bims-instec 2026-03-01 papers

bims-instec

Biomed News

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

Issue of 2026–03–01
twenty-two papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.
Villification of the intestinal epithelium is driven by Foxl1 through activation of PDGFRα and BMPs.
Distinct and cooperative roles of host and tumor Osteopontin in colorectal cancer liver metastasis.
Diet-induced chromatin states influence intestinal stem cell memory.
Lgr5⁺ cells regulate small intestinal morphogenesis before villification.
Beyond the chaos: How architecture structures tumour biology.
Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and attenuate cell senescence.
A translational colorectal cancer organoid biobank mirrors patients' tumor histology, molecular profiles, and treatment responses.
Monocytes acquire a tumor-associated IL1B program upon encountering patient-derived colon cancer organoids.
VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis.
Interrogating the immune landscape of microsatellite stable RAS-mutated colon cancer.
Single-nucleus multi-omics analysis of mouse small-intestinal Lgr5+ cell populations reveals Foxa3-induced Paneth cell-lineage differentiation.
Single Cell-Seeded Human Intestinal Organoids for Organoid Research.
Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer.
Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems.
Single-cell analysis reveals that the hormone T3 affects colon epithelial differentiation and induces a mixed progenitor-like cell population.
The landscape of tissue-resident microbiota across normal, polyp, and colorectal cancer tissues.
Acting on dormancy: the interplay between the actin cytoskeleton and tumor cell dormancy.
Modeling lipid homeostasis using stable isotope tracing and flux analysis.
KIT supports small intestinal tuft cell hyperplasia.
α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer.
Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer.

FEBS J. 2026 Feb 23.

Opposing roles of DGAT-mediated lipid droplet biogenesis in the regulation of ferroptosis sensitivity.

Ana Kump, Leja Perne, Špela Koren, Eva Jarc Jovičić, Nastja Feguš, Carina Pinto Kozmus, Michele Wölk, Kristyna Brejchova, Maria Fedorova, Ondrej Kuda, Toni Petan.

  Lipid droplets (LDs) are dynamic fat storage organelles involved in fatty acid metabolism, signaling, and trafficking. By storing polyunsaturated fatty acids (PUFAs) in the form of neutral lipids, LDs can either mitigate or exacerbate lipotoxic damage. However, their role in regulating cellular fatty acid distribution, membrane unsaturation, and ferroptosis susceptibility remains poorly understood. Here, we show that inhibition of diacylglycerol acyltransferase (DGAT)-mediated LD biogenesis in PUFA-supplemented triple-negative breast cancer cells triggers widespread lipidome reorganization and membrane phospholipid acyl-chain remodeling, promoting lipid peroxidation and ferroptosis sensitivity. Lipidomic analyses reveal that LDs efficiently sequester exogenous PUFAs within triacylglycerols and cholesteryl esters, significantly altering neutral lipid unsaturation profiles. When LD formation is impaired by DGAT inhibition, PUFAs are redistributed into membrane ester and ether glycerophospholipids, enhancing overall membrane unsaturation, lipid peroxidation, and increasing ferroptosis susceptibility, even in the absence of additional ferroptosis inducers. In contrast, in human lung adenocarcinoma cells, LDs exhibit a dual, context-dependent role in ferroptosis regulation, whereby exogenous PUFA levels and the extent of ferroptosis protection determine whether DGAT inhibition promotes or protects against cell death. The pro-ferroptotic function of LDs predominates in these cells and is strongly enhanced by ferroptosis suppressor protein 1 (FSP1) deficiency, which amplifies lipid peroxidation within LDs and promotes its propagation to other cellular compartments. This study highlights LDs as multifaceted regulators of ferroptosis, interlinking metabolic and redox quality control mechanisms.

Keywords:  diacylglycerol acyltransferase; fatty acids; ferroptosis; lipid droplets; lipid peroxidation; lipidomics

DOI:  https://doi.org/10.1111/febs.70467
Nat Commun. 2026 Feb 24.

Villification of the intestinal epithelium is driven by Foxl1 through activation of PDGFRα and BMPs.

Guoli Zhu, Galina Rozenberg, Deeksha Lahori, Jonathan Schug, Mark Tigue, Lan Cheng, Kirill Batmanov, Klaus H Kaestner.

The primitive gut tube of mammals initially forms as a simple cylinder consisting of the endoderm-derived, pseudostratified epithelium and the mesoderm-derived surrounding mesenchyme. During mid-gestation, a dramatic transformation occurs in which the epithelium is both restructured into its final cuboidal form and simultaneously folded and refolded to create intestinal villi and intervillus regions. Here, we show that the mesenchymal winged helix transcription factor Foxl1, itself induced by epithelial hedgehog signaling, controls villification by activating BMP and PDGFRα and the planar cell polarity factor Fat4 in epithelial-adjacent telocyte progenitors either directly or indirectly. In the absence of Foxl1-dependent mesenchymal signaling, villus formation and the separation of epithelial cells into mitotic intervillus and postmitotic villus are delayed, and the differentiation of secretory progenitors temporarily blocked. Thus, Foxl1 orchestrates key events during the epithelial transition of the fetal mammalian gut.

