bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–07–19
twenty papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Colorectal cancer co-opts an epidermal wound healing program during metastasis to generate disseminated tumor cells.
  2. Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
  3. A high-fat, low-carbohydrate diet can feed intestinal tumours.
  4. Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
  5. Targeting POLRMT-driven epigenetic remodeling of Wnt/β-catenin to eradicate colorectal cancer stem cell proliferation.
  6. Furin sustains tumor-promoting signals in KRAS- and BRAF-mutated colorectal cancer by engaging the TGF-β1-COX-2 axis in a reciprocal regulatory network.
  7. In vitro culture of intestinal organoids for cell death assessments.
  8. Epithelial regeneration in the gastrointestinal tract.
  9. Single cell multiomics unravel the transcription networks controlling the different EMT tumor states.
  10. Single-cell transcriptome profiles of Foxl1-lineage cells along the intestinal crypt-villus axis.
  11. Single-Cell and Spatial Analysis Reveal the Differences Between Left-Sided and Right-Sided Colorectal Cancer.
  12. Steatosis fuels replacement liver metastases in colorectal cancer.
  13. Glycocholic acid inhibits TRIB3-ID1 axis to acelerate colitis progression via suppressing intestinal stem cell renewal.
  14. Oncogene inactivation-induced senescence facilitates tumor relapse.
  15. YAP1‑mediated cytoplasmic‑nuclear translocation of SREBP2 promotes colorectal cancer via regulation of cholesterol metabolism.
  16. Protocol for establishing rectal tumor organoid-derived monolayers in a microphysiological system to model radiotherapy.
  17. From Gut to Fat: Intestinal Epithelial Exosomes Target PDGFRα+ Progenitors to Promote Lipogenesis and Counteract Subcutaneous Adipose Tissue Atrophy in Aging.
  18. Hormonal contraception and colorectal cancer.
  19. Fueling Death: The Metabolic Control of Ferroptosis.
  20. Evolution of SPP1+ cavity macrophage-mediated immunotherapy resistance in peritoneal metastasis of colorectal cancer.
  1. Nat Commun. 2026 Jul 11.
    Colorectal cancer co-opts an epidermal wound healing program during metastasis to generate disseminated tumor cells.
    Mizuho Sakahara, Takuya Okamoto, Kohei Kumegawa, Yasuko Natsume, Daisuke Kusama, Hitomi Yamanaka, Rie Komatsuzaki, Katsuyuki Yaginuma, Upasna Srivastava, Atsushi Takahashi-Kanemitsu, Etsuo A Susaki, Kazutaka Obama, Satoshi Nagayama, Reo Maruyama, Ryoji Yao.
      Metastasis is the principal cause of death from colorectal cancer (CRC), yet the cellular states that enable tumor dissemination remain poorly defined. Disseminated tumor cells (DTCs) are rare, transient, and clinically inaccessible, limiting mechanistic insight into their biology. Here we show that CRC cells transiently adopt a wound-healing program normally used by epidermal keratinocytes during tissue repair to enable metastatic dissemination. Using serial orthotopic transplantation of patient-derived organoids to model metastasis, we find that DTCs lose cancer stem cell features and instead express wound-inducible keratins, including KRT17, before metastatic outgrowth. This state is reversible, as cells reacquire primary tumor-like characteristics upon colonization of distant organs. Mechanistically, this transition is associated with reduced EZH2 activity and activation of YAP signaling. Clinically, KRT17⁺ cells localize to the invasive front of primary CRCs and are absent from adjacent normal tissue. These findings uncover unexpected lineage plasticity across distinct developmental origins and identify a transient, targetable state critical for metastatic progression.
    DOI:  https://doi.org/10.1038/s41467-026-75296-y
  2. Nature. 2026 Jul 15.
    Ketogenic diet mediates intestinal tumorigenesis through lipids not ketones.
