bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2026–01–11
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases.
  2. Hypoxia Affects Stem Cell Fate in Patient-Derived Ileum Enteroids in a HIF-1α-Dependent Manner.
  3. Integrated Microfluidic Platform for High-Throughput Generation of Intestinal Organoids in Hydrogel Droplets.
  4. p53 increases phospholipid headgroup scavenging in senescence.
  5. A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis.
  6. Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID.
  7. FOXA2/ALDOB axis modulation of fatty acid beta-oxidation influences irinotecan resistance in colorectal cancer.
  8. SOX2 confers tumour permissiveness in a specific skin progenitor population.
  9. Framework for cancer evolution profiling and interception in colorectal cancer: ASCEND-CRC program.
  10. Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells.
  11. UBR5 regulates the progression of colorectal cancer cells through Snail-induced epithelial-mesenchymal transition.
  12. Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer.
  13. Dictionary of human intestinal organoid responses to secreted niche factors at single cell resolution.
  14. Single-cell resolution of an open chromatin signature in persister tumor cells.
  15. Colorectal microenvironment determines the prognosis of colorectal cancer.
  1. Nat Commun. 2026 Jan 03.
    Tight junction-high and CDH17-positive cell population is the source of colorectal cancer liver metastases.
    Daniel Alvarez-Villanueva, María Maqueda, Dina Harti, Eric Canton, Evelyn Andrades, Joan Bertran, María Martínez-Iniesta, Laura Solé, Violeta García-Hernández, Ángela Montoto, Teresa Lobo-Jarne, Josune Alonso-Marañón, Patricia Herrero-Molinero, Mónica Larrubia-Loring, Anna Tramuns, Kieran Wynne, Indrani Bera, David Matallanas, Alberto Villanueva, Anna Bigas, Mar Iglesias, Lluís Espinosa.
      Colorectal cancer (CRC) frequently develops aggressive metastatic disease, yet the cellular features that enable dissemination remain poorly defined. IKKα, a kinase traditionally linked to stress and inflammatory signaling, is increasingly recognized for broader functions in cancer. Here, we show that loss of IKKα unexpectedly promotes metastasis in CRC. Using patient-derived organoids, we find that genetic or pharmacological inhibition of IKKα stabilizes tight-junction components, leading to the emergence of compact epithelial clusters with a heightened ability to spread and colonize the liver. Single-cell transcriptomics reveals expansion of a CDH17⁺/CLDN2⁺ epithelial subpopulation that dominates metastatic lesions, a finding validated by tissue staining. Remarkably, disrupting CLDN2 completely eliminates the metastatic advantage caused by IKKα loss. These results identify a metastasis-competent epithelial state driven by tight-junction remodeling and uncover a vulnerable node that may be exploited therapeutically in aggressive colorectal cancer.
    DOI:  https://doi.org/10.1038/s41467-025-68169-3
  2. Cells. 2025 Dec 23. pii: 31. [Epub ahead of print]15(1):
    Hypoxia Affects Stem Cell Fate in Patient-Derived Ileum Enteroids in a HIF-1α-Dependent Manner.
    Zina M Uckeley, Carmon Kee, Carlos Ramirez, Victoria Karaluz, Ashwini K Sharma, Josmar Polanco, Freddie D Ortiz Martinez, Christopher I Mederos, Sorin O Jacobs, Ingrid J Groose, James M Ramsden, Carl Herrmann, Megan L Stanifer, Steeve Boulant.
      The intestinal epithelium maintains tissue homeostasis through a dynamic balance of stem cell proliferation and differentiation. This process is spatially regulated along the crypt-villus axis, with intestinal stem cells in the crypt regions proliferating and progenitor cells differentiating as they migrate toward the villus tips. Because the lumen of the gut contains very low levels of oxygen (i.e., hypoxia), an oxygen gradient is established within the crypt-villus axis, placing the crypt regions under normoxic conditions while the villus tips reside under hypoxic conditions. Hence, intestinal epithelial cells encounter distinct oxygen microenvironments throughout their life span as they migrate along the crypt-villus structures during their proliferation and differentiation process. To investigate how oxygen availability influences intestinal stem cell proliferation and differentiation, we cultured patient-derived human ileum organoids (i.e., enteroids) under normoxic (20% oxygen) or hypoxic (1% oxygen) conditions. Under hypoxia, enteroid growth was reduced, and expression of several stem cell markers, such as OLFM4 and LGR5, was decreased. Bulk and single-cell RNA sequencing revealed that hypoxia suppressed Wnt signaling pathways and reduced stem cell activity. Importantly, pharmacological stabilization of HIF-1α under normoxic conditions recapitulated the hypoxia-induced loss of stemness, demonstrating that HIF-1α is a key mediator of oxygen-dependent stem cell regulation in enteroids. These findings establish that physiological hypoxia in the intestinal epithelium directly regulates stem cell fate through HIF-1α stabilization, providing mechanistic insight into how oxygen availability along the crypt-villus structures controls intestinal homeostasis.
