bims-gerecp Biomed News
on Gene regulatory networks of epithelial cell plasticity
Issue of 2026–10–18
thirteen papers selected by
Xiao Qin, University of Oxford
  1. Reframing cancer therapy through tumor plasticity.
  2. Embracing macrophage complexity for research and translation.
  3. The expanding landscape of adult stem cell niches.
  4. Interpretable AI model reveals spatial codes of cell recruitment in tissues.
  5. MACC1 in colorectal cancer: a claim-level evidence audit from metastasis driver to proposed microenvironmental regulator.
  6. A self-amplifying IL-1β-CCL2 circuit between macrophages and cancer-associated fibroblasts drives colorectal cancer progression.
  7. Tracing the origins of CRISPR-Cas.
  8. RasGRP1 promotes efficient intestinal tuft cell differentiation.
  9. Creation of a High-Resolution, Continually Evolvable Lineage Tracer.
  10. Cell identity competes with surface tension to determine stromal organization in tumor spheroids beyond the CAF shell paradigm.
  11. Multiplexed single-cell reduced representation bisulfite sequencing for genome-wide DNA methylation profiling.
  12. Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury.
  13. Launching an independent research laboratory and scientific career: Tools for a rapidly changing landscape.
  1. Nat Cancer. 2026 Oct 14.
    Reframing cancer therapy through tumor plasticity.
    Akansha M Shah, Bryan P Marsh, Frederic J de Sauvage.
      A major barrier to cancer therapy is the emergence of drug-tolerant states that allow tumor cells to bypass the targeted pathway. These refractory states arise through reversible cellular plasticity, a process that also occurs during development and regeneration, giving rise to new lineages or phenotypes and restoring drug sensitivity upon treatment withdrawal. Over time, genetic mutations may accumulate, leading to permanent resistance. This paradigm expands the focus from targeting genetic mechanisms alone to also exploiting nongenetic vulnerabilities, driving clinical strategies that prevent or eliminate plastic and transformed populations. Here, we provide an overview of nongenetic plasticity mechanisms and their emerging clinical applications.
    DOI:  https://doi.org/10.1038/s43018-026-01232-0
  2. Immunity. 2026 Oct 16. pii: S1074-7613(26)00390-0. [Epub ahead of print]
    Embracing macrophage complexity for research and translation.
    Florent Ginhoux, Kevin Mulder, Sebastian Arcila-Barrera, Ido Amit.
      Macrophages are among the most versatile differentiated cell types in the body, serving as key regulators of tissue development, homeostasis, inflammation, repair, and immunity. Their functional diversity cannot be captured by fixed subsets, binary activation states, or single-marker definitions. Macrophage identity emerges instead from the integration of developmental origin, tissue niche, epigenetic history, local environmental cues, and disease-associated signals. Advances in single-cell genomics, spatial profiling, epigenomics, in vivo perturbation, and computational modeling now show that this behavior is organized through modular gene programs, so that any given macrophage state is best described as a weighted combination of program activities rather than a discrete label. We argue that embracing this modular architecture matters not only for annotation but for therapy: macrophage-directed interventions will require defining disease-associated states, identifying surface-accessible entry points into them, and rewiring the underlying programs with spatial and temporal precision.
    Keywords:  immune plasticity; immunotherapy; macrophage; macrophage reprogramming; macrophage-targeted therapies; modular gene programs; single-cell genomics; synthetic immunology; tissue microenvironment; translational immunology
    DOI:  https://doi.org/10.1016/j.immuni.2026.09.015
  3. Curr Opin Cell Biol. 2026 Oct 15. pii: S0955-0674(26)00085-2. [Epub ahead of print]103 102697
    The expanding landscape of adult stem cell niches.
    Madison Conte, Shiri Gur-Cohen.
      Adult stem cells reside within specialized niches that provide the local instructions needed to sustain regenerative fitness. Since the recognition that stem cells are not autonomous, the concept of the niche has widened from a local collection of supportive cells into a landscape of combinatorial microenvironments that stem cells help build rather than simply inhabit. Advances in molecular, genetic and deep imaging approaches and engineered organoid systems have shown these microenvironments to be far more diverse and dynamic than once appreciated. In this review, we consider how diverse cellular components build the stem cell niche across tissues, and how a growing set of non-cellular factors, from mechanical forces to metabolites, work alongside them to govern stem cell fate and regenerative capacity. We then ask how combinatorial niche interactions, spatial organization and reciprocal communication with stem cells support the diverse functions stem cells carry out across the lifespan. Understanding the niche as a dynamic and evolving system, rather than a fixed anatomical unit, promises insight into the fundamental mechanisms of developmental, regenerative, and pathologic stem cell function, with substantial implications for regenerative medicine.