    Jessica E S Shay, Fangtao Chi, Constantine N Tzouanas, Shixun Han, Xiao Zhang, Johanna Ten Hoeve, Kevin J Williams, Seda Neptun, Tolga Sever, Isabela Fuentes, Sangeeta N Bhatia, Gizem Calibasi-Kocal, Matthew G Vander Heiden, Alex K Shalek, Ömer H Yilmaz.
      Diet composition shapes tissue function and disease risk by modulating nutrient availability, metabolic state and cellular dynamics1. In the gastrointestinal tract, obesogenic high-fat diets enhance small-intestinal stem cell activity and tumorigenesis2. However, the impact of ketogenic diets (KDs), which contain even higher lipid content but reduce circulating insulin and induce ketogenesis, remains poorly understood3. This is particularly relevant for patients with familial adenomatous polyposis who face a high risk of small-intestinal tumours4. Here we combine dietary, genetic and metabolic manipulations in mouse models of spontaneous intestinal adenoma formation to dissect the role of systemic and epithelial ketogenesis in intestinal cancer. We show that KD accelerates tumour burden and shortens survival, independent of ketone metabolites. Through genetic manipulation of the ketogenic pathway, we modulate the production of local and systemic ketone metabolites; however, neither inhibition nor augmentation of the ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2 nor disruption of ketolysis altered tumorigenesis. Combined intestinal loss of PPARα/δ/γ attenuates KD-driven intestinal stem cell expansion, proliferation and clonogenicity, whereas inhibition of downstream fatty acid oxidation through CPT1A loss limits adenoma formation specifically under KD, linking tumour initiation to fatty acid oxidation of dietary lipids rather than lipid accumulation. These findings reveal that dietary lipid content, through fatty acid oxidation rather than ketone metabolism, influences intestinal tumorigenesis and highlight the need for nuanced consideration of dietary strategies for cancer prevention in genetically susceptible populations.
    DOI:  https://doi.org/10.1038/s41586-026-10779-y
  3. Nature. 2026 Jul 15.
    A high-fat, low-carbohydrate diet can feed intestinal tumours.
    Souvik Patra, Evan C Lien.
      
    Keywords:  Cancer; Cell biology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-026-02039-w
  4. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00158-5. [Epub ahead of print]209 91-103
    Ferroptosis induction via genetic approaches - CRISPR/Cas9-based disruption on key anti-ferroptotic genes.
    Jiashuo Zheng, Weijia Zhang, Marcus Conrad.
      Unlike apoptosis, necroptosis, or pyroptosis which are executed by dedicated proteins, ferroptosis is a distinct form of regulated cell death driven by lipid peroxidation downstream of metabolic dysfunction. In most physiological settings, the cyst(e)ine/glutathione/glutathione peroxidase 4 (GPX4) axis constitutes the central anti-ferroptotic machinery, and disruption of this axis is usually sufficient to trigger ferroptosis. For in vitro studies, commonly employed ferroptosis inducers include erastin, which blocks cystine uptake by targeting system xc-, and (1S,3R)-RSL3, which inhibits GPX4 activity. However, both compounds exhibit off-target effects - erastin can activate voltage-dependent anion channels in mitochondria, whereas (1S,3R)-RSL3 affects other selenoproteins in addition to GPX4. Thus, genetic approaches to induce ferroptosis provide a valuable complement to chemical inducers by excluding off-target concerns. Here, we describe an efficient CRISPR/Cas9-based strategy to generate SLC7A11- and GPX4-knockout HT1080 cells. These knockout lines require routine culture in medium supplemented with β-mercaptoethanol or liproxstatin-1, while withdrawal of these supplements readily induces ferroptosis.
    Keywords:  CRISPR/Cas9; Ferroptosis; GPX4; HT1080 cells; Knockout; SLC7A11
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.002
  5. Cell Death Differ. 2026 Jul 15.
    Targeting POLRMT-driven epigenetic remodeling of Wnt/β-catenin to eradicate colorectal cancer stem cell proliferation.
    Lei Tang, Siheng Nie, Jialong Qi, Rui Yu, Jinglan Zhang, Ran Zhu, Qi Li, Xiaoshuang Zhou, Shaoxing Dai, Li Wang, Maorong Chen, Fan Yang, Jihong Zhang.
