores intestinal stem cell function under hyperuricemic stress.
  4. Targeting the lipid desaturation network in cancer: from metabolic plasticity to precision therapeutics.
  5. Stearoyl-CoA desaturase 1 integrates tissue-specific oncogenic pathways into a pan-cancer ferroptosis resistance program.
  6. Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.
  7. Single-cell and spatial transcriptomics reveal lactate-active epithelial-immune cell crosstalk that reprograms the immune microenvironment in colorectal cancer.
  8. Amphiregulin drives EGFR-dependent genome stability in colorectal cancer and represents a targetable vulnerability.
  9. Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.
  10. Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
  11. Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
  12. Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
  13. Trans-presentation of IL-6Rα by macrophages drives colorectal cancer development.
  14. Study of ß-catenin signaling pathway modulated by PTHrP in cell and animal colorectal cancer models.
  15. Impact of BECLIN1 haploinsufficiency on goblet cell function and susceptibility to colitis.
  1. FEBS Lett. 2026 Jun 19.
    From mice to humans-divergent strategies for intestinal homeostasis and regeneration.
    Keiko Ishikawa, Shinya Sugimoto, Toshiro Sato.
      The intestinal epithelium is maintained by stem cells that balance self-renewal and differentiation to sustain homeostasis and enable regeneration after injury. Recent advances-including organoid culture, genome editing, orthotopic xenotransplantation, and somatic mutation-based analysis-have created new opportunities to investigate intestinal stem cell (ISC) dynamics in humans. These studies have revealed striking species-specific differences: whereas mouse LGR5+ ISCs divide daily and are chemo-sensitive, human colonic LGR5+ stem cells are predominantly slow-cycling and chemo-resistant. Consistent with this reduced cycling, human ISCs accumulate somatic mutations more slowly than those of mice. Across mammals, ISC proliferation rates inversely correlate with lifespan, a relationship thought to minimize mutation accumulation and reduce cancer risk, in line with Peto's paradox. Regenerative responses in both mice and humans can involve fetal-like reprogramming driven by YAP and other signaling pathways, yet the extent of species differences in intestinal regenerative capacity remains unclear. This review synthesizes current insights into ISC kinetics, injury responses, and evolutionary adaptations, highlighting the need for human-focused studies to bridge translational gaps and guide regenerative medicine strategies.
    Keywords:  LGR5+ stem cell; colonic stem cell; fetal‐like reprogramming; intestinal stem cell; organoid; regeneration; slow‐cycling stem cell; somatic mutation rate
    DOI:  https://doi.org/10.1002/1873-3468.70387
  2. Cancer Lett. 2026 Jun 15. pii: S0304-3835(26)00446-5. [Epub ahead of print]656 218682
    Regulation of EIF5A and hypusination by p53 determines colorectal cancer cell fitness.
    Alain P Gobert, Caroline V Hawkins, Mohammad Asim, Daniel P Barry, Alberto G Delgado, Regina N Tyree, Kate S Carson, Nikhil P S Kahlon, Mark V Ciampa, Kristie L Rose, Purvi Patel, Ganesh V Pusapati, Rajat Rohatgi, Wang Yu, Shilin Zhao, Lori A Coburn, M Blanca Piazuelo, Keith T Wilson.
      Hypusination of eukaryotic translation initiation factor 5 A (EIF5A) by the enzyme deoxyhypusine synthase (DHPS) is a mechanism of regulation of translation that plays a role in cell proliferation. Herein, we assessed the role of hypusination in established colorectal cancer (CRC). Using molecular and biochemical approaches in established CRC cell lines and human colon organoids, we found that the tumor suppressor p53 is a critical regulator of expression of the gene EIF5A1 in the colon, thus supporting EIF5A synthesis and hypusination. Therefore, tissues and cells isolated from patients with CRC harboring TP53 mutation associated with loss of function of p53 exhibited a marked reduction of EIF5A and hypusine level. Further, TP53 mutant CRC cells remained unresponsive to a DHPS inhibitor. However, restoration of wild-type TP53 in these mutated cells supported hypusination-dependent translation of proteins involved in cell growth and rendered them susceptible to DHPS inhibition. Our studies show that loss of EIF5A is an unrecognized molecular feature of TP53 mutation in CRC cells and patients with WT TP53 CRC may benefit from drugs that can inhibit hypusination.
