bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–08–23
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. The Dynamic Alliance of p53 and Metabolism in the Tumor Microenvironment Shapes Tumor Evolution.
  2. HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
  3. Single-cell transcriptomics and functional analyses identified SPIN.DOC as a regulator for Wnt signaling and cancer stemness in colorectal cancer.
  4. Cancer cell plasticity: new insights from developmental programs.
  5. Identifying phenotype-genotype-function coupling in 3D organoid imaging using Shape, Appearance and Motion Phenotype Observation Tool (SPOT).
  6. WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer.
  7. Inference of lineage hierarchies, growth, and drug response mechanisms in cancer cell populations without tracking.
  8. Circadian clock regulates intestinal epithelial cell differentiation via NOTCH/Hes1 oscillations.
  9. Metabolic regulation of stem cell plasticity.
  10. Mechanisms underlying propagation of ferroptotic cell death.
  11. CHTOP regulates the NRF2/HO-1 axis to modulate chemoresistance in colorectal cancer.
  12. Fate patterns originate through structural relations between cell and supracellular levels of organization.
  13. Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression.
  14. Organ-specific colonization and niche remodeling in a human tissue model of metastasis.
  1. Bioessays. 2026 Aug;48(8): e70175
    The Dynamic Alliance of p53 and Metabolism in the Tumor Microenvironment Shapes Tumor Evolution.
    Sebastien M Joruiz, Francesco Napoletano, Rebecca Bertolio, Giannino Del Sal.
      Tumor evolution, from premalignant lesions to metastasis, is increasingly recognized as shaped by continuous interplay between tumor cells metabolism and their microenvironment. During tumor initiation, major oncogenic pathways drive early metabolic reprogramming of lipid, amino acid, and energy pathways to promote cell competition and clonal expansion. These metabolic changes reciprocally shape the tumor microenvironment (TME) through metabolite fluxes, extracellular matrix remodeling, and immune reprogramming, generating adaptive niches that sustain tumor progression and metastasis. Cancer cell metabolic adaptability becomes even more crucial to survive dissemination and adapt to a new, distant microenvironment. Here, we discuss these dynamic interplays and highlight the p53 pathway as an integrative hub linking oncogenic signaling, metabolic rewiring, and tumor microenvironmental adaptation throughout carcinogenesis. We will also outline how emerging technologies may redefine the TME-p53-metabolism interplay uncovering therapeutically exploitable metabolic vulnerabilities.
    Keywords:  cell competition; metabolic plasticity; metastasis; mutant p53; p53; p53 isoforms; tumor microenvironment
    DOI:  https://doi.org/10.1002/bies.70175
  2. Sci Adv. 2026 Aug 21. 12(34): eaeg3424
    HMOX1 controls a heme-ferritin switch that protects cells from ferroptosis.
    Izadora de Souza, Izabela Amélia Marques Andrade, Florencio Porto Freitas, Ana Beatriz da Silva Teixeira, Maria Carolina Clares Ramalho, Karoline Almeida Lima, Ancely Ferreira Dos Santos, Werner Schmitz, Gholamreza Fazeli, Clarissa Ribeiro Reily Rocha, José Pedro Friedmann Angeli.
      Modulating the intracellular labile iron pool (LIP) has emerged as a promising strategy to induce ferroptosis in cancer cells, offering a way to overcome resistance to apoptosis-based therapies. One of the main contributors to LIP is heme catabolism mediated by heme oxygenase-1 (HMOX1), which promotes ferroptosis sensitivity by releasing free iron. Beyond its role as an iron donor, heme can influence diverse proteins and signaling pathways that drive tumor progression, but how heme regulates ferroptosis remains poorly understood. Here, we uncover a paradoxical, protective function of heme in the absence of HMOX1 activity. When HMOX1 is inactive, heme becomes stabilized, leading to ferritin up-regulation, suppression of ferroptosis, and rescue of cell death induced by both pharmacological and genetic inhibition of GPX4. Our findings reveal an unrecognized heme-HMOX1-ferritin axis that controls ferroptosis sensitivity. Targeting this pathway may offer a new therapeutic strategy to modulate ferroptosis in cancer.