    Keywords:  enteroids; epithelium; hypoxia; ileum; intestinal stem cells; organoid formation
    DOI:  https://doi.org/10.3390/cells15010031
  3. Adv Sci (Weinh). 2026 Jan 05. e16507
    Integrated Microfluidic Platform for High-Throughput Generation of Intestinal Organoids in Hydrogel Droplets.
    Barbora Lavickova, Hannah Kronabitter, Mar Cervera-Negueruela, Eylul Ceylan, Laura Benito-Zarza, Rubén López-Sandoval, Irineja Cubela, J Gray Camp, Jose L Garcia-Cordero.
      Organoid research offers valuable insights into human biology and disease, but reproducibility and scalability remain significant challenges, particularly for epithelial organoids. Here, we present an integrated microfluidic platform that addresses these limitations by enabling high-throughput generation of uniform hydrogel microparticles embedded with primary-derived human adult intestinal stem cells. Our platform includes a cell distribution system for homogeneous cell encapsulation and a microfluidic oil-removal module for efficient particle transfer to aqueous media. We demonstrate the successful culture and differentiation of both healthy- and tumor-derived intestinal organoids within these microparticles, achieving high homogeneity and reproducibility. This integrated microfluidic approach holds promise for scalable and standardized organoid production, with potential applications in drug screening, disease modeling, and personalized medicine. encapsulation; high-throughput; hydrogels; microfluidics; organoids.
    DOI:  https://doi.org/10.1002/advs.202516507
  4. Nat Cell Biol. 2026 Jan 07.
    p53 increases phospholipid headgroup scavenging in senescence.
    Jossie J Yashinskie, Xianbing Zhu, Grace H McGregor, Karl A Wessendorf-Rodriguez, Katrina Paras, Julia S Brunner, Benjamin T Jackson, Abigail Xie, Richard Koche, Christian M Metallo, Lydia W S Finley.
      Changes in cell state are often accompanied by altered metabolic demands, and homeostasis depends on cells adapting to their changing needs. One major cell state change is senescence, which is associated with dramatic changes in cell metabolism, including increases in lipid metabolism, but how cells accommodate such alterations is poorly understood. Here we show that the transcription factor p53 increases recycling of the lipid headgroups required to meet the increased demand for membrane phospholipids during senescence. p53 activation increases the supply of phosphoethanolamine, an intermediate in the Kennedy pathway for de novo synthesis of phosphatidylethanolamine, in part by increasing lipid turnover and transactivating genes involved in autophagy and lysosomal catabolism that enable membrane turnover. Disruption of phosphoethanolamine conversion to phosphatidylethanolamine is well tolerated in the absence of p53 but results in dramatic organelle remodelling and perturbs growth and gene expression following p53 activation. Consistently, CRISPR-Cas9-based genetic screens reveal that p53-activated cells preferentially depend on genes involved in lipid metabolism and lysosomal function. Together, these results reveal lipid headgroup recycling to be a homeostatic function of p53 that confers a cell-state-specific metabolic vulnerability.
    DOI:  https://doi.org/10.1038/s41556-025-01853-0
  5. Cancers (Basel). 2025 Dec 23. pii: 44. [Epub ahead of print]18(1):
    A Tissue Renewal-Based Mechanism Drives Colon Tumorigenesis.
    Ryan M Boman, Gilberto Schleiniger, Christopher Raymond, Juan Palazzo, Anne Shehab, Bruce M Boman.