    Keywords:  Colon; Colorectal cancer; Deoxyhypusine synthase; Hypusine; Polyamine; Tumor suppressor p53
    DOI:  https://doi.org/10.1016/j.canlet.2026.218682
  3. Stem Cell Reports. 2026 Jun 18. pii: S2213-6711(26)00181-5. [Epub ahead of print] 102970
    Targeting CCDC90B restores intestinal stem cell function under hyperuricemic stress.
    Xiuying Peng, Moxuan Li, Kaixuan Zeng, Wantong Lv, Shuai Huang, Zhaopeng Chen, Yunwei Guo, Taoli Liu, Fengping Zheng, Peng Huang.
      Hyperuricemia (HUA) affects diverse biological processes and signaling pathways across multiple organ systems; however, its impact on the intestine remains poorly understood. Here, we show that HUA disrupts intestinal barrier function primarily by impairing intestinal stem cell (ISC) function, which is essential for epithelial renewal. Mechanistically, elevated uric acid (UA) directly binds to the mitochondrial protein CCDC90B, leading to excessive mitochondrial ROS accumulation, activation of the NLRP3 inflammasome, and subsequent initiation of downstream pyroptotic signaling. The resulting exhaustion of the intestinal stem cell pool impairs epithelial regeneration and further weakens intestinal barrier integrity. Collectively, these findings reveal a previously unrecognized mechanism linking UA to ISC dysfunction and highlight CCDC90B as a potential therapeutic target for HUA-associated intestinal dysfunction.
    Keywords:  CCDC90B; hyperuricemia; intestinal organoids; intestinal stem cells; pyroptosis
    DOI:  https://doi.org/10.1016/j.stemcr.2026.102970
  4. J Exp Clin Cancer Res. 2026 Jun 17.
    Targeting the lipid desaturation network in cancer: from metabolic plasticity to precision therapeutics.
    Justyna J Gleba, John A Copland, Han W Tun.
      Lipid desaturation is a fundamental biochemical process essential for maintaining membrane fluidity, energy storage, and cellular signaling. It is increasingly recognized that this homeostatic network is frequently dysregulated by malignant cells to support proliferation, evade programmed cell death, and facilitate immune evasion. There are two primary lipid desaturation pathways: the conversion of saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs) by stearoyl-CoA desaturase 1 (SCD1), and the biosynthesis of long-chain polyunsaturated fatty acids (LC-PUFAs) via the fatty acid desaturases (FADS). This review explores how tumors utilize the SCD1 axis to mitigate lipotoxic endoplasmic reticulum (ER) stress and ferroptosis. Furthermore, we discuss how the FADS axis presents a distinct metabolic paradox: while it promotes oncogenic signaling and structural plasticity, it concurrently creates an actionable vulnerability to ferroptosis by enriching membranes with peroxidation-prone PUFAs. This metabolic rewiring provides a strong biological rationale for precision therapeutics.We trace the clinical development of desaturase inhibitors, highlighting the recent entry of SCD1 inhibitor, MTI-301, in a Phase 1 clinical trial for solid tumors and the potential repurposing of Aramchol, while detailing how FADS2 plasticity (the "sapienic shunt") drives therapeutic resistance. By integrating these insights into desaturation lipidomics, metabolic modulation via diet-drug interactions, synergistic combination regimens, and stimuli-responsive nanomedicine, we highlight the translational potential of targeting lipid desaturation to overcome metabolic plasticity and treatment resistance in aggressive malignancies.