      Colorectal cancer stem cells (CSCs) drive tumor progression through poorly understood metabolic-epigenetic crosstalk. Here, we identify mitochondrial RNA polymerase POLRMT as a key link connecting mitochondrial transcription to CSC maintenance. Clinically, POLRMT is overexpressed in colorectal cancer (CRC) tissues and correlates with poor prognosis. Genetic ablation or pharmacological inhibition of POLRMT suppresses CSC self-renewal and tumorigenicity across cell line-derived CSCs, CRC organoids, and xenograft models. Mechanistically, POLRMT deficiency triggers mitochondrial dysfunction, which unexpectedly elevates the demethylase KDM6B expression, α-ketoglutarate (α-KG) levels, and Dickkopf-1 (DKK1) expression, thereby transcriptionally silencing Wnt/β-catenin signaling and collapsing the CSC niche. Restoration of β-catenin rescues tumorigenicity in POLRMT-knockout (KO) cells, confirming the hierarchy of this signaling cascade. Crucially, POLRMT catalytic activity and mitochondrial localization are indispensable for sustaining this axis. Our work unveils POLRMT as a metabolic gatekeeper that licenses CSC plasticity through KDM6B-α-KG/H3K27me3-mediated chromatin remodeling, proposing the mitochondrial transcription machinery as a therapeutic target for dismantling the CSC hierarchy in CRC.
    DOI:  https://doi.org/10.1038/s41418-026-01807-5
  6. Oncogene. 2026 Jul 12.
    Furin sustains tumor-promoting signals in KRAS- and BRAF-mutated colorectal cancer by engaging the TGF-β1-COX-2 axis in a reciprocal regulatory network.
    Yiyang Liu, Géraldine Siegfried, Simon Pernot, Zongsheng He, Marta Martin Bornez, Sabine Tejpar, Fanny Castanet, Gregoire Desolneux, Serge Evrard, Torsten Steinmetzer, John W M Creemers, Abdel-Majid Khatib.
      KRAS and BRAF mutations drive colorectal cancer (CRC) progression by sustaining aberrant signaling and promoting therapeutic resistance. Here, we identify TGF-β1-COX-2 axis as a critical regulatory pathway mediated by Furin in CRC harboring KRAS or BRAF mutation. Genetic silencing or pharmacological inhibition of Furin in KRAS-mutant (KPN) and BRAF-mutant (BPN) tumor-derived cells suppressed tumor growth, reduced angiogenesis, and enhanced CD8⁺ T cell infiltration in mouse tumor models. KRAS- and BRAF-mutant organoids with impaired Furin activity exhibited increased sensitivity to 5-FU and irinotecan, whereas only KPN organoids were sensitive to oxaliplatin. Mechanistically, Furin inhibition via shRNA or the Furin inhibitor MI1148 blocked IGF-1 receptor and TGF-β1 precursor maturation and signaling, which was associated with repressed COX-2 expression. Conversely, COX-2 overexpression elevated TGF-β1 levels, which in turn enhanced Furin expression, establishing a feed-forward loop that promoted tumor progression and angiogenesis. Moreover, Furin inhibition largely disrupted the activity of multiple kinases linked to KRAS and BRAF oncogenic signaling. In CRC patient samples, Furin expression positively correlated with KRAS, BRAF, TGF-β1, and COX-2. Collectively, these findings identify Furin as a pivotal regulator of oncogenic signaling in KRAS- and BRAF-mutant CRC, and highlight the therapeutic potential of targeting the Furin-TGF-β1-COX-2 axis.
    DOI:  https://doi.org/10.1038/s41388-026-03875-w
  7. Methods Cell Biol. 2026 ;pii: S0091-679X(26)00157-3. [Epub ahead of print]209 55-65
    In vitro culture of intestinal organoids for cell death assessments.
    Luying Zheng, Daichao Xu.
