bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–04–05
eight papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
  2. Nup358 Sustains Intestinal Epithelial Homeostasis by Preventing Dvl1 Condensate Formation to Restrain Wnt Signaling.
  3. In vitro models of cell competition: current approaches and future directions.
  4. A Physical Framework to Control Cancer Cell Heterogeneity and Plasticity.
  5. The lipid transfer protein STARD7 controls intestinal tumor development in a context-dependent manner.
  6. Regional and age-related differences of crypts in the human large intestine: A 3-D surface metrology study.
  7. Reconstructing tumor tissues in 3D: From organoids to bioengineered niches.
  8. Fueling the fatal voyage: How metabolic plasticity empowers every step of cancer metastasis.
  1. iScience. 2026 Apr 17. 29(4): 115193
    Therapeutic manipulation and spatial quantification of the tumor microenvironment in colorectal cancer.
    Eoghan J Mulholland-Illingworth, Joshua W Moore, Muyang Lin, Raheleh Amirkhah, Lucile Grzesiak, Amelia Ligeza, Joshua A Bull, Joseph Boen, Gabriel N Valbuena, Michael A Gillespie, Tamsin R M Lannagan, Kathryn Gilroy, Megan L Mills, Shania M Corry, Rachel A Ridgway, Hayley L Belnoue-Davis, Philip D Dunne, Owen J Sansom, Helen M Byrne, Simon J Leedham.
      Colorectal cancer (CRC) is a complex ecosystem shaped by bidirectional interactions between epithelium and the tumor microenvironment, prominently mediated by TGFβ signaling. Cancer-associated fibroblasts (CAFs) are regulators of epithelial plasticity and immune cell recruitment; yet, their diversity has impacted translationally applicable spatial analysis. Here, we distil the fibroblast continuum into two overarching CAF populations that are largely transcriptomically distinct and are marked by PDGFRA+ and ACTA2+ expression, enabling robust spatial identification using single immunohistochemical markers. We show that TGFβ signaling drives dynamic transitions between these states. In a preclinical model, selective ALK5 inhibition remodels CAF composition in vivo, reconfiguring local immune neighborhoods and indirectly altering epithelial stem cell states. Finally, we demonstrate that multiscale spatial analysis provides a quantitative readout of stromal-immune-epithelial remodeling following therapy. These findings establish a simplified, translationally relevant CAF framework and highlight spatially resolved stromal dynamics as measurable indicators of therapeutic response in CRC.
    Keywords:  cancer; health sciences; medicine; oncology
    DOI:  https://doi.org/10.1016/j.isci.2026.115193
  2. bioRxiv. 2026 Mar 28. pii: 2026.03.25.714063. [Epub ahead of print]
    Nup358 Sustains Intestinal Epithelial Homeostasis by Preventing Dvl1 Condensate Formation to Restrain Wnt Signaling.
    Valeria Guglielmi, Stephen Sakuma, Ethan Y S Zhu, Davina Lam, Maximiliano A D'Angelo.
      Nucleoporins are increasingly recognized as tissue-specific regulators beyond their structural roles in the nuclear pore complex. Here, we identify nucleoporin Nup358 as a critical repressor of Wnt signaling required for intestinal epithelium integrity. Ablation of Nup358 in adult mice causes a catastrophic loss of crypt-villus architecture and disrupts the intestinal epithelial layer. Notably, while the intestinal stem cell (ISC) pool remains stable, the transit-amplifying (TA) progenitor compartment is depleted. Mechanistically, we show that the interaction of Nup358 with Dvl1 through its N-terminal domain inhibits Dvl1 spontaneous phase separation. In the absence of Nup358, Dvl1 biomolecular condensates promote Tankyrase-mediated degradation of Axin1, leading to the constitutive stabilization of β-catenin and ligand-independent Wnt activation, negatively impacting cell differentiation and TA progenitor survival. Our results demonstrate that Nup358 acts as a molecular safeguard that dampens Wnt signaling levels in intestinal crypts. By preventing Dvl1-mediated Wnt signal amplification, Nup358 allows ISCs to transition into the TA compartment and initiate the differentiation programs essential for intestinal homeostasis.