    Keywords:  Cancer metabolism; ER stress; FADS2; Ferroptosis; Lipid desaturation; MTI-301 (SSI-4); Metabolic plasticity; Precision therapeutics; SCD1; Sapienic shunt
    DOI:  https://doi.org/10.1186/s13046-026-03747-x
  5. Cell Death Dis. 2026 Jun 19.
    Stearoyl-CoA desaturase 1 integrates tissue-specific oncogenic pathways into a pan-cancer ferroptosis resistance program.
    Francesca Ascenzi, Giovanni Blandino, Gennaro Ciliberto, Rita Mancini.
      Ferroptosis, a regulated form of cell death driven by iron-dependent lipid peroxidation, has recently emerged as a promising therapeutic vulnerability in cancer. Among its key modulators, stearoyl-CoA desaturase 1 (SCD1) plays a pivotal role in ferroptosis resistance by converting saturated fatty acids into monounsaturated fatty acids (MUFAs), thereby limiting the accumulation of highly peroxidizable polyunsaturated fatty acids (PUFAs) and stabilizing membrane integrity under oxidative stress. Multiple oncogenic, transcriptional, epigenetic, and microenvironmental cues enhance tumor survival by promoting SCD1-dependent ferroptosis resistance. Despite this diversity of regulatory inputs, a unifying principle emerges across tumor types: SCD1 activity preserves lipid desaturation as a dominant metabolic strategy to suppress ferroptotic cell death. In this review, we critically analyze how SCD1-dependent ferroptosis resistance is shaped by tumor-specific metabolic states, microenvironmental pressures, and regulatory hierarchies across multiple malignancies. We identify recurring mechanistic themes through which SCD1 integrates redox control, lipid metabolism, stemness, and therapy resistance, while highlighting how these processes are differentially regulated across tissues. Preclinical evidence indicates that targeting SCD1, particularly in rational combination with ferroptosis inducers, chemotherapy, radiotherapy, or immunotherapy, can lower the ferroptotic threshold and overcomes treatment resistance. Finally, we discuss translational challenges and emerging strategies, including tumor-selective delivery, adaptive dosing, and context-specific combinations, that may enable safe and effective exploitation of the SCD1-ferroptosis axis in cancer therapy.
    DOI:  https://doi.org/10.1038/s41419-026-08982-w
  6. Cell Metab. 2026 Jun 17. pii: S1550-4131(26)00222-6. [Epub ahead of print]
    Hepatocyte-to-intestinal stem cell remote communication regulates blood glucose homeostasis.
    Jinbao Ye, Qianyi Wan, Xingzhu Liu, Yawen Deng, Zehong Zhang, Haiou Chen, Chaoxin Gao, Shiyu Zhang, Yuedan Zhu, Jinhua Yan, Yu Yuan, Yi Chen, Haiyang Chen.
      The liver is known to play a pivotal role in modulating blood glucose homeostasis through intrahepatic glucose metabolism. Here, we reveal a unique mechanism by which fatty liver exacerbates hyperglycemia through remote communication from hepatocytes to intestinal stem cells (ISCs), independent of enhanced intrahepatic gluconeogenesis. Mechanistically, hepatocyte-derived alkaline phosphatase (ALP) targets α2δ-1 in ISCs to promote the membrane translocation of Cav1.2. This process triggers increased intracellular calcium levels, which subsequently activates the calcineurin/NFATC2 signaling axis, thereby inhibiting SOX21 expression. Then, decreased expression of SOX21 downregulated bone morphogenetic protein 7 (BMP7), ultimately hindering ISCs differentiation into intestinal L-cells. Consequently, the levels of hypoglycemic enteroendocrine hormones secreted by L-cells are decreased, thereby promoting hyperglycemia. Therapeutically, inhibiting ALP synthesis in fatty liver independently reduces blood glucose and synergistically enhances the hypoglycemic effect of metformin. Our study highlights the role of liver-gut communication in regulating the fate of ISC differentiation and blood glucose homeostasis.