      In vitro cultured organoids exhibit highly similar structures to their corresponding tissues and organs. Intestinal organoids derived from intestinal stem cells faithfully recapitulate the key characteristics of native intestinal epithelium, including morphological features, physiological functions, and personalized responses to specific stimuli. This protocol focuses on the isolation of intestinal crypts from murine intestinal tissues and the subsequent establishment of stable intestinal organoid cultures in vitro. Furthermore, propidium iodide (PI) staining coupled with high-content imaging analysis was employed to characterize organoid cell death. This optimized protocol provides a robust platform for high-throughput screening of intestinal disease-related cell death factors, thereby facilitating mechanistic investigations into intestinal pathogenesis.
    Keywords:  Immunostaining; Intestinal organoid; Organoid cell death; Propidium iodide staining
    DOI:  https://doi.org/10.1016/bs.mcb.2026.05.001
  8. Curr Opin Genet Dev. 2026 Jul 15. pii: S0959-437X(26)00082-1. [Epub ahead of print]100 102515
    Epithelial regeneration in the gastrointestinal tract.
    Eunah Kim, Bon-Kyoung Koo.
      The gastrointestinal tract possesses a remarkable regenerative capacity to maintain tissue homeostasis against various injuries. However, the intestine and stomach exhibit distinct regenerative strategies. In the intestine, damage to Lgr5-positive (Lgr5+) stem cells induces cellular plasticity and the emergence of transient Revival stem cells (RevSCs), a process critically dependent on YAP/TAZ signaling. Conversely, the stomach utilizes paligenosis, where quiescent p57-positive (p57+) mature chief cells act as reserve stem cells, dedifferentiating to restore damaged tissue. Although the cellular origins differ, both organs appear to share some common regenerative features, including transient activation of pro-proliferative programs such as YAP/TAZ signaling. In contrast, whether Retinoic Acid (RA) signaling also serves as a conserved mechanism for regenerative resolution in the stomach remains to be determined. In this review, we discuss the cellular and molecular mechanisms governing regeneration in these two organs. This comparative analysis provides a framework for future research.
    DOI:  https://doi.org/10.1016/j.gde.2026.102515
  9. Nat Commun. 2026 Jul 11.
    Single cell multiomics unravel the transcription networks controlling the different EMT tumor states.
    Andrea Pérez-González, Gabriel Windels, Kevin Bévant, Justine Lengrand, Sophie Lemaire, Virginie Moers, Samuel Scozzaro, Ulysse Debroux, Christine Dubois, Sebastiaan Vanuytven, Cédric Blanpain.
      Epithelial-to-mesenchymal transition (EMT) is a dynamic process during which cells lose their epithelial characteristics and acquire mesenchymal traits. In cancer, EMT is closely associated with tumor initiation, progression, invasion, metastasis, and therapy resistance. Rather than being a binary state switch, EMT encompasses a spectrum of tumor states with distinct functional properties. However, the transcription factors (TFs) that govern transitions between these EMT states remain poorly defined. Here, using multi-omic approaches combining single-cell RNA-seq and single-cell ATAC-seq, we delineate the transcriptomic and chromatin landscapes of distinct EMT states in a mouse model of skin squamous cell carcinoma (SCC). Through CRISPR/Cas9-mediated loss-of-function studies coupled with in vitro and in vivo functional assays, we identify TFs regulating specific EMT states. Klf5 and Pitx1 control the early stages of EMT and are essential for metastasis formation. In contrast, Nfatc1 and Creb3l1 act at later stages of EMT. Similar EMT states and regulatory patterns are found in mouse pancreatic adenocarcinoma and human cancers. Altogether, our study defines the transcriptional and chromatin landscape controlling EMT progression in mouse skin SCC, identifies EMT state-specific TFs and highlights their essential roles in regulating metastasis.
    DOI:  https://doi.org/10.1038/s41467-026-75521-8
  10. Cell Mol Gastroenterol Hepatol. 2026 Jul 16. pii: S2352-345X(26)00127-X. [Epub ahead of print] 101849
    Single-cell transcriptome profiles of Foxl1-lineage cells along the intestinal crypt-villus axis.