DOI: https://doi.org/10.1038/s41467-026-69791-5
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706899. [Epub ahead of print]

Distinct and cooperative roles of host and tumor Osteopontin in colorectal cancer liver metastasis.

Patrick Czabala, Yang Zhao, John D Klement, Priscilla S Redd, Dakota Poschel, Kristen Carver, Kendra Fick, Zainab Tiamiyu, Martina Zoccheddu, Patricia V Schoenlein, Jennifer Waller, Huidong Shi, Kebin Liu.

Osteopontin (OPN) is a secreted phosphoprotein implicated in colorectal cancer liver metastasis (CRCLM), yet the distinct spatial contributions of host-and tumor-derived OPN in driving this disease remain unclear. Using a 2 x 2 genetic knockout mouse model targeting OPN in host and tumor compartments, combined with spatial transcriptomics, we investigated compartment-specific OPN functions in CRCLM. Tumor-derived OPN promotes tumor proliferation through MEK/ERK signaling. Host OPN licenses monocyte-to-macrophage differentiation, while tumor OPN polarizes macrophages towards an M2-like state. Both host and tumor OPN suppress T cells in the tumor microenvironment, whereas loss of host OPN reveals an interferon-driven, anti-tumor niche. Translational studies using OPN-blockade immunotherapy in syngeneic and patient-derived xenograft mouse models reduced tumor burden and enhanced T cell infiltration. Together, these findings redefine the OPN-myeloid paradigm in CRC and nominate OPN as a potential therapeutic target.

DOI: https://doi.org/10.64898/2026.02.19.706899
bioRxiv. 2026 Feb 20. pii: 2026.02.19.706894. [Epub ahead of print]

Diet-induced chromatin states influence intestinal stem cell memory.

Dominic R Saiz, Yesenia Barrera Millan, Thomas Hartley McDermott, Gabriella Cerna, Swathi Sankar, Fiona Farnsworth, Eric Uher, Gourab Lahiri, Kelly Lintecum, Karla Mullen, Benjamin B Bartelle, Miyeko D Mana.

Intestinal stem cells (ISCs) integrate dietary cues through a metabolic-transcriptional axis, but whether these mechanisms create a lasting epigenetic memory remains unclear. Here, we investigate diet-induced chromatin adaptations in ISCs using a high-fat Western diet (HFD) mouse model. HFD broadly remodels chromatin accessibility, altering pre-existing open regulatory regions. Many differentially accessible regions (DARs) persist during the differentiation of ISCs into transient amplifying cells (TACs). Notably, HFD-induced DARs are retained following diet normalization despite phenotypic reversibility, and HFD re-exposure enhances ISC self-renewal and adenoma growth compared with naïve HFD exposure. The HFD-induced chromatin changes require Ppar-d/a nuclear receptors but are independent of their transcriptional targets. Although a subset of HFD-induced DARs is maintained following Apc loss, extensive chromatin remodeling driven by tumor suppressor inactivation largely overrides diet-dependent differences in Lgr5 ⁺ ISCs. Together, these findings demonstrate that ISCs retain a chromatin-based memory of dietary fat exposure.

DOI: https://doi.org/10.64898/2026.02.19.706894
Cell Regen. 2026 Feb 26. pii: 10. [Epub ahead of print]15(1):

Lgr5⁺ cells regulate small intestinal morphogenesis before villification.

Lianzheng Zhao, Yuchen Xie, Wanlu Song, Yonghui Shen, Huidong Liu, Shiwen Luo, Ye-Guang Chen.

  Lgr5 marks both adult intestinal stem cells and embryonic intestinal stem/progenitor cells. However, the stemness properties and physiological roles of embryonic intestinal Lgr5⁺ cells prior to villification (PVLCs) remain largely unknown. In this study, we show that PVLCs in the embryonic small intestine exhibit region-specific stemness, with progressively enhanced stemness potential from the proximal to distal region. Through inducible cell ablation and gene knockout experiments, we demonstrate that PVLCs regulate small intestinal morphogenesis via Hedgehog signaling in a region-dependent manner, with distal morphogenesis being more dependent on this mechanism. This study reveals the stemness and functional roles of PVLCs in the embryonic small intestine prior to villification, highlighting regionalized cellular heterogeneity as a critical determinant of intestinal morphogenesis.

Keywords:   Lgr5 + cells; Embryonic small intestine; Hedgehog signaling; Morphogenesis; Stemness

DOI:  https://doi.org/10.1186/s13619-026-00284-y
FEBS J. 2026 Feb 22.

Beyond the chaos: How architecture structures tumour biology.

Lea Dörner, Catrin Lutz, Stefan Prekovic, Hendrik A Messal.