    Keywords:  SOX21; alkaline phosphatase; blood glucose; fatty liver; intestinal stem cells
    DOI:  https://doi.org/10.1016/j.cmet.2026.05.012
  7. Transl Oncol. 2026 Jun 19. pii: S1936-5233(26)00201-9. [Epub ahead of print]71 102864
    Single-cell and spatial transcriptomics reveal lactate-active epithelial-immune cell crosstalk that reprograms the immune microenvironment in colorectal cancer.
    Haisheng Lan, Yang Li, Hua Li, Junyu Guo, Cunchuan Wang, Qianli Tang.
      The metabolic reprogramming of tumor microenvironment is a critical driver of colorectal cancer (CRC) pathogenesis. In this context, dysregulated lactate metabolism plays a pivotal role in immunosuppression and therapeutic resistance. Integrating single-cell transcriptomics, spatial transcriptomics, and bulk sequencing datasets, this research delineated the lactate metabolic landscape across colorectal cancer (CRC) tumor ecosystems. Single-cell profiling revealed significant metabolic activity in both the epithelial and myeloid compartments. Consequently, a lactate metabolism score (LMscore) was developed, which is based on four core genes (COX15, SLC25A13, COX10, MPC1). An elevated LMscore has been demonstrated to reprogram epithelial developmental trajectories and reconfigure intercellular communication networks, notably through EFNA1-EPHA3-mediated crosstalk with fibroblasts and endothelial cells. Spatial transcriptomics corroborated intimate spatial colocalization and metabolic pathway co-enrichment between lactate-active epithelia and fibroblasts. Clinically, high LMscore independently predicts a decreased overall survival across multiple cohorts and defines a "cold" tumor immune phenotype. This phenotype is characterized by an accumulation of immunosuppressive cells including M2 macrophages and cancer-associated fibroblasts (CAFs) and a reduction in effector T-cell infiltration. This ultimately results in a refractory response to immune checkpoint blockade. Mechanistically, COX15 emerges as a central regulator of lactate metabolic dysregulation, coinciding with fibroblast-derived TGF-β secretion and immunosuppressive niche formation. Functional validation confirms that COX15 targeting suppresses tumor proliferation. This work establishes LMscore as a clinically robust biomarker for prognostication and immunotherapy response prediction, thereby providing a mechanistic foundation for metabolic reprogramming-targeted combinatorial therapies in CRC.
    Keywords:  Colorectal cancer; Immune microenvironment; Lactate metabolism; Prognostic biomarker; Single-cell transcriptomics
    DOI:  https://doi.org/10.1016/j.tranon.2026.102864
  8. Oncogene. 2026 Jun 15.
    Amphiregulin drives EGFR-dependent genome stability in colorectal cancer and represents a targetable vulnerability.
    Sun-Ji Park, Sung-Woo Lee, Heegyum Moon, Su-Min Jung, Jin-Man Kim, Dong-Seok Lee, Eui-Hwan Choi.
      Amphiregulin (AREG) functions as an epidermal growth factor receptor (EGFR) ligand that modulates signaling and supports nuclear processes involved in DNA replication and repair in colorectal cancer (CRC). Immunohistochemistry and western blot revealed high expression of AREG in CRC tumors compared to other CRCs. Our findings indicate that AREG translocates into the nucleus, a process potentially facilitated by the inhibition of endocytosis. Transcriptomic analyses suggest an association between AREG expression and genes regulating EGFR signaling, replication fork dynamics, and homologous recombination. Depletion of AREG via siRNA or CRISPR-Cas9 led to S/G₂ arrest, replication tract shortening, and increased RAD51, RPA, and γH2AX foci, resulting in a 40-60% reduction in proliferation effects that were not fully recapitulated by small-molecule EGFR inhibitors. In xenograft models, AREG knockout reduced tumor growth and suppressed the phosphorylation of EGFR, ERK, STAT3, and BRAF. Furthermore, combining AREG loss with EGFR inhibition appeared to enhance antitumor effects. These findings suggest that AREG may function as a mediator of EGFR signaling and genome maintenance in CRC.