    Amal Gharbi, Noa Corem, Sharona Elgavish, Inbar Plachkes, Abrar Jamous, Marco Canella, Moriya Shmuel, Hadar Horowitz, Jianmei Tan, Hongqian Chen, Bing Su, Mahmud Abu-Gazala, Noam Shussman, Michal Shoshkes-Carmel.
       BACKGROUND & AIMS: Intestinal epithelial cells rely on a complex array of stromal signals to determine their fate and function along the crypt-villus axis, but the precise cellular sources and combinations of signals at each position remain poorly defined.
    METHODS: We generated an atlas of Foxl1-lineage cells along the crypt-villus axis using single-cell RNA sequencing integrated with in-situ hybridization, immunofluorescence, and reporter mouse models.
    RESULTS: We identify four spatially distinct Foxl1-lineage subepithelial populations: crypt, villus-base, villus-mid and villus-tip, that segregate into two related pairs. Crypt and villus-mid Foxl1-lineage cells share a low-PDGFRα transcriptional program enriched for canonical Wnts and R-spondins, consistent with regenerative signaling functions. In contrast, villus-base and villus-tip Foxl1-lineage cells are PDGFRα-high and express non-canonical Wnt5a and BMP ligands. Crypt Foxl1-lineage cells are additionally enriched for extracellular matrix proteins and complement components, whereas villus-base Foxl1-lineage cells express contractility-associated genes, suggesting a role in villus architecture. Villus-mid Foxl1-lineage cells display signatures of immune regulation and inflammation, while villus-tip Foxl1-lineage cells are specialized for regulation of ribonucleoprotein complexes and nutrient sensing. This atlas provides a foundational resource for understanding how diverse Foxl1-lineage stromal populations coordinate signaling niches and influence intestinal epithelial homeostasis.
    CONCLUSIONS: This atlas provides a foundational resource for understanding how diverse stromal populations coordinate signaling niches and influence intestinal epithelial homeostasis.
    Keywords:  Foxl1; functional zonation; mesenchyme; signaling gradients; stem cells; stem-cell niche
    DOI:  https://doi.org/10.1016/j.jcmgh.2026.101849
  11. Cell Prolif. 2026 Jul 14. e70260
    Single-Cell and Spatial Analysis Reveal the Differences Between Left-Sided and Right-Sided Colorectal Cancer.
    Zongnai Zhang, Jiaqi Xu, Yingchao Wu, Tao Liu, Junling Zhang, Mai Zhou, Jie Qiao, Heng Pan, Xin Wang.
      Colorectal cancer (CRC) exhibits heterogeneity based on tumour laterality, with right-sided tumours demonstrating distinct genetic, immunogenic and clinical behaviours compared to left-sided counterparts. In this study, we conducted single-cell RNA sequencing and spatial transcriptomics to dissect the distinct molecular landscapes of left- and right-sided CRC. We identified enhanced germinal centre B cell infiltration and CXCL13+ T cell enrichment, features linked to adaptive immune priming and better immunotherapy responsiveness. Right-sided CRC epithelial cells exhibited proliferative and immunogenic phenotypes, marked by upregulated immune-related pathways and chemokine-driven interactions with lymphocytes. Spatial analysis revealed organized tertiary lymphoid structure-immune microenvironment crosstalk in right-sided tumours, mediated by CCL19/21-CCR7 signalling. In contrast, left-sided CRC tumours displayed stromal-epithelial interactions favouring angiogenesis and metabolic reprogramming. Our findings established a laterality-specific immune microenvironment in CRC, providing insights for precise therapeutic strategies of left- and right-sided CRC.
    Keywords:  colorectal cancer; tertiary lymphoid structure; tumour laterality; tumour microenvironment
    DOI:  https://doi.org/10.1111/cpr.70260
  12. Nat Rev Gastroenterol Hepatol. 2026 Jul 16.
    Steatosis fuels replacement liver metastases in colorectal cancer.
    Eleni Kotsiliti.