  Cancer is increasingly recognised as a complex and heterogeneous disease, shaped not only by genetic mutations but also by the physical and biochemical context in which tumours develop. The spatial position of a cell, including its physical, cellular and molecular surroundings, shapes its fate, phenotypic plasticity and potential to transform and drive tumour progression and evolution. Tissue architecture provides a powerful framework for understanding the complex dynamics of cancer. It integrates the structural organisation of the tumour and its surrounding tissue, the distribution of physical forces, biochemical niches, cellular neighbourhoods, and the broader tissue and organ context in which the tumour develops. Together, these elements form a dynamic and evolving landscape that is continuously remodelled through the multiscale communication of cellular, biochemical and mechanical components. Understanding the principles that govern these interactions reveals that cancer is not merely a chaotic aggregation of cells, but a patterned system shaped by coordinated spatial relationships. Here, we discuss the recent literature to examine how physical, biochemical and cellular relationships orchestrate tumour initiation, progression and treatment resistance, and how their collaboration acts not as a passive scaffold, but as the architect of tumour behaviour.

Keywords:  Tissue architecture; biochemistry; biophysics; cellular neighbourhoods; microenvironment; tumour biology

DOI:  https://doi.org/10.1111/febs.70470
Cell Death Dis. 2026 Feb 26.

Histone 3 lysine 36 trimethylation by SETD2 shapes an epigenetic landscape in intestinal stem cells to orchestrate lipid metabolism and attenuate cell senescence.

Yue Xu, Ziyi Wang, Wenxin Feng, Hanyu Rao, Dehuan Wang, Wei Zhang, Rebiguli Aji, Ningyuan Liu, Jiahe Li, Xiuying Xiao, Wei-Qiang Gao, Li Li.

The self-renewal capacity of intestinal stem cells (ISCs) declines with aging, leading to a loss of homeostasis and an increased susceptibility to intestinal diseases. Despite the established significance of lipid metabolism and epigenetic regulation in ISC function, the molecular mechanisms that connect these processes to aging-related ISC dysfunction remain elusive. Here, we hypothesize that histone 3 lysine 36 trimethylation (H3K36me3) might act as a bridge between these processes. In this study, we demonstrate that H3K36me3 caused by SETD2 is critical for ISC stemness. H3K36me3 deficiency results in reduced ISC proliferation and differentiation, disrupts fatty acid oxidation (FAO), and promotes ISC senescence. Mechanistically, the loss of H3K36me3 triggers the activity of the SWI/SNF chromatin remodeling complex and leads to increased chromatin accessibility and enhancer activation, which alters FAO- and senescence-related gene expression. Importantly, our data demonstrate that metabolic intervention can prevent the senescence of ISC due to H3K36me3 deficiency. Our findings reveal a crucial role for H3K36me3 in maintaining the epigenetic landscape that orchestrates FAO and determines intestinal stem cell functions, emphasizing the role of FAO as a key modulator between H3K36me3 and ISC aging, suggesting that metabolic intervention may help mitigate age-related ISC dysfunction.

DOI: https://doi.org/10.1038/s41419-026-08518-2
J Exp Clin Cancer Res. 2026 Feb 25.

A translational colorectal cancer organoid biobank mirrors patients' tumor histology, molecular profiles, and treatment responses.

Moritz Jesinghaus, Miguel Gomes Silva, Antonio Enrico Zaurito, Valentina Brunner, Frederic Saab, Anantharamanan Rajamani, Niklas de Andrade Krätzig, Nicholas Bodenstein, Rémi Guillemant, Junika Pohl, Maxime Schmitt, Rupert Öllinger, Federico Fusco, Julius Shakhtour, Peter Klare, Klaus-Peter Janssen, Sebastian Foersch, Katja Steiger, Roland Rad, Nicole Pfarr, Dieter Saur, Markus Tschurtschenthaler.

   BACKGROUND: Colorectal cancer (CRC) exhibits pronounced inter- and intratumoral heterogeneity, emphasizing the need for preclinical models that accurately capture its molecular and histological diversity. Patient-derived organoids (PDOs) represent valuable ex vivo systems to model CRC, yet whether they can preserve subtype-specific features and maintain fidelity upon in vivo transplantation remains unclear.
METHODS: We established a biobank of PDOs from both treatment-naïve and neoadjuvant-treated CRC patients, encompassing the major histological subtypes - micropapillary, medullary, serrated, mucinous, and adenocarcinoma not otherwise specified (NOS). PDOs were comprehensively characterized by histomorphological, genomic, and transcriptomic analyses. To assess in vivo fidelity, PDOs were orthotopically transplanted into immunodeficient mice to generate patient-derived organoid xenografts (PDOXs). PDOX-derived tumors and organoids were analyzed to evaluate the preservation of histological and molecular traits, as well as therapy responses.
RESULTS: PDOs displayed distinct, subtype-specific morphologies and growth patterns that closely paralleled their respective patient tumor histologies. Orthotopic PDOXs recapitulated the histological architecture, gene expression profiles, and signaling pathway activation of the original tumors. PDOX-derived organoids retained these subtype-specific morphologies, molecular features, and exhibited similar responses to FOLFOX treatment as their corresponding PDOs, confirming both molecular and functional stability of the organoid-xenograft cycle.
CONCLUSION: This study establishes orthotopic transplantation of CRC PDOs as a robust and predictive preclinical model that captures the full spectrum of CRC heterogeneity. The model preserves histological and molecular subtype fidelity across in vitro and in vivo contexts and enables functional assessment of therapy response. By bridging patient-derived tumor biology with translational modeling, this platform provides a valuable resource for dissecting CRC pathogenesis and advancing patient-tailored precision oncology.