    DOI:  https://doi.org/10.1016/j.ceb.2026.102697
  4. Nat Biomed Eng. 2026 Oct 13.
    Interpretable AI model reveals spatial codes of cell recruitment in tissues.
    Jia Yao, Ji Seon Shim, Kelly Wong, James Zhu, Yunhe Liu, Sung Wook Kang, Kelli McCord, Bryan M Burt, Jong Min Choi, Claire Lee, Idania Carolina Lubo Julio, Luisa Maren Solis Soto, Sharia Hernandez, Karen Colbert Maresso, Yang Liu, Yibo Dai, Tian Chu, Wei Lu, Khaja Khan, Paul F Mansfield, Hee-Jin Jang, William H Hudson, Tao Yue, Bing Zhang, Changwei Li, Linghua Wang, Hao Zhu, Hyun-Sung Lee, Tao Wang.
      Understanding which molecular signals recruit specific cells to precise tissue locations is fundamental to tissue biology, immunity and disease. Existing computational tools for spatially resolved transcriptomics (SRT) describe where cells reside but cannot explain why. Here we introduce SPACER, a fully interpretable multi-instance learning framework that decodes gene-level recruitment rules directly from SRT data. Applied to 37 SRT datasets spanning multiple human tumour types and mouse heart, SPACER achieved 4-21-fold improvement over existing methods in various tasks of recovering biologically meaningful recruitment signals. SPACER revealed (1) that tumour-expressed mucins are associated with physical barriers to T cell engagement, which predicts resistance to immune checkpoint inhibitors and patient prognosis, (2) that local antigen presentation is the dominant correlate of T cell engagement across cancer types and (3) that Cd4+ T cells are the dominant functional effectors in severe immune checkpoint inhibitor-induced myocarditis. These findings establish SPACER as a discovery engine for cellular recruitment biology with direct translational applications.
    DOI:  https://doi.org/10.1038/s41551-026-01804-6
  5. Clin Transl Oncol. 2026 Oct 15.
    MACC1 in colorectal cancer: a claim-level evidence audit from metastasis driver to proposed microenvironmental regulator.
    Rui Yang, Ruilan Deng, Hao Lin, Dongyang Huang, Ting Su, Xuhong Song, Bin Liang, Lingzhu Xie.
      Metastasis-associated in colon cancer 1 (MACC1) is an established regulator of colorectal cancer (CRC) progression and metastatic competence, but its proposed role in the tumour microenvironment is less certain. We performed a critical claim-level audit of original studies, classifying evidence by cancer-type match, manipulated cellular compartment, direct MACC1 perturbation, functional recipient cell endpoint, and immune context. The audit identifies convergent CRC evidence for tumour cell-intrinsic functions and inflammatory regulation of tumour cell MACC1. It also supports MACC1-dependent extracellular vesicle communication between CRC cells. By contrast, direct immune or stromal causality in CRC is not yet demonstrated: the available macrophage result is pharmacologically conditioned, functional immune and fibroblast mechanisms come from other cancers, and CRC immune associations are mainly computational. We define the conclusions permitted by each evidence class, specify clinical guardrails for prognostic and treatment-predictive claims, and propose two experiments that could establish or falsify cell-specific microenvironmental functions.
    Keywords:  Colorectal cancer; Evidence boundaries; Extracellular vesicles; MACC1; Metastasis; Tumour microenvironment
    DOI:  https://doi.org/10.1007/s12094-026-04588-y
  6. Cancer Lett. 2026 Oct 14. pii: S0304-3835(26)00660-9. [Epub ahead of print]661 218896
    A self-amplifying IL-1β-CCL2 circuit between macrophages and cancer-associated fibroblasts drives colorectal cancer progression.
    Yijin Wang, Weiwen Bao, Jiahang Li, Runze Jiang, Chengyao Jiang, Shenglong Li.