      
    DOI:  https://doi.org/10.1038/s41575-026-01236-2
  13. Nat Commun. 2026 Jul 11.
    Glycocholic acid inhibits TRIB3-ID1 axis to acelerate colitis progression via suppressing intestinal stem cell renewal.
    Shuang Shang, Jing Liu, Shu-Yuan Dai, Xiao-Xi Lv, Yu-Xin Liu, Rui Lu, Yi-Xuan Wei, Rong-Kai Xie, Qing-Yu Shi, Cang-Jie Shen, Fang Hua.
      Intestinal stem cell number or their regeneration ability is crucial for attaining mucosal healing. Deciphering the molecular mechanisms responsible for the impairment of intestinal stem cells in inflammatory bowel disease could yield innovative therapeutic insights. Altered bile acid metabolism is a hallmark feature of inflammatory bowel disease, typically characterized by elevated fecal levels of primary bile acids, such as glycocholic acid. However, the relationship between glycocholic acid and inflammatory bowel disease remains unclear. Here, we report that glycocholic acid accelerates inflammatory bowel disease progression through downregulating TRIB3 expression to disrupt intestinal stem cells self-renewal. TRIB3 is highly expressed in crypt cells and sustains intestinal epithelial stemness by preventing ID1 palmitoylation and AP3D1-mediated lysosomal degradation. Glycocholic acid is found to suppress TRIB3-ID1 axis, thereby compromising intestinal epithelium integrity. Notably, we identify Bergenin, a natural compound, as a potential therapeutic agent against inflammatory bowel disease via upregulating TRIB3. These findings highlight the TRIB3-ID1 axis as a promising therapeutic target for inflammatory bowel disease therapy.
    DOI:  https://doi.org/10.1038/s41467-026-74713-6
  14. Nat Commun. 2026 Jul 15. pii: 6244. [Epub ahead of print]17(1):
    Oncogene inactivation-induced senescence facilitates tumor relapse.
    Philipp Schmitt, Katrin Hönig, Maria Teresa Norcia, Marta F Nogueira, Viktoria Flore, Inés Simó Vesperinas, Maria Villoro-Agud, Lushan Peng, Zuhal Safyürek, Mehreen Tariq, Ana Milojkovic, Kathleen Anders, Evelin Schröck, Sascha Sauer, Bora Uyar, Altuna Akalin, Gerald Willimsky, Simon Haas, Inmaculada Martínez-Reyes, Thomas Blankenstein.
      Oncogene-directed therapies can induce profound tumor regression in oncogene-addicted cancers, but their long-term benefit is often limited by resistance and relapse. Here we show that oncogene inactivation rapidly induces senescence and a pro-inflammatory senescence-associated secretory phenotype (SASP). In vivo, oncogene inactivation-induced senescence (OIIS) predisposes tumors to relapse, accompanied by polyploidy, chromosomal instability, acquisition of alternative oncogenic pathways including mouse double minute 2 homolog (Mdm2) upregulation, and tumor microenvironmental remodeling toward neovascularization and immunosuppression. Spectral flow cytometry reveals a shift from an immune-activated to an immunosuppressive milieu during relapse. OIIS features are also observed in human BRAFV600E melanoma cells treated with vemurafenib, supporting clinical relevance. Together, our findings establish OIIS as a double-edged process: it initially restrains tumor growth but simultaneously creates conditions that favor recurrence. By defining the genetic, metabolic and microenvironmental hallmarks of OIIS, our study highlights adaptations to oncogene deprivation that limit the durability of targeted therapies.
    DOI:  https://doi.org/10.1038/s41467-026-75021-9
  15. Int J Oncol. 2026 Sep;pii: 105. [Epub ahead of print]69(3):
    YAP1‑mediated cytoplasmic‑nuclear translocation of SREBP2 promotes colorectal cancer via regulation of cholesterol metabolism.
    Luhui Zhong, Min Sun, Di Wu, Yulan Zeng, Min Zhou, Rui Gong, Feifei Gu, Kai Zhang, Xiaoyan Hu, Yue Hu.