Keywords:  Colorectal cancer; Histological subtypes; PDOX models; Patient-derived organoids (PDOs); Tumor heterogeneity

DOI:  https://doi.org/10.1186/s13046-026-03666-x
Oncoimmunology. 2026 Dec 31. 15(1): 2633012

Monocytes acquire a tumor-associated IL1B program upon encountering patient-derived colon cancer organoids.

Bianca M Balzasch, Andreas von Kries, Saskia Hüll, Indra A Shaltiel, Kim E Boonekamp, Volker Ast, Elke Burgermeister, Johannes Betge, Matthias Ebert, Michael Boutros, Laura Helming, Viktor Umansky, Adelheid Cerwenka.

  Tumor-associated macrophages (TAMs) and monocytes that accumulate in colorectal cancer (CRC) play a crucial role in shaping the tumor microenvironment (TME) and anti-tumor immune responses. Although TAMs have been linked to both pro- and anti-tumor functions, our understanding of the cues instructing their heterogeneous phenotypes and function in cancer patients remains limited. Here, we established co-cultures comprising primary human monocytes and patient-derived organoids (PDOs) from patients with microsatellite-stable CRC to emulate myeloid/tumor cell interactions in vitro. Upon encountering PDOs, monocytes acquire phenotypic changes that are distinct from those induced by typical polarization protocols. Single-cell RNA sequencing revealed that PDO-exposed monocytes transcriptionally resembled IL1B-programmed monocytes previously identified in the tumor tissues of CRC patients. This phenotype emerged independently of tumor mutational profiles or consensus molecular subtypes. Mechanistically, soluble PDO-derived mediators induced the production of CXCL2, CXCL5 and CXCL7 chemokines, whereas the phagocytic uptake of tumor debris impaired the MHC class II-mediated antigen presentation capabilities of monocytes in co-culture. In addition, our in vitro system allowed functional assessment of PDO-exposed monocytes demonstrating a compromised capacity to mount an inflammatory response upon TLR stimulation. Together, PDO-monocyte co-cultures offer a platform to dissect the interplay between cancer cells and monocytes, and advance our understanding of myeloid plasticity and function in cancer patients.

Keywords:  IL1B; Organoid; colon cancer; tumor-associated macrophages

DOI:  https://doi.org/10.1080/2162402X.2026.2633012
Cell Stem Cell. 2026 Feb 23. pii: S1934-5909(26)00032-9. [Epub ahead of print]

VIPR1 acts as an enteric neural checkpoint that suppresses intestinal stem cell-driven epithelial regeneration and exacerbates colitis.

Chaoliang Li, Haohao Wang, Panrui Zhang, Jianbo Yang, Chao Ye, Xiaowei Wei, Yuchen Zhou, Zhentao Yang, Dan Cao, Kaiguang Zhang, Rongbin Zhou, Shu Zhu, Wen Pan.

  Intestinal stem cells (ISCs) drive epithelial renewal and regeneration, yet how neural cues shape ISC behavior remains unclear. Here, we identify a neuronal checkpoint that directly restrains ISC regenerative output during injury. We show that vasoactive intestinal peptide (VIP)-producing enteric neurons directly signal to ISCs through the epithelial receptor VIP receptor 1 (VIPR1). In steady state, VIP-VIPR1 signaling restrains ISC hyperproliferation by engaging an extracellular signal-regulated kinase (ERK)-Notum-Wnt/β-catenin inhibitory axis. During colitis, VIPergic neurons expand within the ulcerated regions and amplify this pathway, thereby suppressing ISC-driven regeneration and exacerbating epithelial injury. Selective deletion of Vipr1 in the epithelium or in ISCs releases this neuronal brake, restores early regenerative activity, and markedly alleviates colitis. The ISC-suppressive function of VIP-VIPR1 signaling is conserved in human intestinal models. Together, these findings define VIPR1 as an ISC-intrinsic neuronal checkpoint that restricts ISC-driven epithelial regeneration and highlight epithelial VIPR1 blockade as a potential strategy to enhance mucosal regeneration in colitis.

Keywords:  Notum; WNT signaling; epithelial regeneration; gut-innervating neurons; inflammatory bowel disease; intestinal stem cells; neuron-epithelial interaction

DOI:  https://doi.org/10.1016/j.stem.2026.01.009
Mol Oncol. 2026 Feb 24.