      Our Goal is to identify how colorectal cancer (CRC) arises in the single-layered cell epithelium (simple columnar epithelium) that lines the luminal surface of the large intestine. Background: We recently reported that the dynamic organization of cells in colonic epithelium is encoded by five biological rules and conjectured that colon tumorigenesis involves an autocatalytic tissue renewal reaction. Introduction Our objective was to define how altered crypt turnover explains tissue disorganization that leads to adenoma morphogenesis and CRC. Hypothesis: Changes in rate of tissue renewal-based cell polymerization leads to epithelial expansion and tissue disorganization during adenoma histogenesis. Methods: Accordingly, we created a computational model that considers the structure of colonic epithelium to be a polymer of cells and that tissue renewal is autocatalytic. Indeed, self-renewal of stem cells in colonic crypts continuously produces cells that act like monomers to form a polymer of cells (an interconnected, continuous cell sheet) in a polymerization-based process. Our model is a system of nonlinear differential equations that simulates changes in human crypt cell population dynamics. Results: We investigated how changes occur in the proportion of different cell types during adenoma development in FAP patients. The results show premalignant colonic crypts have a decreased rate of tissue renewal due to APC-mutation. Discussion: This slower rate of cell polymerization causes a rate-limiting step in the crypt renewal process that expands the proliferative cell population size. Conclusions: Our findings provide a mechanism that explains how a prolonged rate of crypt renewal leads to tissue disorganization with local epithelial expansion, infolding, and contortion during adenoma morphogenesis.
    Keywords:  APC gene; colorectal cancer; familial adenomatous polyposis; systems biology; tissue renewal
    DOI:  https://doi.org/10.3390/cancers18010044
  6. Dev Cell. 2026 Jan 05. pii: S1534-5807(25)00747-6. [Epub ahead of print]
    Impaired VLCFA-peroxisome-mediated intestinal epithelial repair causes gastrointestinal sequelae of long COVID.
    Man Wang, Yi Chen, Ming Guo, Pengzhi Xie, Xinzhe Zhao, Shulin Chen, Yian Deng, Rui Hu, Qianyi Wan, Juanyu Zhou, Zhuzhen Zhang, Ke Lan, Haiyang Chen, Yuan Liu.
      Long COVID has emerged as a significant public health challenge with no effective treatments currently available, yet the pathophysiological mechanisms underlying its persistent gastrointestinal (GI) symptoms remain poorly understood. Here, integrating clinical data with transgenic animal models, we discover a critical role for impaired intestinal epithelial repair in the local intestinal etiology of long COVID. Mechanistically, we show that intestinal SARS-CoV-2 reservoirs disrupt very-long-chain fatty acid (VLCFA) metabolism, suppressing activation of peroxisome proliferator-activated receptor (PPAR) signaling and reducing peroxisome abundance. This disruption impairs intestinal stem cell differentiation and epithelial regeneration, resulting in prolonged GI symptoms including diarrhea, inflammation, and microbiota dysbiosis. Importantly, the FDA-approved sodium phenylbutyrate (NaPB) and fenofibrate alleviate these symptoms by promoting peroxisome proliferation and restoring epithelial repair. These findings provide insights into the GI pathogenesis of long COVID and highlight the therapeutic potential of enhancing the VLCFA-PPAR-peroxisome axis to mitigate persistent GI complications.
    Keywords:  GI sequelae; NaPB; PPAR; SARS-CoV-2 pathogenesis; fenofibrate; intestinal epithelial repair; intestinal stem cell; long COVID; peroxisome; very-long-chain fatty acid
    DOI:  https://doi.org/10.1016/j.devcel.2025.12.003
  7. Biochim Biophys Acta Mol Cell Res. 2026 Jan 07. pii: S0167-4889(26)00004-2. [Epub ahead of print] 120108
    FOXA2/ALDOB axis modulation of fatty acid beta-oxidation influences irinotecan resistance in colorectal cancer.
    Yuan Jin, Chao Hu, Dianfu Pang.
      Colorectal cancer (CRC) exhibits altered lipid metabolism associated with therapy resistance. FOXA2, a lipid metabolism activator, mediates fatty acid β-oxidation in CRC, but its role in irinotecan (CPT-11) resistance remains unclear. Through bioinformatics analysis, clinical sample assessment, and cell line validation, we confirmed the expression of FOXA2 in CRC. The impact of FOXA2 on the viability and CPT-11 sensitivity of CRC cells was tested via CCK-8 assay. DNA damage was evaluated using the comet assay and monitoring of γ-H2AX foci. Assay kits determined the concentrations of triglycerides, cholesterol, and phospholipids, as well as the rate of fatty acid β-oxidation. Protein expression related to lipid metabolism (ACLY, SCD1) was identified by WB. Bioinformatic tools were used to analyze the potential transcriptional control of Aldolase B (ALDOB) by FOXA2 and to scrutinize ALDOB expression in CRC. The molecular interaction was substantiated by dual-luciferase and CHIP assays. IHC was performed on an xenograft tumor model in mice to measure FOXA2, ALDOB, and Ki67 expression. Oil Red O staining was applied to detect triglyceride presence, and TUNEL was used to gauge apoptosis. The results showed that FOXA2 overexpression correlated with CPT-11 resistance in CRC. FOXA2 transcriptionally activated ALDOB, enhancing fatty acid β-oxidation and suppressing drug sensitivity. FOXA2 inhibition sensitized CRC cells to CPT-11 in vitro/vivo, while ALDOB overexpression restored resistance. These findings indicate that FOXA2 promotes CPT-11 resistance by upregulating ALDOB-mediated fatty acid β-oxidation. Targeting the FOXA2/ALDOB axis may overcome chemoresistance in CRC.