      Reciprocal interactions between immune and stromal cells are increasingly recognized as major determinants of colorectal cancer (CRC) progression. However, the specific macrophage and fibroblast states cooperating to establish and sustain a tumor-promoting microenvironment remains incompletely understood. Here, we identify a self-reinforcing inflammatory circuit linking monocyte-derived IL-1β+ macrophages with IL1R1+ cancer-associated fibroblasts (CAFs) in CRC. Integrated single-cell transcriptomic analyses of human CRC revealed a marked expansion of IL1B-associated inflammatory macrophages and IL1R1+ inflammatory CAFs, with their respective and combined transcriptional signatures associated with adverse clinical outcomes. Pseudotime analysis and Ms4a3 lineage tracing supported a predominantly monocyte-derived origin of IL-1β+ macrophages in the tumor microenvironment. Mechanistically, macrophage-derived IL-1β activated IL1R1 signaling in fibroblasts, promoting the acquisition and expansion of an inflammatory CAF state. Myeloid Il1b deletion or fibroblast-lineage Il1r1 deletion disrupted this interaction and suppressed tumor growth in vivo. In turn, IL1R1+ CAFs produced abundant CCL2, which recruited CCR2+ monocytes and replenished the IL-1β+ macrophage population. Fibroblast-lineage Ccl2 deletion, myeloid Ccr2 deletion, and CCL2 rescue experiments established the functional requirement of the CCL2-CCR2 axis for closure of this reciprocal circuit. Acquisition of the IL-1β+ inflammatory macrophage program was further supported by coordinated NF-κB and AP-1 activity, with RELA and JUN/FOS contributing to IL1B transcriptional regulation. Finally, therapeutic blockade of either IL-1β or CCL2 disrupted the macrophage-CAF circuit, increased intratumoral CD8+ T-cell responses, and enhanced the antitumor efficacy of anti-PD-1 therapy. Collectively, our findings establish the IL-1β-IL1R1-CCL2-CCR2 axis as a self-amplifying immune-stromal circuit that sustains a tumor-promoting and immunosuppressive microenvironment in CRC. By demonstrating that disruption of this circuit restores antitumor immune activity and sensitizes tumors to PD-1 blockade, our study provides a mechanistic and preclinical rationale for targeting IL-1β-CCL2-mediated macrophage-CAF crosstalk as a combination strategy to improve immunotherapy responses in CRC.
    Keywords:  Cancer-associated fibroblasts; Tumor immunology; Tumor microenvironment, Colorectal cancer; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.canlet.2026.218896
  7. Nat Biotechnol. 2026 Oct;44(10): 1617
    Tracing the origins of CRISPR-Cas.
    Dario Ummarino.
      
    DOI:  https://doi.org/10.1038/s41587-026-03353-4
  8. bioRxiv. 2026 Oct 01. pii: 2026.09.30.755407. [Epub ahead of print]
    RasGRP1 promotes efficient intestinal tuft cell differentiation.
    Lauren A Shechtman, Philippe Depeille, Eric Smith, Hong-Erh Liang, Tammie S Y Tam, Annabelle Duflock, Victor S Cortez, Claire E O'Leary, Alan Shen, Wouter Bos, Gabriela Fradiadakis, Alexis Combes, Hugo Gonzalez, Richard M Locksley, Jeroen P Roose.
      Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation. Rasgrp1 is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory, Rasgrp1 deficiency has little impact on tuft cell maturation, including expression of the Pou2f3 tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing Pou2f3 , that is largely lost upon Rasgrp1 deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in Rasgrp1 -deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation. Rasgrp1 -deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.
    DOI:  https://doi.org/10.64898/2026.09.30.755407
  9. bioRxiv. 2026 Oct 01. pii: 2026.09.30.754670. [Epub ahead of print]
    Creation of a High-Resolution, Continually Evolvable Lineage Tracer.
    Ryan N Delgado, Yichen Si, Rebecca E Andersen, ChangHee Lee, Henry L Bushnell, Jordan L Doman, Smriti Pandey, Alexander A Sousa, Emma R West, Carina E Dagotto, David R Liu, Constance L Cepko.
      Cellular diversity is required for the proper function of many tissues, including the retina, with its ∼130 cell types. 1-3 Previous lineage studies suggested that retinal progenitor cells (RPCs) generate cell diversity through biased cell divisions. 4-9 However, the extent to which each progenitor cell contributes to diversity, and the overarching rules governing the lineages of the collection of progenitor cells, are unknown. While classic lineage tracing approaches including retroviral labeling 4,6,10 , dye injection 11,12 , and time-lapse microscopy 13,14 were used to make the foundational insights regarding retinal lineages, they cannot be used to interrogate multigenerational lineages at scale. Here we describe the creation of an evolvable lineage tracing tool, "SCRIBBLE" for S equential C ombinatorial R ecorder for Iterative B arcode- B ased L ineage E volution. SCRIBBLE uses prime editor to iteratively edit a barcode sequence while preserving the order of genesis of clonally related progeny. Through a series of rationally designed high-throughput screens and design optimizations, we identified novel sequences that support a high level of barcode editing and information content. Evaluation of SCRIBBLE in embryonic mouse retina recapitulated known lineages in retinal development, demonstrating that SCRIBBLE is capable of high-resolution lineage tracing in a complex tissue.
    DOI:  https://doi.org/10.64898/2026.09.30.754670
  10. Proc Natl Acad Sci U S A. 2026 Oct 20. 123(42): e2624455123
    Cell identity competes with surface tension to determine stromal organization in tumor spheroids beyond the CAF shell paradigm.
    Claire Wilhelm.