    DOI:  https://doi.org/10.1126/sciadv.aeg3424
  3. Hum Cell. 2026 Aug 19. pii: 126. [Epub ahead of print]39(9):
    Single-cell transcriptomics and functional analyses identified SPIN.DOC as a regulator for Wnt signaling and cancer stemness in colorectal cancer.
    Khuraijam Mrinalini Devi, Eshan Abbas, Thangjam Davis Singh, Rubismita Deka, Aditya Kumar, Lisam Shanjukumar Singh, Thiyam Ramsing Singh.
      The role of SPIN.DOC in tumorigenesis remains unclear. In this study, we utilized single-cell RNA sequencing (scRNA-seq) data to investigate SPIN.DOC expression in a cohort of normal, primary human colorectal cancer (CRC) and metastatic tissues from CRC patients. Our findings revealed differential expressions of SPIN.DOC across multiple cell clusters in different conditions and with the highest expression observed in tumor samples, suggesting its potential role in CRC progression. Further analysis showed that SPIN.DOC positive cell-cluster showed upregulation of β-catenin and cancer stem cell (CSC) marker genes, indicating its role in activating Wnt signaling for cell proliferation. Additionally, these cells also showed downregulation of genes associated with cell-cell junctions, promoting epithelial-mesenchymal transition (EMT) and cancer progression in colon tumors. To validate these findings experimentally, we analyzed the expression of SPIN.DOC in normal colorectal and three colorectal cancer cell lines by immunofluorescence and western blotting. SPIN.DOC was expressed at low level in human normal colon epithelial cells but was highly expressed in all the three colorectal cancer cell lines tested. Consistent with the scRNA data, overexpression of SPIN.DOC in CRC cell line, enhanced cell proliferation, cell migration, invasion, colony-forming capability and Wnt signaling. Moreover, these cells upregulate EMT-associated genes and cancer stem cell markers, as determined by qRT-PCR and immunoblotting. Enhanced spheroid formation in SPIN.DOC overexpressing cells further indicated increased stemness of the cells. Conversely, the knockdown of SPIN.DOC diminished the aforesaid phenotypes. Overall, these data suggest that SPIN.DOC promotes cancer cell proliferation, metastasis and regulates pluripotency and self-renewal of colorectal CSCs. Overall, our study highlights SPIN.DOC as a key essence of CRC by regulating cancer stemness and provides an opportunity of using SPIN.DOC, as a diagnostic and prognostic biomarker of colorectal cancer.
    Keywords:  Cancer stem cell; Colorectal cancer; Oncogene; SPIN.DOC; Wnt signalling
    DOI:  https://doi.org/10.1007/s13577-026-01442-9
  4. Trends Cancer. 2026 Aug 21. pii: S2405-8033(26)00165-2. [Epub ahead of print]
    Cancer cell plasticity: new insights from developmental programs.
    Vincent J Guen, Robert A Weinberg.
      Tumors represent a heterogeneous set of neoplastic diseases, each composed of an intricate network of cancer cells residing in multiple alternative phenotypic states. Transitions between these phenotypic states, often termed 'phenotypic plasticity', enable them to execute specific steps in tumor progression and to develop therapeutic resistance. The phenotypic plasticity of tumor cells is mediated, in part, by cellular processes that orchestrate normal embryonic development and are hijacked by tumors. In this review, we discuss the contributions of these developmental programs to cancer cell phenotypic plasticity. We focus on epithelial-mesenchymal transition and ciliogenesis programs and discuss new insights into the mechanistic roles of these cellular processes in cancer progression and response to treatment.
    Keywords:  cancer cell plasticity; ciliogenesis; epithelial–mesenchymal transition; intratumor heterogeneity
    DOI:  https://doi.org/10.1016/j.trecan.2026.07.009
  5. Nat Commun. 2026 Aug 17. pii: 8410. [Epub ahead of print]17(1):
    Identifying phenotype-genotype-function coupling in 3D organoid imaging using Shape, Appearance and Motion Phenotype Observation Tool (SPOT).