    DOI:  https://doi.org/10.1038/s41388-026-03850-5
  9. Cell Death Dis. 2026 Jun 17.
    Fatty acid synthesis therapy-induced senescence (FASTIS) in cancer cells.
    Sara Verdura, Àngela Llop-Hernández, Travis Van der Steen, José Antonio Encinar, Begoña Martin-Castillo, Elisabet Cuyàs, Ruth Lupu, Javier A Menendez.
      Therapy-induced senescence (TIS) in cancer cells can be triggered by radiotherapy, chemotherapy, and certain targeted therapeutics. Here, we demonstrate that a new form of TIS, termed fatty acid synthesis therapy-induced senescence (FASTIS), can be induced by pharmacologically targeting de novo lipogenesis. Cancer cells can evade the anti-proliferative effects of clinically relevant inhibitors of core lipogenic enzymes, such as acetyl-CoA carboxylase (ACC) and fatty acid synthase (FASN), by entering in a senescence-like state. FASTIS cancer cells acquire the classical senescence hallmarks, such as cytomorphological remodeling, increased senescence-associated beta-galatosidase (SA-β-gal) activity, activation of cell cycle arrest markers, and hypersensitivity to IFNγ-induced activation of the immune checkpoint PD-L1. mRNA sequencing reveals an FASTIS-associated transcriptomic profile that overlaps between ACC and FASN inhibitors yet differs significantly from that of other mechanistically diverse TIS inducers, including bleomycin, alisertib, doxorubicin, and palbociclib. The FASTIS-encoding transcriptome is characterized by the activation of cholesterol- and acetyl-CoA-related lipogenic pathways, as well as cell-intrinsic innate immune responses. This profile is characterized as highly senescent (≥0.95) by the machine learning-based senescence predictor SENCAN. Mapping the metabolome and lipidome in FASTIS cells reveals a significant sterol lipid enrichment, including substantial increases in intracellular cholesterol levels. Pharmacological blockade of cholesterol synthesis or promotion of lysosomal cholesterol accumulation, prevents or potentiates the occurrence of SA-β-gal+ FASTIS cells, respectively. Cytokine arrays and miR-146a reporter-based screens revealed that the FASTIS-associated secretory phenotype (FASASP) is highly enriched in immunomodulatory factors but not in inflammatory components. FASTIS cancer cells exhibit an increased overall level of mitochondrial priming, making them highly susceptible to targeted senolysis by BCL-xL-targeting BH3 mimetics and cytokine-activated T cells. The FASTIS phenomenon is a therapeutic outcome through which cancer cells adapt to survive clinical-grade lipogenesis inhibitors. The cholesterol-addicted FASTIS fate can be rationally exploited as a collateral sensitivity in "one-two punch" senogenic-(immuno)senolytic strategies.
    DOI:  https://doi.org/10.1038/s41419-026-08992-8
  10. Nat Commun. 2026 Jun 17.
    Intermediate accumulated upon interruption of fatty acid oxidation flux promotes tumoral ferroptosis and improves immunotherapy.
    Yuhan Zhou, Jing Li, Fangfang Liu, Yuan Gao, Songlin Yin, Liguo Yang, Xiaoxiao Li, Junhong Lin, Yan Li, Haotian Shang, Xiang Cheng, Tengfei Chao, Qian Chu, Fujia Lu, Weimin Wang.