      Cancer-associated fibroblasts (CAFs) are often found forming a peripheral stromal barrier around tumors. Here, this paradigm is challenged using microfabricated 3D cancer-CAF spheroid models combined with quantitative magnetic force tensiometry. A surface tension atlas is established for eight cancer cell lines, three CAF populations, and heterotypic tumor-CAF assemblies, spanning nearly two orders of magnitude. Surface tension is first shown to govern spheroid morphology and modulate drug response. Besides, CAFs consistently occupy the highest end of the surface tension hierarchy, predicting core rather than peripheral localization and directly challenging the shell paradigm. Yet confocal imaging reveals not only central accumulation but also complete CAF-tumor mixing, including in spheroids where cancer cells exhibit surface tensions nearly two orders of magnitude lower than CAFs. Surface tension alone therefore fails to predict CAF organization. Instead, the epithelial-to-mesenchymal transition (EMT) state of cancer cells emerges as a major determinant: epithelial-like tumors promote CAF core accumulation, whereas mesenchymal-like states favor persistent mixing. Peripheral CAF localization emerges only under restricted conditions combining high tumor cohesion and sequential stromal recruitment. Together, these results identify surface tension, EMT state, and assembly chronology as joint determinants of tumor-stroma architecture, revealing a context-dependent organization landscape rather than a universal CAF shell.
    Keywords:  cancer spheroids; cancer-associated fibroblasts; epithelial-mesenchymal transition; magnetic force tensiometry; surface tension
    DOI:  https://doi.org/10.1073/pnas.2624455123
  11. Nat Protoc. 2026 Oct 15.
    Multiplexed single-cell reduced representation bisulfite sequencing for genome-wide DNA methylation profiling.
    Fang Liu, Jian Huang, Yanhua Zheng, Lina Fu, Xuanlu Wu, Ningning Zhao, Yunfei Wang, Andreas Gnirke, Alexander Meissner, Xiaoxue Wang, Fan Zhang, Hongcang Gu.
      DNA methylation is a fundamental epigenetic modification that regulates gene expression, maintains genomic integrity and defines cellular identity. Conventional bulk sequencing methods, such as reduced-representation bisulfite sequencing (RRBS), have elucidated genome-wide methylation landscapes but do not reveal cell-to-cell variation, limiting insights into methylation heterogeneity during development, differentiation and disease. Here, we present multiplexed single-cell RRBS (Msc-RRBS), a streamlined and scalable protocol for parallel DNA methylation profiling of hundreds of individual cells. All enzymatic reactions, including cell lysis, restriction digestion, end repair and adapter ligation, are carried out in a single microwell, which eliminates the need for buffer exchange and minimizes DNA loss. Short, indexed adapters are used to efficiently remove adapter dimers and enable effective purification of library DNA by magnetic bead clean-up. The workflow supports the generation of sequencing libraries from single cells, pooled cells or sub-nanogram amounts of purified genomic DNA. The full workflow, from cell sorting to sequencing-ready libraries and data analysis, requires ~6 d for one or more 96-well plates. Msc-RRBS thus provides an efficient, reproducible and high-throughput approach for dissecting cell-to-cell DNA methylation heterogeneity across diverse biological and disease contexts. The experiments require basic molecular biology skills, and primary data processing can be performed by someone with limited bioinformatics training. More advanced analyses need additional computational expertise.
    DOI:  https://doi.org/10.1038/s41596-026-01452-9
  12. Cell Stem Cell. 2026 Oct 13. pii: S1934-5909(26)00389-9. [Epub ahead of print]
    Transplantation of Expanded Fetal Intestinal Progenitors Contributes to Colon Regeneration after Injury.
    Robert P Fordham, Shiro Yui, Nicholas R F Hannan, Christoffer Soendergaard, Alison Madgwick, Pawel J Schweiger, Ole H Nielsen, Ludovic Vallier, Roger A Pedersen, Tetsuya Nakamura, Mamoru Watanabe, Kim B Jensen.
      
    DOI:  https://doi.org/10.1016/j.stem.2026.10.008
  13. J Exp Med. 2026 Nov 02. pii: e20261370. [Epub ahead of print]223(11):
    Launching an independent research laboratory and scientific career: Tools for a rapidly changing landscape.
    Simon F Roy, Amy C Fan, Kelsey B Bennion, Mehdi Chaib, Hokyung K Chung, Katey S S Enfield, Yael Gruper, Shelley M Herbrich, Dongya Jia, Murad R Mamedov, Annapaola Mariniello, Raphaël Mattiuz, Ray Pillai, Marie R Siwicki, Alvaro Teijeira, Kate M Warde, Chien-Huan Weng, Sean A Yamada-Hunter, Jaroslav Zak, Zeda Zhang, Nir Hacohen.
      Scientific independence alone does not create a sustainable research program. Drawing on the 2026 Irving Cancer Immunology Symposium, we offer practical strategies for navigating uncertainty and limited resources to build a coherent research program and resilient team across funding systems.
    DOI:  https://doi.org/10.1084/jem.20261370
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