    DOI:  https://doi.org/10.64898/2026.03.25.714063
  3. Oncogene. 2026 Mar 28.
    In vitro models of cell competition: current approaches and future directions.
    Selami Baglamis, Przemek M Krawczyk, Louis Vermeulen, Sanne M van Neerven, Kristiaan J Lenos.
      Cell competition is an evolutionarily conserved quality control mechanism that eliminates less-fit cells to ensure optimal tissue integrity during development, homeostasis, and regeneration. Beyond these physiological roles, recent evidence implicates a role for cell competition in disease, particularly in cancer, where it can function by either suppressing or promoting malignant progression. In this review, we provide an overview of the different molecular mechanisms that drive cell competition and their impact on cancer development and progression. We will evaluate the current state-of-the-art in vitro experimental systems that can be employed to study these processes. Ranging from classical 2D co-culture systems to advanced organoid and organ-on-chip platforms, these model systems collectively enhance our understanding of the complex cellular interactions that underlie the competitive differences between cells. By integrating insights from diverse model systems, we highlight how cell competition shapes tumor dynamics and discuss how this knowledge could inspire novel therapeutic strategies to prevent or control tumor growth.
    DOI:  https://doi.org/10.1038/s41388-026-03751-7
  4. Cancer Discov. 2026 Apr 01. 16(4): 637-643
    A Physical Framework to Control Cancer Cell Heterogeneity and Plasticity.
    Hadrien De Blander, Jean-Christophe Marine.
      We propose a physics-based framework in which cancer cell state is defined by position and velocity in a continuous space of directly measurable physical variables-cell surface area (S) and volume (V)-and motion through S-V space as an interpretable proxy for plasticity. Therapy generates S-V vector fields that govern trajectories, enabling the design of drug combinations to steer heterogeneous cell populations toward nonviable states, offering a predictive and physically interpretable alternative to therapies directed against oncogenic mutations and/or predefined cell subpopulations.
    DOI:  https://doi.org/10.1158/2159-8290.CD-26-0083
  5. EMBO Mol Med. 2026 Mar 30.
    The lipid transfer protein STARD7 controls intestinal tumor development in a context-dependent manner.
    Kateryna Shostak, Yu Chen, Chloé Maurizy, Gilles Rademaker, Xinyi Xu, Arnaud Blomme, Pierre Close, Olivier Renson, Matthias Van Hul, Patrice D Cani, Sebastian Klein, Alexandra Florin, Reinhard Büttner, Didier Cataldo, Philippe Delvenne, Ivan Nemazanyy, Caroline Wathieu, Alexandre Hego, Sandra Ormenese, Olivier Peulen, Marc Thiry, Roopesh Krishnankutty, Jair Marques, Alex von Kriegsheim, Alain Chariot.
      The role of phosphatidylcholine transporters such as Stard7 in intestinal cancer development is unknown. To explore this issue, we generated a mouse model lacking Stard7 in intestinal epithelial cells (IECs). Loss of Stard7 impaired mitochondrial Complex I activity, led to a severe metabolic and lipid reprogramming, enhanced mitochondrial ROS production and potentiated an mTORC1/ATF4 signature. As a result, levels of enzymes involved in serine biosynthesis were enhanced in Stard7-deficient IECs. We next assessed the consequences of Stard7 deficiency in both Wnt-dependent tumor initiation and in inflammation-driven tumor development. Strikingly, despite generating similar molecular signatures, Stard7 deficiency inhibited tumor development in Azoxymethane (AOM)/Dextran Sulfate Sodium (DSS)-treated mice but promoted Wnt-driven cancer initiation in the intestine. Apc+/Min mice lacking Stard7 in IECs developed more tumors in the distal colon as well as a specific microbiota signature. Collectively, our results suggest that the genetic status critically controls the effects of Stard7 deficiency on intestinal tumor development.
    Keywords:  Inflammation-driven Intestinal Cancers; STARD7; Wnt-driven Tumor Initiation; mTORC1
    DOI:  https://doi.org/10.1038/s44321-026-00409-5
  6. J Anat. 2026 Mar 31.
    Regional and age-related differences of crypts in the human large intestine: A 3-D surface metrology study.