      Therapeutic strategies targeting cancer metabolism are advancing rapidly. However, perturbing distinct nodes within the same metabolic pathway often yields divergent outcomes. Ferroptosis, a metabolic cell death driven by lipid peroxidation, has garnered attention for potentiating antitumor immunity. Here, we demonstrate that interruption of fatty acid oxidation (FAO) at hydroxyacyl-CoA dehydrogenase (HADHA) node promotes tumoral ferroptosis, whereas targeting upstream enzymes does not. HADHA inhibition causes accumulation of hydroxylated C18 (C18-OH) acylcarnitine to exacerbate mitochondrial lipid peroxidation. In vivo, HADHA ablation or acylcarnitine C18-OH supplementation suppresses tumor growth, enhances antitumor T-cell immunity, and potentiates PD-1 blockade therapy. Clinically, elevated plasma acylcarnitine C18-OH correlates with improved prognosis and immunotherapy response in lung cancer patients. Trimetazidine, an approved anti-ischemic drug and HADHA inhibitor, similarly delays tumor progression and augments immunotherapy. Together, our findings identify HADHA as a ferroptosis regulator and offer a clinically actionable strategy to enhance ferroptosis and immunotherapy through metabolic intervention.
    DOI:  https://doi.org/10.1038/s41467-026-74430-0
  11. Nat Cell Biol. 2026 Jun 15.
    Integrated stress response couples mitochondrial fitness with lineage reprogramming to drive cancer evolution.
    Shiqi Diao, Jia Yi Zou, Shuo Wang, Jason E Chan, Roderik M Kortlever, Nicolas Poulain, Nour Ghaddar, Hyungdong Kim, Gerard I Evan, Constantinos Koumenis, Maria Hatzoglou, Peter Walter, Nahum Sonenberg, John Le Quesne, Tuomas Tammela, Antonis E Koromilas.
      Tumour progression towards dedifferentiated cell clusters plays a critical role in intratumour heterogeneity and therapy resistance. While tumour microenvironmental stress has been implicated, the underlying mechanisms remain poorly defined. Using mouse models of lung adenocarcinoma, we demonstrate that activation of the integrated stress response (ISR)-marked by phosphorylation of eIF2 (p-eIF2) and ATF4 induction-drives tumour heterogeneity. ISR activation facilitates the emergence of high-plasticity, undifferentiated and pre-epithelial-to-mesenchymal transition clusters characterized by elevated ATF4 and MYC activity. This process is MYC dependent and involves ISR-mediated repression of NKX2-1, a key determinant of alveolar identity, and induction of CHCHD10, a regulator of mitochondrial integrity and metabolic fitness. Disruption of the p-eIF2-ATF4 axis induces mitochondrial dysfunction, limits dedifferentiation and suppresses tumour growth. In human lung adenocarcinoma, ISR-driven dedifferentiation correlates with advanced disease and poor prognosis, identifying the ISR as a central driver of lineage reprogramming and metabolic fitness in tumour progression.
    DOI:  https://doi.org/10.1038/s41556-026-01991-z
  12. Nat Cell Biol. 2026 Jun 19.
    Lysosome-derived methylated arginine is a signalling metabolite controlling the lipidome.
    Steven T Nguyen, Richard L Watson, Fangyuan Gao, Melissa Campos, Sunhee Jung, Laurence J Seabrook, Maxwell C Kim, Eric A Hanse, Ying Yang, Mei Kong, Jonathan E Zuckerman, Renata C Pereira, Isidro B Salusky, Sergio D Catz, Cholsoon Jang, Dorota Skowronska-Krawczyk, Lauren V Albrecht.
      Lysosomes are integral organelles that communicate cellular status to an entire tissue through mechanisms that are poorly defined. Here we developed an unbiased platform, integrating human plasma metabolomes and single-lysosome metabolomics, and show the byproducts of proteolysis are an unexpected class of signalling molecules. We show that dimethylarginine is a lysosomal-derived metabolite and a predictor of patient morbidity. Genetic depletion of a lysosomal exporter, cystinosin, accumulated dimethylarginine in lysosomes. Leveraging a lysosomal storage disease with cystinosin mutations, we show that the rapid plasticity of dimethylarginine compartmentalization ensures cell and tissue homeostasis. Strikingly, lysosomal entrapment of dimethylarginine in patients and disease models corresponds with lipid accumulation, lipid droplets and lipotoxicity. Exogenously restoring asymmetric dimethylarginine buffers oxidative stress, decreasing lipid peroxidation and cell death. These data show that dimethylarginine engages an interorganellar process-with peroxisomes, lysosomes and lipid droplets-that confers a crucial adaptive response mechanism.