    Felix Y Zhou, Brittany-Amber Jacobs, Adam Norton-Steele, Xiaoyue Han, Linna Zhou, Thomas M Carroll, Carlos Ruiz Puig, Joseph Chadwick, Xiao Qin, Richard Lisle, Lewis Marsh, Helen M Byrne, Heather A Harrington, Xin Lu.
      Live cells in tissue are plastic, phenotypically dynamic, and modify their function in response to genetic and environmental perturbations. To unleash the power of live-cell imaging to identify phenotype-genotype-function coupling over time, we report the development of a standardized Shape-Appearance-Motion (SAM) "phenome" and SAM-Phenotype-Observation-Tool (SPOT), that act as an image-"transcriptome" and image-"transcriptome analyzer" respectively, and provide an unbiased and comprehensive description of morpho-dynamic phenotypes without prior knowledge. We apply SAM-SPOT to our simulated organoids database with known ground-truth and >1.6 million mouse and human organoid instances with defined genetic and chemical perturbations. SAM-SPOT can effectively and robustly characterize 3D morpho-dynamics from 2D projection videos. Combined with single-cell RNA sequencing, SAM-SPOT reveals that altered WNT signaling, but not mutant RAS or p53, predisposes intestinal organoids to irregular morphogenesis. SAM-SPOT advances biomedical discovery by empowering live-cell imaging to identify phenotype-genotype-function relationships through large-scale and cost-effective label-free live-cell imaging.
    DOI:  https://doi.org/10.1038/s41467-026-75506-7
  6. Gastroenterology. 2026 Aug 18. pii: S0016-5085(26)07158-1. [Epub ahead of print]
    WNT-driven immune evasion promotes malignant transformation of BRAF-mutant colorectal cancer.
    Manuel Mastel, Aitana Guiseris Martinez, Umberto Pozza, Jasmin Meier, Ioannis Chiotakakos, Sandra Jaun, Carolin Artmann, Gabriele Diamante, Nikolaos Georgakopoulos, Philipp Albrecht, Yvonne Petersen, Saskia Reuter, Barbara Schmitt, Michael Günther, Alexandra Thiran, Istiffa Nurfauziah, Ian Ghezzi, Kyanna S Ouyang, Michael D Milsom, Jens Puschhof, Nic G Reitsam, Kim E Boonekamp, Johannes Betge, Steffen Ormanns, Michael Boutros, Rene Jackstadt.
       BACKGROUND & AIMS: BRAF-mutant colorectal cancer (CRC) is a clinically aggressive subtype arising from the serrated pathway and is associated with poor prognosis and therapy resistance. The mechanisms driving malignant transformation in microsatellite-stable (MSS) BRAF-mutant CRC remain incompletely understood. We aimed to define the role of WNT pathway activation in serrated CRC progression and tumor-immune interactions.
    METHODS: We generated multiple genetically engineered mouse models (GEMMs) of BRAF-mutant MSS CRC and complementary organoid-based transplantation models. Genetic alterations in WNT pathway components were functionally interrogated. Tumor development and immune microenvironment remodeling were analyzed using bulk RNA sequencing, single-cell RNA sequencing, CITE-seq, and functional in vivo assays.
    RESULTS: WNT pathway activation via APC or CTNNB1 mutations, but not RNF43 loss, was required for tumor initiation in BRAF-mutant CRC models. WNT activation induced a molecular subtype shift and suppressed immune response pathways. Mechanistically, WNT signaling suppressed CCL20 expression and remodeled the tumor microenvironment (TME) by promoting immunosuppressive myeloid populations and altering T-cell states. Functional assays demonstrated that WNT activation enhances tumor progression in immunocompetent settings, indicating immune evasion as a key driver of malignant progression.
    CONCLUSIONS: WNT pathway activation is a critical determinant of malignant transformation in BRAF-mutant MSS CRC by enabling immune escape. These findings identify WNT signaling as a central regulator of tumor-immune interactions and a potential therapeutic target in this aggressive CRC subtype.
    Keywords:  WNT signaling; mouse models; serrated neoplasia; tumor microenvironment
    DOI:  https://doi.org/10.1053/j.gastro.2026.07.035
  7. Cell Rep Methods. 2026 Aug 17. pii: S2667-2375(26)00267-5. [Epub ahead of print] 101566
    Inference of lineage hierarchies, growth, and drug response mechanisms in cancer cell populations without tracking.