    Michelle Raja, Chrissy Chow, Vladimir Grubisic, Brian Lee Beatty.
      Large intestinal crypts are tightly packed tubular indentations of the epithelium that act both as an absorptive surface and as a protective barrier. The crypt base consists of stem cells involved in the continuous regeneration of the intestinal surface. Thus, these crypts serve as the etiology of 95% of colon cancer and other colon-related pathologies such as inflammatory bowel disease. However, we still need a better understanding of these important structures in the human intestine. We collected and scanned four different regions of the large intestine (cecum, descending colon, sigmoid colon, and rectum) from 15 cadavers to study the surface characteristics of the crypts such as crypt density, opening area, depth, and volume. The cecum had a significantly larger crypt opening area when compared to the rectum. Further analysis showed that this difference is age dependent and only observed in older cadavers. The rectum also showed age-dependent changes in crypt depth. The varying morphology of crypts between the proximal/distal regions and individuals could be attributed to functional differences and naturally occurring adaptations to protect areas of the colon that are more susceptible to colon-related pathologies.
    Keywords:  colon; crypt; surface metrology
    DOI:  https://doi.org/10.1111/joa.70131
  7. Cell Stem Cell. 2026 Apr 02. pii: S1934-5909(26)00115-3. [Epub ahead of print]33(4): 546-570
    Reconstructing tumor tissues in 3D: From organoids to bioengineered niches.
    Verena J Kast, Fatemeh Navaee, Majid Halvaei, Stefan Liebau, Ninel Azoitei, Markus Breunig, Peter Loskill, Alexander Kleger.
      Tumor tissue engineering, integrating organoid, microfluidic, and biofabrication technologies, has opened new avenues for cancer research. Leveraging advanced bioengineering and biomaterials, these 3D models capture tumor architecture, cellular heterogeneity, biomechanics, and biochemical characteristics for disease modeling. Despite recognition that tissue organization influences malignancy and drug resistance, clinically oriented 3D approaches are rare, largely due to tumor microenvironment complexity, cellular plasticity, and interpatient heterogeneity. With a primary emphasis on gastrointestinal malignancies, we outline the capabilities and remaining limitations of organoid-based cancer models, including developmentally defined stem cell-derived systems that enable controlled early-stage modeling when premalignant material is scarce. We discuss patient-derived organoids as clinical avatars for therapy response prediction and summarize recent clinical trials that delineate key bottlenecks hindering routine implementation. Finally, we outline how innovations in biomaterial design, biofabrication, and microfluidics, benchmarking against patient data, and artificial intelligence are converging to better reconstruct tumor complexity, improve experimental tractability, and accelerate translation.
    Keywords:  AI; biofabrication; biomaterials; cancer; clinical translation; microfluidics; organoids
    DOI:  https://doi.org/10.1016/j.stem.2026.03.005
  8. Cancer Lett. 2026 Mar 28. pii: S0304-3835(26)00207-7. [Epub ahead of print]648 218444
    Fueling the fatal voyage: How metabolic plasticity empowers every step of cancer metastasis.
    Junhua Liao, Qing Ji.
      Metastasis is the primary cause of cancer mortality, a complex cascade driven by intertwined cellular adaptability and microenvironmental reprogramming. Although its mechanistic origins are multifactorial and context-dependent, metabolic plasticity, manifested by dynamic shifts in glycolysis, lipid oxidation, amino acid utilization, and mitochondrial bioenergetics, is increasingly recognized as a central orchestrator of metastatic progression. Emerging therapeutic strategies that target these metabolic adaptations, such as diet-exercise modulation, nanotechnology-enabled pathway inhibition, and metabolite neutralization, show promise for disrupting metastatic niches and enhancing immune surveillance. This review synthesizes the systemic and spatial roles of metabolism across the metastatic cascade to advocate a fundamental reconceptualization of metastasis as a metabolically programmable process. Future efforts should focus on mapping the dynamic heterogeneity of tumor metabolism to develop stage-specific, ecologically informed interventions against disseminated disease.
    Keywords:  Metabolic reprogramming; Metastatic cascade; Therapeutic strategies
    DOI:  https://doi.org/10.1016/j.canlet.2026.218444
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