    DOI:  https://doi.org/10.1038/s41556-026-01970-4
  13. Cell Rep. 2026 Jun 19. pii: S2211-1247(26)00627-3. [Epub ahead of print]45(7): 117549
    Trans-presentation of IL-6Rα by macrophages drives colorectal cancer development.
    Fanwu Gong, Qiming Zhang, Jiaojiao Qian, Yuanyuan He, Kaiming Du, Haopeng Fang, Qiangsheng Li, Yang Yang, Hua-Xing Wei, Tengchuan Jin, Yi Wang, Bofeng Li.
      IL-10-signaling-deficiency-induced macrophage hyperactivation drives epithelial barrier disruption and severe colitis, but its role in colitis-associated colorectal cancer (CAC) remains unclear. Here, we report that macrophage-specific IL-10Rα deletion aggravates AOM-DSS-induced CAC in mice. These IL-10Rα-deficient macrophages exhibited a pro-inflammatory phenotype and secreted excessive IL-6 to stimulate intestinal epithelial cell (IEC) proliferation and tumorigenesis via the IL-6/p-STAT3 pathway. Genetic ablation or neutralization of macrophage-specific IL-6Rα reduced IEC p-STAT3 levels and tumor burden, whereas epithelial IL-6Rα deficiency or sgp130 treatment did not. IEC-BMDM co-culture and imaging flow cytometry identify a previously unrecognized macrophage-derived IL-6 trans-presentation as the dominant driver of IEC proliferation and tumorigenesis, rather than classical/trans-signaling. Targeting macrophage IL-6Rα in combination with PD-L1 blockage exerts complementary effects in CAC. Collectively, our data reveal that macrophage-specific IL-10 signaling protects against CAC by suppressing macrophage-dependent IL-6 trans-presentation, which drives excessive IEC proliferation and tumor development.
    Keywords:  CP: cancer; CP: immunology; IL-10 signaling; IL-6 trans-presentation; IL-6Rα; STAT3 signaling; cancer immunotherapy; colitis-associated colorectal cancer; colorectal cancer; intestinal epithelial cells; macrophages; tumorigenesis
    DOI:  https://doi.org/10.1016/j.celrep.2026.117549
  14. Front Oncol. 2026 ;16 1773635
    Study of ß-catenin signaling pathway modulated by PTHrP in cell and animal colorectal cancer models.
    Cintia Birkenstok, Pedro Carriere, María Belén Novoa Díaz, María Julia Martín, Claudia Gentili.