Interrogating the immune landscape of microsatellite stable RAS-mutated colon cancer.

Rodrigo Dienstmann, Eduardo García-Galea, Alice O'Farrell, Zak Kinsella, Maxime Meylan, Florent Petitprez, Ingrid Arijs, Tom Venken, Hari Ps, Adrian Lärkeryd, Ian Miller, Janick Selves, Nadja Meindl-Beinker, Fiorella Ruiz-Pace, Elena Élez, Raquel Comas-Navarro, Frank Lincoln, Dirk Fey, Gift Nyamundanda, Aoife Nolan, Joern Lewin, Raquel Perez-Lopez, Jonathan Briody, Kathleen Bennett, Walter Kolch, David Matallanas, Alexander Kel, Enrique Arenas, Joaquín Arribas, Bart Ghesquière, Josep Tabernero, Julie Meilleroux, Deborah McNamara, Ray McDermott, Marvin Lim, Mary O'Reilly, Brian Bird, Lisa Stack, Lucia Moloney, Patrick Morris, Keith Egan, Maciej Milewski, Lars Scheuer, Joachim Behringer, Georg Bolz, Ramon Salazar, Cristina Santos, Andrea Ruiz, Orla Casey, Verena Murphy, Matthias Ebert, Livio Trusolino, Diether Lambrechts, Anguraj Sadanandam, Catherine Sautès-Fridman, Jochen Prehn, Paolo Nuciforo, Jacques Fieschi, Florence Monville, Darran O'Connor, Wolf Fridman, Annette Byrne.

  To explore the immune microenvironment of RAS-mutated (RASmt) microsatellite stable (MSS) colon cancer (CC), we retrospectively performed whole exome sequencing, RNA sequencing, and robust digital pathology analyses and studied immune markers in a cohort of 161 patients treated with standard-of-care therapies with early stage disease (both fresh frozen and formalin-fixed paraffin-embedded [FFPE] samples) or 121 patients with metastatic setting (primary tumor FFPE samples). Only a small proportion of cases exhibited a highly infiltrated immune microenvironment, with a strong association between Immunoscore® (IS)-high (13% of the samples) and Tumor Lymphocytes Infiltrating Score (TuLIS)-high scores (25% of the samples). Immunoscore Immune-Checkpoint (ISIC)-high tumors (52% of the samples) shared a similar microenvironment composition to IS-high and TuLIS-like high tumors and displayed higher mutational burdens than ISIC-low tumors. In conclusion, a substantial proportion of MSS RASmt CCs exhibit high ISIC scores, meriting evaluation in prospective trials of immunotherapy-based combination regimens.

Keywords:  RAS mutation; colorectal cancer; immunoscore; immuno‐markers; microsatellite stable; tumor‐infiltrating lymphocytes

DOI:  https://doi.org/10.1002/1878-0261.70225
Commun Biol. 2026 Feb 21.

Single-nucleus multi-omics analysis of mouse small-intestinal Lgr5+ cell populations reveals Foxa3-induced Paneth cell-lineage differentiation.

Xinran Deng, Shenfei Sun, Chenqi Lu, Hanxiao Du, Xiaoyu You, Fujing Huang, Kai Gong, Jingxin Guo, Yumou Gong, Runrong Li, Xingyu Yu, Bing Zhao, Xinhua Lin, Ning Jiang.

Lgr5+ stem cells play crucial roles in maintaining intestinal epithelial cell homeostasis. However, the cellular heterogeneity and underlying regulatory programs of Lgr5+ small intestinal stem cells (ISCs) remain elusive. In this study, we profiled gene expression and chromatin accessibility of Lgr5+ ISCs at single-cell resolution to gain a deeper understanding of the lineage specification and early fate determining mechanisms. Our analysis identified a total of 6 subsets of Lgr5+ cell populations, which exhibited heterogeneity in gene expression and chromatin structure. We found that early fate-determining processes diverged the absorptive and secretory lineages within Lgr5+ cells. We further constructed gene regulatory networks controlling lineage determination and identified Foxa3 as a key transcription factor that regulates the differentiation of the intestinal secretory precursor. In vitro knockdown of Foxa3 disrupted the differentiation of Paneth cells by modulating Peroxisome-Proliferator-Activated Receptors (PPARs). Further Foxa3-targeted CUT&Tag sequencing analysis also verified that Foxa3 predominantly drives Paneth cell differentiation in the small intestine by regulating the expression of core genes in the PPAR signaling pathway. These results provide a comprehensive reference map for advancing our understanding of intestinal epithelial development and related diseases.

DOI: https://doi.org/10.1038/s42003-026-09736-2
J Vis Exp. 2026 Feb 06.

Single Cell-Seeded Human Intestinal Organoids for Organoid Research.

A Young Sim, Ha Young Kim, Gil Young Jung, Jordan E Axelrad, Ken Cadwell, Kyung Ku Jang.