    Keywords:  ALDOB; Colorectal cancer; FOXA2; Fatty acid beta-oxidation; Irinotecan resistance
    DOI:  https://doi.org/10.1016/j.bbamcr.2026.120108
  8. Nat Commun. 2026 Jan 08. 17(1): 304
    SOX2 confers tumour permissiveness in a specific skin progenitor population.
    Patricia P Centeno, Christopher Chester, Georgios Kanellos, Catriona A Ford, Patrizia Cammareri, Gareth J Inman, Thomas Jamieson, Rachel A Ridgway, Richard Marais, Andrew D Campbell, Owen J Sansom.
      The continuous renewal of the skin relies on stem and progenitor cells, yet their differential susceptibility to oncogenic mutations in cutaneous squamous cell carcinoma (cSCC) remains unclear. Rapid cSCC develops in melanoma patients on BRAF inhibitors due to paradoxical MAPK activation. To model this in mice, we use two complementary approaches: HRASG12V with a BRAF inhibitor to mimic paradoxical MAPK activation, and BRAFV600E, which drives MAPK hyperactivation without further treatment. We target these mutations to the interfollicular stem and differentiation-committed progenitors of the basal epidermis. While stem cells rapidly form tumours, progenitors exhibit long-latency resistance despite retaining mutations and repopulating the basal layer. Ultimately, both populations produce similar tumours, showing a shared transformation process. However, SOX2 is uniquely upregulated in progenitor-derived tumours and is expressed in 20% of human cSCC, indicating it might mark tumours arising from committed progenitors. Here, we show that SOX2 overexpression, along with MAPK activation, in progenitors induces a stem-like state and renders this otherwise resistant population permissive to rapid transformation.
    DOI:  https://doi.org/10.1038/s41467-025-66251-4
  9. Cancer Cell. 2026 Jan 08. pii: S1535-6108(25)00550-1. [Epub ahead of print]
    Framework for cancer evolution profiling and interception in colorectal cancer: ASCEND-CRC program.
    Salvador Alonso, Kanwal Raghav, Van K Morris, Kristin Alfaro-Munoz, Tanios Bekaii-Saab, Timothy L Cannon, Ryan B Corcoran, Nicholas Duesbery, Manju George, David Hsu, Christopher Lieu, Anirban Maitra, Dipen Maru, Jasmine A McQuerry, David Menter, Jonathan Mizrahi, Kimmie Ng, Aparna Parikh, Kunal Rai, Michelle C Sangar, Kenna R Shaw, John Paul Shen, John H Strickler, Ann D Feehan, Alda L Tam, Guglielmo Vetere, Rona Yaeger, Ying Yuan, Xiling Shen, Andrea H Bild, Scott Kopetz.
      Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.
    DOI:  https://doi.org/10.1016/j.ccell.2025.12.016
  10. Nat Metab. 2026 Jan 08.
    Obesity impairs gut repair via AFABP-mediated iron overload in intestinal stem cells.
    Zhiming Liu, Yi Chen, Jinhua Yan, Yu Yuan, Qianyi Wan, Rui Zhao, Fang Fu, Xinxin Fan, Yawen Deng, Xiaoxin Guo, Haiou Chen, Xingzhu Liu, Jinbao Ye, Haiyang Chen.
      Obesity impairs the function of multiple organs, but its effect on gut regeneration remains poorly defined. Here, we show that adipocyte fatty acid-binding protein (AFABP), an adipokine involved in fatty acid transport, impedes intestinal repair by disrupting iron homeostasis in intestinal stem cells (ISCs). Mechanistically, elevated AFABP secretion in obesity binds to plasma transferrin, leading to iron accumulation in ISCs. This accumulation disrupts peroxisome-mediated ISC differentiation, which is essential for intestinal repair following injury. Notably, AFABP overexpression in adipocytes of lean mice impedes ISC differentiation and gut repair. Conversely, AFABP depletion or the administration of AFABP inhibitors, iron chelators or peroxisome activators effectively mitigates colitis in obese animals. Overall, our findings reveal a mechanistic link between obesity and intestinal repair, and identify the adipose-gut axis as a therapeutic target for obesity-associated intestinal disorders.