      Colorectal cancer (CRC) cells reprogram multiple metabolic pathways, including anaerobic glycolysis, lipogenesis and amino acid metabolism, to support their rapid cell division. However, the key regulators driving these metabolic alterations in CRC remain unknown. In the present study, immunohistochemistry staining of a tissue microarray demonstrated that yes‑associated protein 1 (YAP1) was markedly upregulated in CRC tissues and strongly associated with worse patient survival. Knocking down YAP1 inhibited the proliferation and cholesterol accumulation of CRC cells both in vitro cell growth assays and in vivo xenograft model. Mechanistically, western blotting, co‑immunoprecipitation and immunofluorescence assays showed that YAP1 not only transcriptionally upregulated sterol regulatory element binding protein 2 (SREBP2) expression but also physically interacted with it to facilitate its nuclear translocation. This coordinated regulation drove the expression of genes governing de novo cholesterol synthesis and exogenous cholesterol influx. Functional experiments revealed that the SREBP2‑dependent cholesterol metabolic pathway was essential for YAP1‑driven tumorigenesis and proliferation in CRC. These findings uncovered a YAP1‑SREBP2 axis involved in CRC metabolic reprogramming and suggested that targeting this interaction may represent a promising metabolic intervention strategy for CRC management.
    Keywords:  cholesterol metabolism; colorectal cancer; cytoplasmic‑nuclear translocation; sterol regulatory element binding protein 2; yes‑­associated protein 1
    DOI:  https://doi.org/10.3892/ijo.2026.5918
  16. STAR Protoc. 2026 Jul 15. pii: S2666-1667(26)00361-8. [Epub ahead of print]7(3): 104708
    Protocol for establishing rectal tumor organoid-derived monolayers in a microphysiological system to model radiotherapy.
    Eloïse Bouges, Charlotte Segers, Marco Lezzerini, Natalie Leys, Sarah Lebeer, Jianbo Zhang, Felice Mastroleo.
      Patient-derived organoids offer greater human translational relevance than mouse models or immortalized cell lines, owing to their multicellular composition and patient-specific responses. Here, we present a protocol for establishing a human in vitro rectal tumor model for radiotherapy studies using patient-derived tumor organoids (PDTOs) and monolayer derivatives integrated into a microphysiological system (MPS). We describe steps for cultivating PDTOs, their transition into monolayers, and transfer into an MPS. This protocol enables radiotherapy modelling, toxicity testing, and adjuvant therapies screening.
    Keywords:  Biotechnology and bioengineering; Cancer; Molecular Biology; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2026.104708
  17. Aging Cell. 2026 Jul;25(7): e70625
    From Gut to Fat: Intestinal Epithelial Exosomes Target PDGFRα+ Progenitors to Promote Lipogenesis and Counteract Subcutaneous Adipose Tissue Atrophy in Aging.
    Tingting Huang, Ye Huang, Yin Zhou, Xuanbei Lu, Lijun Yang, Jing Yu, Yunlu Sheng, Fan Xia, Guoxian Ding, Yifan Lv, Shan Lv.
      Age-related subcutaneous adipose tissue (SAT) atrophy is a hallmark of aging, contributing to metabolic dysfunction and systemic aging. The mechanisms underlying SAT atrophy and potential therapeutic strategies remain poorly understood. Here, we report that small intestinal epithelium-derived exosomes (SI-Exos) mediate gut-adipose communication and play a pivotal role in age-related SAT remodeling. We found that the miRNA cargo of SI-Exos undergoes significant age-related changes. Administration of young SI-Exos to aged mice enhanced lipid droplet formation, reversed SAT atrophy, and reduced inflammation in visceral adipose tissue (VAT). These beneficial effects were mediated by young SI-Exos targeting PDGFRα+ progenitor cells, the major adipocyte precursors in SAT. Mechanistically, young SI-Exos were enriched with miR-379-5p, which targeted Usp34, a negative regulator of lipogenesis. Inhibition of Usp34 downregulated the Wnt/β-catenin pathway, promoting lipid droplet formation and differentiation of PDGFRα+ progenitor cells. Single-cell RNA sequencing analysis further confirmed that young SI-Exos enhanced lipid transport and synthesis in SAT cell populations. Additionally, NK cells were increased. Our findings reveal a previously unrecognized role of SI-Exos in regulating SAT progenitor cell dynamics through the miR-379-5p/Usp34/Wnt/β-catenin axis, offering a potential therapeutic strategy for combating age-associated SAT atrophy and promoting healthy aging.