Recent developments in organoid technology have enabled the creation of patient-derived intestinal organoids (PDIOs) that recapitulate the structural, functional, genetic, and epigenetic features of their original tissues. However, conventional passage-derived organoids inevitably yield heterogeneous populations in size and number, leading to inconsistent results even under identical conditions. To address this, a standardized approach, referred to here as "single cell-seeded PDIOs," was established. In this method, mature PDIOs were enzymatically dissociated into single cells and seeded at a defined number into individual wells of a 96-well plate. This controlled seeding normalized the size and number of PDIOs. Compared with passage-derived organoids, single cell-seeded PDIOs displayed reduced inter-well variability in organoid numbers and intra-well variability in organoid sizes, which enables the determination of generation efficiency and improves the reproducibility of viability assays. Moreover, this platform is compatible with downstream analysis, including transcriptomic analysis and protein expression profiling. Collectively, this approach may enhance experimental consistency and provide a practical foundation for reproducible PDIO-based studies.

DOI: https://doi.org/10.3791/69265
Pharmaceuticals (Basel). 2026 Feb 01. pii: 252. [Epub ahead of print]19(2):

Ferroptosis as a Novel Therapeutic Strategy to Overcome Multidrug Resistance in Colorectal Cancer.

Dina Mahemuti, Lanfei Ma, Waqas Siddiqe, Ziyue Tang, Yuxin Kong, Wenfang Li, Zhiwei Zhang, Zhengding Su, Ayitila Maimaitijiang.

  Colon cancer (CC) remains a leading cause of cancer-related mortality worldwide, with multidrug resistance (MDR) presenting a formidable barrier to successful chemotherapy. Ferroptosis-an iron-dependent, lipid peroxidation-driven form of cell death-offers a novel therapeutic avenue to bypass MDR by exploiting metabolic vulnerabilities distinct from traditional apoptosis pathways. Emerging evidence reveals a dynamic interplay between MDR and ferroptosis: MDR cancer cells suppress ferroptosis through NRF2/GPX4-mediated antioxidant upregulation, iron sequestration by ferritin, and lipid metabolism reprogramming, including SREBP1-driven monounsaturated fatty acid accumulation, while ABC transporters actively efflux ferroptosis inducers. On the other hand, ferroptosis inducers such as erastin and RSL3 have the potential to overcome apoptotic resistance and avoid efflux pathways, which recover therapeutic efficacy. This review first describes the primary mechanisms of chemotherapy resistance in colon cancer and then explains the molecular processes that prevent ferroptosis in resistant cells. We also review recent data on the complex interactions between resistance to chemotherapy and ferroptosis, and outline approaches that may stimulate iron accumulation to reverse MDR. By emphasizing novel methods to induce ferroptosis, this review highlights that this approach is a promising strategy to overcome chemotherapy resistance in colon cancer and will facilitate the development of more precise and efficient treatment.

Keywords:  chemotherapy; colon cancer; drug resistance; ferroptosis

DOI:  https://doi.org/10.3390/ph19020252
bioRxiv. 2026 Feb 11. pii: 2026.01.14.699600. [Epub ahead of print]

Metabolic plasticity of sphingolipids governs cancer cell fitness in acidic tumor ecosystems.

Raafat Chalar, Naheel Khatri, Jowana Obeid, Emma Downey, Joon-Hyun Song, Yujie Xiao, Saiful Samad, Andrew Chen, Andrew E Resnick, Khadijeh Karbalaei, Janet Allopenna, Cungui Mao, Christopher J Clarke, Fabiola Velazquez, Chiara Luberto, Bo Chen, Daniel Canals, Yusuf A Hannun, Mehdi Damaghi.

Cancer cells must adapt to harsh tumor microenvironments, including acidic stress, to survive and thrive. Understanding how cancer cells achieve this adaptation can uncover new biomarkers and therapeutic strategies. In this study, we investigated the spatial metabolic phenotypic heterogeneity of breast cancer cells in acidic habitats using spatial multi-omics approaches on 3D spheroids. We found that cancer cells dynamically regulate sphingolipid metabolism to fine-tune their cell state to cope with acidic selection pressures. Cancer cells evolve mechanisms to deal with initially accumulating toxic ceramides but later adapt to it by rerouting SL metabolic pathways to eliminate them. Using advanced MALDI image analysis, and SL inhibitors on patient derived organoids, we demonstrated that cancer cells can switch between metabolic routes when key pathways are blocked, showcasing remarkable cell state plasticity. These insights highlight the potential to target metabolic plasticity as a novel therapeutic strategy to disrupt cancer adaptation and evolution, offering new avenues for cancer treatment.

DOI: https://doi.org/10.64898/2026.01.14.699600
Sci Rep. 2026 Feb 24.

Single-cell analysis reveals that the hormone T3 affects colon epithelial differentiation and induces a mixed progenitor-like cell population.

Carlotta Bidoli, Mathieu Reslinger, Celine Sieffert, Brayann Weis, Gilles Laverny, Marco Gerdol, Michelina Plateroti.