    Andrea Piras, Federica Galvagno, Letizia Pizzini, Matteo Nunziante, Sabrina J Fletcher, Elena Grassi, Andrea Bertotti, Luca Primo, Antonio Celani, Alberto Puliafito.
      Lineage hierarchies and plasticity regulate development and tissue homeostasis, while diverted lineage dynamics and aberrant phenotypic plasticity are among the causes of incomplete drug response and resistance in cancer. Knowing the dynamics of phenotypically heterogeneous populations is therefore central to understanding growth regulation principles and to rationally design therapeutic approaches anticipating drug-tolerant states. While lineage inference can be addressed by barcoding technologies, these approaches often yield average clonal behaviors that neglect the underlying phenotypic plasticity of individual cells. Directly observing single-ancestor pedigrees in multi-type populations remains an experimental challenge. To address these difficulties, we developed a method to infer active phenotypic transitions in a multi-type tumor or clone and to quantify them, solely relying on counting cell-type abundances. We demonstrate the effectiveness of our approach to address cancer phenotypic heterogeneity and drug tolerance in silico. We then perform experiments on cancer cell populations and infer growth mechanisms and transition probabilities.
    Keywords:  Bayesian inference; CP: computational biology; CP: systems biology; Monte Carlo expectation maximization; branching processes; cancer; drug tolerance; inference; lineage hierarchies; patient-derived tumoroids; phenotypic plasticity; population dynamics
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101566
  8. bioRxiv. 2026 Jul 30. pii: 2026.07.30.741736. [Epub ahead of print]
    Circadian clock regulates intestinal epithelial cell differentiation via NOTCH/Hes1 oscillations.
    Sevde Goker, Suengwon Lee, Bence Gaizer, Toru Matsu-Ura, Sabrina Tsoi, Gang Wu, Heewoong Lim, János Juhász, Attila Csikász-Nagy, Christian I Hong.
      The circadian clock regulates diverse cellular processes, including intestinal epithelial cell (IEC) proliferation. However, mechanisms regulating clock-dependent IEC differentiation remain unknown. We performed a time course RNA-Seq using the mouse small intestine and identified NOTCH signaling, a key mechanism regulating IEC differentiation, as one of the pathways under the control of circadian rhythms. Using mouse enteroids, we discovered that a NOTCH reporter, Hes1-luciferase, exhibits both ultradian or circadian oscillations depending on the stemness of mouse enteroids. Furthermore, single-cell analysis of Hes1-mCherry revealed that the period of Hes1 oscillations varies widely, but circadian rhythms modulate the number of Hes1-mCherry+ cells in the population. Finally, we show that Paneth cell numbers fluctuate over the circadian cycle, suggesting that circadian clock-regulated Hes1 drives the circadian dynamics of IEC composition. Our study provides a deeper insight into circadian regulation of IEC differentiation, which will be critical for applications of chronotherapies for digestive diseases.
    DOI:  https://doi.org/10.64898/2026.07.30.741736
  9. Curr Opin Genet Dev. 2026 Aug 15. pii: S0959-437X(26)00097-3. [Epub ahead of print]100 102530
    Metabolic regulation of stem cell plasticity.
    Emilia Kuuluvainen, Swetha Gopalakrishnan, Pekka Katajisto.
      Stem cells must accurately balance self-renewal with the generation of specialized cells that each adopt the type of metabolism facilitating their specific function. However, recent advances demonstrate that metabolism can regulate decisions between self-renewal and differentiation, in addition to being a downstream outcome of transcriptional programs of differentiation. Here we discuss how metabolism influences mammalian stem cells, focusing on the conundrum of how cell fate determination can be accurately controlled if the endpoint product - the specialized cellular metabolism - can influence the process. We propose that most stem cells are guided by intrinsic and extrinsic metabolic cues, creating dynamic metabolic states that may differ in lineage preferences and activity but do not pose a deterministic impact on stem cell potency. Such metabolic plasticity safeguards tissue maintenance and regeneration from modest metabolic fluctuations, but disruptions beyond the limits of metabolic plasticity can impair stem cell function and fate potential.