    Keywords:  aging; exosome; lipid droplet; small intestinal epithelium; white adipose tissue
    DOI:  https://doi.org/10.1111/acel.70625
  18. BMJ. 2026 Jul 15. 394 e100222
    Hormonal contraception and colorectal cancer.
    Pelin Batur.
      
    DOI:  https://doi.org/10.1136/bmj-2026-100222
  19. Adv Exp Med Biol. 2026 ;1501 453-478
    Fueling Death: The Metabolic Control of Ferroptosis.
    Giovanna Carrà, Alfonso Scalera, Isaia Barbieri, Alessio Menga, Paolo E Porporato.
      Ferroptosis is a metabolically regulated, iron-dependent form of cell death driven by lipid peroxidation. This chapter dissects the core metabolic circuits that converge to determine ferroptotic susceptibility and explores the interplay between ferroptosis and other cell death programs, highlighting its physiological roles in development, immunity, and aging, and examines its dual function in disease. Emerging pharmacological strategies to modulate ferroptosis in cancer and degenerative conditions are discussed. By integrating metabolic checkpoints with redox biology, ferroptosis emerges as a therapeutic target with vast translational potential.
    Keywords:  Cancer metabolism; Ferroptosis; Glutathione peroxidase 4 (GPX4); Iron; Metabolic remodeling
    DOI:  https://doi.org/10.1007/978-3-032-12166-0_16
  20. Cell Rep Med. 2026 Jul 16. pii: S2666-3791(26)00347-2. [Epub ahead of print] 102930
    Evolution of SPP1+ cavity macrophage-mediated immunotherapy resistance in peritoneal metastasis of colorectal cancer.
    Xiaomeng Dai, Chunyu Lai, Libing Hong, Yuzhi Jin, Jinlin Cheng, Haimeng Yan, Xuqi Sun, Bin Li, Chuan Liu, Hangyu Zhang, Yanwei Lu, Haibo Zhang, Danyang Wang, Peng Zhao, Yu Shi, Weijia Fang, Shan Xin, Xia Yu, Xuanwen Bao.
      The immunometabolic basis of therapy-resistant colorectal cancer (CRC) peritoneal carcinomatosis with malignant ascites remains poorly defined. Here, we profile ascites immune cells from 20 patients across treatment-naive, chemo/targeted therapy-refractory, and immune checkpoint blockade (ICB)/adoptive T cell therapy (ACT)-resistant CRC. Single-cell RNA sequencing identifies SPP1+ cavity macrophages as drivers of CD8+ T cell dysfunction. Proteomic profiling of 36 patients confirms SPP1 enrichment in ICB/ACT-resistant peritoneal metastases. Mechanistically, SPP1 sustains an M2-like program via PPARγ activation and lipid uptake. SPP1 deficiency reduces PPARγ ligand precursors, triggering NF-κB-driven macrophage reprogramming and reversing CD8+ T cell suppression. Supplementation with 15 d-PGJ2 and fatty acids restores the M2 phenotype. In vivo, macrophage-specific SPP1 knockout enhances cytotoxic T lymphocyte infiltration and ICB efficacy, while SPP1 neutralization overcomes ICB resistance and augments ACT efficacy. Thus, SPP1+ cavity macrophages are central immunometabolic regulators, and SPP1 inhibition represents a promising strategy to overcome immunotherapy resistance in this lethal disease.
    Keywords:  CRC; PPARγ; Spp1(+) macrophage; immunometabolism; peritoneal metastasis
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102930
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