Keywords:  Mouse colon epithelium; Thyroid hormone T3; scRNA-seq

DOI:  https://doi.org/10.1038/s41598-026-40397-7
Nat Commun. 2026 Feb 24.

The landscape of tissue-resident microbiota across normal, polyp, and colorectal cancer tissues.

Haoyi Xiang, Baining Shen, Weifeng Lao, Bingjun Bai, Min Chen, Leqi Zhou, Guanyu Yu, Wei Zhang, Huan Chen, Yuhao Wang, Hangjin Jiang, Zhangfa Song.

Emerging evidence suggests that tissue-resident microbiota (TRM) is associated with tumor biology; however, their distribution and compositional characteristics across different colorectal tissue types remain incompletely defined. Here, we conducted a comprehensive cross-sectional analysis of TRM distribution and abundance across 1134 clinical specimens, including normal mucosa, precancerous polyps, and colorectal cancer (CRC) tissues. Our results reveal distinct microbial profiles among these diagnostic groups, with consistent differences in community composition between normal, polyps, and CRC samples. Integrative analyses further identified microbial signatures capable of distinguishing tissue categories and reflected differences in the local tumor microenvironment. In contrast, intratumoral microbiota composition showed subtle variation across established tumor stages and was not associated with clinical outcomes. These findings define diagnostic group-associated patterns of TRM in colorectal tissues and establish a foundation for future mechanistic investigations into the biological roles of TRM in colorectal cancer.

DOI: https://doi.org/10.1038/s41467-026-69705-5
Cancer Res. 2026 Feb 24.

Acting on dormancy: the interplay between the actin cytoskeleton and tumor cell dormancy.

Hayley M Sabol, Jose Javier Bravo-Cordero, Lucia Borriello.

Dormant disseminated tumor cells (DTCs) can survive long term and drive metastatic relapse years to decades after primary tumor treatment, which remains a major clinical problem. EMT allows these dormant cells to evade immune surveillance, highlighting a potential therapeutic target to prevent metastatic recurrence. In a recent study, Wang ad colleagues demonstrated that a transforming growth factor-β (TGF-β) driven atypical or hybrid EMT state allows lung adenocarcinoma cells to evade the immune system and persist in a dormant state. This atypical EMT state relies on the upregulation of the cytoskeletal protein gelsolin, which mediates the conversion to round, softer cells, that are resistant to immune surveillance and promote dormant cell survival. The inhibition of TGF-B or gelsolin prevents the change in cell morphology, and the cells remain stiff and become susceptible to immune clearance in vivo. This study identifies a novel vulnerability of dormant tumor cells that could be exploited to eliminate dormant DTCs and prevent metastatic relapse.

DOI: https://doi.org/10.1158/0008-5472.CAN-26-0793
Cell Metab. 2026 Feb 20. pii: S1550-4131(26)00020-3. [Epub ahead of print]

Modeling lipid homeostasis using stable isotope tracing and flux analysis.

Karl Wessendorf-Rodriguez, Maureen L Ruchhoeft, Christopher W Murray, Yale Huang, Ethan L Ashley, Hector M Galvez, Grace H McGregor, Shrikaar Kambhampati, Reuben J Shaw, Christian M Metallo.

  Lipids enable compartmentation and coordinate membrane-localized signaling events in cells, and dysregulation of lipid metabolism is linked to many disease states. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To measure fluxes encompassing lipid homeostasis in cells and tissue slices, we apply stable isotope tracing, liquid chromatography-high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Lipid metabolic flux analysis (Lipid-MFA) enables quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Using Lipid-MFA, we observed decreased fatty acid synthase and very long-chain fatty acid (VLCFA) elongation fluxes, along with increased sphingolipid recycling, in p53-deficient versus liver kinase B1 (LKB1)-deficient NSCLC tumors using precision-cut lung slice culture. We also apply Lipid-MFA to demonstrate the unique trafficking of ceramides with distinct n-acyl chain lengths, highlighting the utility of this approach in elucidating molecular mechanisms in lipid homeostasis.

Keywords:  ELOVL1; LKB1; TP53; ceramide; lipid homeostasis; metabolic flux analysis; non-small cell lung cancer; precision-cut lung slice culture; sphingolipids; very long-chain fatty acids

DOI:  https://doi.org/10.1016/j.cmet.2026.01.020
Sci Adv. 2026 Feb 27. 12(9): eady0883

KIT supports small intestinal tuft cell hyperplasia.

Heber I Lara, Madeleine R Bell, Shealyn O'Connor, Hung-An Ting, Jakob von Moltke.