    DOI:  https://doi.org/10.1016/j.gde.2026.102530
  10. Nat Cell Biol. 2026 Aug 21.
    Mechanisms underlying propagation of ferroptotic cell death.
    Francesca Maremonti, Alireza Dehdari, Nadja Leinung, Derek A Pratt, Andreas Linkermann.
      Necrotic zones in tissues occur in a wide variety of diseases. Ferroptosis, an iron-promoted necrosis driven by lipid peroxidation, has been identified as a key cell death modality in these conditions. Cells undergoing ferroptosis are unique in that they can induce death in their neighbours. Here we review salient aspects of ferroptosis propagation on the molecular, cellular and tissue levels. Cell death propagation is restricted by several ferroptosis-suppression systems. Glutathione peroxidase 4 (GPX4) and ferroptosis-suppressor protein 1 (FSP1) are now well established as master regulators, but various additional systems dictate ferroptosis sensitivity. We discuss how these mechanisms contribute to the suppression of cell death propagation, and how they cause various tissues to be more or less resistant to ferroptosis propagation. Understanding tissue-specific dynamics is critical to interpret the beneficial effects and limitations of future therapeutic approaches for ferroptosis-driven diseases.
    DOI:  https://doi.org/10.1038/s41556-026-02053-0
  11. Redox Biol. 2026 Aug 15. pii: S2213-2317(26)00352-6. [Epub ahead of print]96 104353
    CHTOP regulates the NRF2/HO-1 axis to modulate chemoresistance in colorectal cancer.
    Jing Li, Xiaopeng Li, Chenye Zhao, Peiwen Wu, Weibin Hu, Xu Zhao, Yuan Ma, Zepeng Dong, Hang Yuan, Shihui Chen, Zilu Chen, Jing Lu, Wei Wang, Xuejun Sun, Qin Zhang, Mingchao Mu.
      Chemotherapy resistance remains a significant challenge in colorectal cancer (CRC) treatment, with disrupted redox balance playing a central role. Here we identify CHTOP as a key regulator of oxidative stress and chemoresistance in CRC. Mechanistically, CHTOP promotes NRF2 transcriptional activity by recruiting the SENP3-containing 5FMC complex to deSUMOylate NRF2, thereby sustaining HO-1 expression and redox balance. Notably, CHTOP expression itself is tightly controlled by a feedback mechanism. The p52 isoform of PSIP1 inhibits CHTOP expression by interfering with HNRNPH1-mediated splicing, leading to CHTOP degradation via nonsense-mediated decay (NMD). Conversely, elevated oxidative stress stabilizes SENP3, which promotes deSUMOylation and degradation of p52, thereby relieving p52-mediated suppression of CHTOP expression. This establishes an oxidative stress-SENP3-p52-CHTOP feedback loop that fine-tunes CHTOP levels. In 5-FU-resistant CRC cells, CHTOP downregulation shifts cells into an elevated oxidative stress state, which correlates with reduced 5-FU sensitivity. Notably, either restoring CHTOP expression or further depleting CHTOP disrupts this redox balance and resensitizes resistant cells to 5-FU. These findings suggest that modulating CHTOP expression may offer a therapeutic strategy to overcome chemoresistance in CRC through redox regulation.
    Keywords:  CHTOP; Chemoresistance; NRF2; Oxidative stress; PSIP1
    DOI:  https://doi.org/10.1016/j.redox.2026.104353
  12. bioRxiv. 2026 Jul 28. pii: 2025.10.24.683925. [Epub ahead of print]
    Fate patterns originate through structural relations between cell and supracellular levels of organization.
    Clint S Ko, Ruonan Chen, Nina T Magid, Katharine Courtemanche, Pearson W Miller, Alan R Rodrigues, Amy E Shyer.