      Colorectal cancer (CRC) is a complex disease and a major cause of cancer-related deaths worldwide. One of the main obstacles in treating advanced CRC is chemotherapy resistance. In previous studies, we demonstrated that parathyroid hormone-related peptide (PTHrP) acts as a pro-tumor cytokine in CRC-derived cells, capable of modulating several mitogenic pathways and inducing β-catenin nuclear localization. Furthermore, we observed that PTHrP favors the communication between tumor cells and their microenvironment, promoting a more aggressive tumor phenotype. Using different CRC models, the first goal of this work was to further explore, how PTHrP is able to modulate the complex β-catenin signaling pathway, whereas the second aim was to examine whether this modulation by PTHrP is associated with resistance to chemotherapy agents commonly used in CRC treatment, particularly platinum-based compounds. The findings obtained in vitro by subcellular fractionation, Western blot analysis and immunocytochemistry technique, suggest that PTHrP induces the phosphorylation of β-catenin at Ser552 and its nuclear accumulation. Through viability assays, we found that PTHrP, either directly or indirectly through tumor microenvironment-derived endothelial cells, is associated with reduced oxaliplatin sensitivity in HCT116 cells from CRC. Pharmacological inhibition studies further support the involvement of β-catenin signaling in this effect. In vivo, the impact of PTHrP on the oxaliplatin response was model-dependent. In HCT116 xenografts generated in N:NIH(S)_nu mice, in contrast to our in vitro findings, oxaliplatin-treated animals showed no significant differences between mice with and without PTHrP within the experimental timeframe. However, we observed that PTHrP reduces oxaliplatin sensitivity in murine CT-26 intestinal tumor cells. In a CT-26 syngeneic murine model, PTHrP was associated with reduced oxaliplatin efficacy and increased β-catenin immunoreactivity. Overall, our findings provide consistent in vitro evidence supporting an association between PTHrP, β-catenin signaling, and decreased oxaliplatin sensitivity in CRC cells. However, in vivo results suggest a more complex and context-dependent role, highlighting the need for further studies to clarify the mechanistic contribution of β-catenin and the extent to which PTHrP drives chemoresistance in diverse settings.
    Keywords:  PTHrP; chemoresistance; colorectal cancer; microenvironment; β-catenin
    DOI:  https://doi.org/10.3389/fonc.2026.1773635
  15. Cell Death Dis. 2026 Jun 17.
    Impact of BECLIN1 haploinsufficiency on goblet cell function and susceptibility to colitis.
    Juliani Juliani, Sharon Tran, Tiffany J Harris, Sarah L Ellis, Aysha H Al-Ani, Yashodha Wijebandara, Komal M Patel, Samuel N Young, Marco Evangelista, David Baloyan, Camilla M Reehorst, Rebecca Nightingale, Laura J Jenkins, Peter De Cruz, Kinga Duszyc, Benjamin T Kile, Alpha S Yap, John M Mariadason, Britt Christensen, André L Samson, James M Murphy, Walter D Fairlie, Erinna F Lee.
      BECLIN1 is a central regulator of autophagy and endocytic trafficking essential for epithelial homoeostasis. While complete intestinal epithelial loss of BECLIN1 causes fatal enteritis originating in the small intestine, the consequences of its partial loss in the gut remain unclear. Given that BECLIN1 expression can vary in human disease, we investigated whether reduced BECLIN1 is sufficient to impair gut barrier function. Heterozygous Becn1 deletion (Becn1IEC+/-) in the mouse intestinal epithelium caused subtle but significant defects. These included shortened small intestines and altered epithelial architecture, despite preservation of basal autophagy, implicating trafficking-related functions. Supporting this conclusion, Becn1IEC+/- small intestinal epithelial cells showed modest increases in RAB5+ve vesicles, redistribution of E-CADHERIN and F-actin along lateral membranes and altered apico-basal cell morphology. Given the absence of overt small intestinal epithelial disruption or inflammation, as seen with complete loss of BECLIN1, we next addressed whether BECLIN1 insufficiency manifests a phenotype under stress or in other gut regions. Indeed, in the colon, Becn1IEC+/- mice exhibited reduced colonic crypt length, baseline goblet cell loss and reduced mucin production, particularly in mature goblet cells, indicating vulnerability of the mucus barrier. When challenged with dextran sulfate sodium (DSS), Becn1IEC+/- mice exhibited greater weight loss, higher disease activity, more severe histological colitis, and disproportionate loss of neutral mucins, with inflammation confined to the mucosa. Together, these findings show that BECLIN1 insufficiency does not trigger spontaneous inflammation but destabilises epithelial organisation and barrier defence, thereby sensitising the gut to inflammatory challenge and further positioning BECLIN1 as a threshold-dependent determinant of intestinal resilience.
    DOI:  https://doi.org/10.1038/s41419-026-08984-8
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