The small intestine balances the competing tasks of nutrient absorption, immune tolerance, and defense through dynamic differentiation of short-lived epithelial cells. During helminth infection, interleukin-13 (IL-13) or IL-4 drive a 10-fold expansion of tuft cells to promote helminth clearance. While IL-4/13 signaling in epithelial cells is required for tuft cell hyperplasia, few signals that support this process have been identified. Here, we show that tuft cells across all tissues express the receptor tyrosine kinase KIT and that IL-4/13 is necessary and sufficient to up-regulate KIT on small intestinal (SI) tuft cells. Although epithelial KIT is dispensable for homeostatic turnover, KIT deletion from tuft cells during helminth infection reduces tuft cell hyperplasia and delays helminth clearance. Mechanistically, KIT signaling supports the generation of new tuft cells in SI crypts. These findings thus identify a unique tuft cell-specific function for KIT in type 2 immunity.

DOI: https://doi.org/10.1126/sciadv.ady0883
Cell Death Dis. 2026 Feb 21.

α-ketoglutarate/succinate ratio imbalance impairs thymine DNA glycosylase function and base excision repair process increasing susceptibility to pancreatic cancer.

Silvia Malatesta, Virginia Vigiano Benedetti, Emanuela Salviati, Barbara Illi, Isabella Manni, Emanuele Middonti, Gian Luca Rampioni Vinciguerra, Valerio Licursi, Francesca Troilo, Gianni Colotti, Lina Cipolla, Simone Sabbioneda, Livia Perfetto, Giulia Piaggio, Federico Bussolino, Federica Di Nicolantonio, Pietro Campiglia, Eduardo Maria Sommella, Mattia Mori, Chiara Cencioni, Francesco Spallotta.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with chronic metabolic disorders increasing risk and severity. Prolonged exposure to altered metabolism changes specific metabolite levels, impacting epigenetic landscape contributing neoplastic lesion acquisition. This study examines the interplay between metabolism and epigenetics in dysmetabolic-driven PDAC tumorigenesis, exploiting LSL-KrasG12D;PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD) and KRAS-mutated human pancreatic ductal epithelial (HPDE) cells. Untargeted metabolomics of HFD-fed KC pancreata reveals altered free fatty acid and elevated S-adenosyl methionine levels during tumorigenesis. Targeted metabolomics shows increased succinate alongside reduced α-ketoglutarate levels. This imbalance suggests an epigenetic derangement, targeting DNA methylation. In KRAS-mutated HPDE cells exposed to altered metabolism, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 and thymine DNA glycosylase (TDG) is disrupted, leading to iterative cytosine modification and apurinic/apyrimidinic (AP) site accumulation. Succinate directly binds TDG at arginine 275, hyperactivating it and increasing AP site formation. This alteration combined with the methylation-prone metabolic environment, impairs the base excision repair pathway by hypermethylating and downmodulating DNA ligases LIG1 and LIG3. This predisposes to genomic instability and pancreatic preneoplastic lesion development. These findings uncover a metabolic-epigenetic axis in dysmetabolic PDAC, highlighting how metabolite-driven epigenetic changes compromise DNA repair and drive tumorigenesis.

DOI: https://doi.org/10.1038/s41419-026-08475-w
Br J Cancer. 2026 Feb 23.

Exploratory biomarkers for oxaliplatin-induced nivolumab responsiveness in metastatic microsatellite-stable colorectal cancer.

Anne Hansen Ree, Paula A Bousquet, Tina Visnovska, Torben Lüders, Benjamin P Geisler, Shixiong Wang, Diana L Bordin, Hilde L Nilsen, Hanne M Hamre, Christian Kersten, Eva Hofsli, Marianne G Guren, Halfdan Sorbye, Jens P Berg, Kjersti Flatmark, Sebastian Meltzer.

BACKGROUND: The randomised METIMMOX trial evaluated short-course oxaliplatin-based chemotherapy alternating with nivolumab for metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer. In a post hoc analysis, we investigated whether tumour mutations or patients' systemic inflammation might provide insights into responsiveness to the METIMMOX regimen.
METHODS: Patients received either oxaliplatin-based chemotherapy (control group) or alternating two cycles each of chemotherapy and nivolumab (experimental group), with progression-free survival (PFS) as the primary endpoint. Tumour biopsies were sequenced with the TruSight Oncology 500 assay.
RESULTS: The median tumour mutational burden (TMB; in mutations/megabase) was 8 (range, 1-13). The experimental-arm patients with TMB ≥9 or BRAF-V600E mutation (n = 17) achieved median PFS of 19.8 months (95% confidence interval, 11.3-28.3), longer (p = 0.0090) than experimental-arm patients with TMB < 9 not BRAF-V600E (n = 19) and control-arm patients with either TMB and BRAF status combination (n = 31). With TMB ≥9 or BRAF-V600E and normal, non-inflammatory level of C-reactive protein when starting nivolumab (n = 11), median PFS was 35.0 months (95% confidence interval, 6.8-63.0; p < 0.0001).
CONCLUSIONS: TMB, somatic BRAF status and systemic inflammation should be prospectively investigated as practical biomarkers for predicting potential responsiveness to immune checkpoint inhibitors in metastatic microsatellite-stable/mismatch repair-proficient colorectal cancer.

DOI: https://doi.org/10.1038/s41416-026-03357-6