      How patterns of cell state emerge across a tissue field is a fundamental question brought into renewed focus by spatial omics tools that map molecular states onto tissue organization. Here, we investigate how a field of limb progenitor mesenchyme transforms into distinct, adjacent cartilage and soft tissue compartments. We find that mesenchymal tissue fields self-organize their own differentiation through co-constitutive relationships between cell and supracellular structures, which produce cell-ECM or cell-cell-based supracellular cues that canalize cartilage or soft tissue cell fate change, respectively. At the tissue level, bifurcation in intrinsically generated supracellular structures guides the specification of tissue compartment size. We find that Wnt secreted from neighboring epithelial tissue influences mesenchymal cell fate and patterning by functioning as a modulator of cell-supracellular structural relations. Taken together, our results provide insight into how mesenchymal self-organization interfaces with epithelial signaling to enable a tissue compartmentalization process that initiates the skeleton.
    DOI:  https://doi.org/10.1101/2025.10.24.683925
  13. bioRxiv. 2026 Aug 07. pii: 2026.08.06.743310. [Epub ahead of print]
    Spatial multi-omics and single-cell transcriptomics uncover senescence-associated cellular programs during colon adenoma to cancer progression.
    Ming Yu, Yumo Xie, Lena Allen, Kelly Carter, Elizabeth Donato, Lingxin Cheng, Christina Kendziorski, Kristina A Matkowskyj, Angelo M DeMarzo, Jessica Hicks, Deepti Reddi, Evan W Newell, Wei Sun, William M Grady.
      Colorectal cancer develops through a normal-adenoma-carcinoma sequence, yet only 5-10% of adenomas progress to malignancy, and the cellular programs governing that sequence remain poorly defined. Here we generate a spatial multi-omics atlas of human colon adenomas, combining Visium CytAssist and protein co-detection across 24 nonadvanced and advanced tubular adenomas with single-cell resolution Xenium Prime 5K profiling of 101 patient-matched normal, adenoma, and carcinoma cores from 16 patients. Integrating whole-transcriptome and 31-plex protein data identifies nine spatial clusters and two dysplastic epithelial populations that co-express stemness, proliferation, and senescence programs. These programs occupy a shared, spatially confined epithelial niche that expands from adenoma to carcinoma. Spatial analysis revealed GDF15, a senescence-associated secretory factor, mediated the coupling between senescence and stemness in advanced adenomas, and that GDF15-high epithelium locally excludes CD8+ T cells in adenoma and, more broadly, in carcinoma. These findings position senescence as a spatially instructive rather than merely tumor-suppressive program during colorectal carcinogenesis and suggest GDF15 might be a potential candidate target for cancer prevention and interception in the colon.
    DOI:  https://doi.org/10.64898/2026.08.06.743310
  14. Sci Transl Med. 2026 Aug 19. 18(863): eadv6871
    Organ-specific colonization and niche remodeling in a human tissue model of metastasis.
    Alan G Chramiec, Ilaria Baldassarri, Ece Öztürk, Daniel Naveed Tavakol, Miranda C Wang, Max Summers, Keith Yeager, Richard Z Zhuang, Anushka Srivastava, Somnath Tagore, Diogo Teles, Hanina Hibshoosh, Andrea Califano, Peter A Sims, Gordana Vunjak-Novakovic.
      For metastatic colonization to occur, disseminated tumor cells must survive, adapt to, and remodel distant microenvironments in an organ-specific manner. We established a human multitissue model of cancer spread, with engineered bone and lung linked by vascular flow containing circulating cancer cells. Parental MDA-MB-231 cells extravasated toward both tissues, remodeled their niches, and acquired transcriptional programs reflecting adaptation to the local microenvironment, particularly upon homing to bone. Tissue-specific colonization by the bone- and lung-tropic MDA-MB-231 derivatives was quantified in independently perfused bone or lung platforms. Consistent with in vivo behavior, bone-tropic cells showed stronger bone colonization than lung-tropic cells and induced more pronounced osteolysis. In contrast, lung-tropic cells caused greater epithelial disruption in lung tissue and only modest colonization of bone. Distinct patterns of tissue colonization and secreted factors demonstrate that this device recapitulates key features of organ-specific metastasis observed in vivo for this family of cell lines.
    DOI:  https://doi.org/10.1126/scitranslmed.adv6871
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