    DOI:  https://doi.org/10.1038/s42255-025-01425-4
  11. Genes Dis. 2026 Mar;13(2): 101679
    UBR5 regulates the progression of colorectal cancer cells through Snail-induced epithelial-mesenchymal transition.
    Xinyue Zhao, Ruiying Liu, Zhihui Han, Zehao Li, Ling Mei, Yuyang Liu, Xueqi Fu, Yue Jin.
      Snail is a core inducer of epithelial-to-mesenchymal transition. Here, we show that UBR5 promotes ubiquitin-mediated degradation of Snail and regulates the progression of colorectal cancer cells through its E3 ubiquitin ligase function. UBR5 specifically binds to Snail in vitro, but not Slug, and its degradation depends on snail phosphorylation. Depletion of endogenous UBR5 causes Snail protein accumulation, epithelial-to-mesenchymal transition, and tumor invasion in colorectal cancer cells. Conversely, the overexpression of UBR5 reduces Snail protein abundance and cellular invasiveness. The activity-deficient mutant UBR5 C2768S disrupts its binding and degradation to Snail, thereby losing the ability to regulate epithelial-to-mesenchymal transition in colorectal cancer cells. UBR5 is lowly expressed in human colorectal cancer versus normal tissues, and high UBR5 levels correlate with favorable prognosis, suggesting that UBR5 sustains the epithelial state and inhibits cancer progression. These findings establish the UBR5-Snail axis as a mechanism of post-translational regulation of epithelial-to-mesenchymal transition and colorectal cancer metastasis.
    Keywords:  Colorectal cancer; EMT; Metastasis; Snail; UBR5
    DOI:  https://doi.org/10.1016/j.gendis.2025.101679
  12. Mol Cancer Ther. 2026 Jan 09.
    Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer.
    Jin Suk Park, Carson Kenum, Lan He, Abdul G Khan, Mary Ann Pohl, Thomas E White, Sreekumar R Kodangattil, Charles M Rudin, Paul J Balderes, Ivo C Lorenz, Joan Massagué, Karuna Ganesh.
      Effective treatment for metastatic cancer has remained elusive due to the persistence of drug-resistant metastasis stem cells (MetSCs) that drive relapse. MetSCs are tumor cell subpopulations enriched for their ability to reinitiate and sustain metastatic growth, displaying phenotypic plasticity and resistance to chemotherapy. These cells express the L1 cell adhesion molecule (L1CAM), a transmembrane protein detected in numerous human solid tumor types and at multiple disseminated organ sites. As a selective surface marker of MetSCs, L1CAM is a promising candidate for molecularly targeted drugs aimed at eliminating metastases, yet strategies to date have not achieved clinical success. Here, we develop antibody-drug conjugates (ADCs) to deliver highly toxic PNU-159682 payloads to L1CAM-expressing cells. We report the generation of monoclonal antibodies (mAb) with high binding affinity, specificity and selectivity for the human L1CAM extracellular domain. Optimized L1CAM-targeting mAbs were conjugated to PNU-159682 to generate ADC variants with both cleavable and non-cleavable linkers, with an average drug-antibody-ratio (DAR) of four. ADCs derived from three antibodies targeting various epitopes of the L1CAM extracellular portion potently killed cells exhibiting varying levels of surface L1CAM expression. L1CAM ADCs given as monotherapy resulted in robust tumor control and extended survival in mice harboring subcutaneous L1CAM+ xenografts or L1CAM+ lung metastases from triple-negative basal breast cancer and lung adenocarcinoma. Safety analyses with mouse cross-reactive antibodies indicate a feasible therapeutic window. Our findings offer strong proof-of-concept to support the preclinical development of these novel L1CAM ADCs as therapeutic agents for advanced solid tumors.
    DOI:  https://doi.org/10.1158/1535-7163.MCT-25-1184
  13. Nat Commun. 2026 Jan 09.
    Dictionary of human intestinal organoid responses to secreted niche factors at single cell resolution.
    Meghan M Capeling, Bob Chen, Kazeera Aliar, Elisa Penna, Veronica Ibarra Lopez, Conrad Foo, Sandra Rost, Loryn Holokai, Xinming Tong, Devan Phillips, Caden Sweet, Jing Li, Sharmila Chatterjee, Elizabeth Skippington, Zora Modrusan, Lisa M McGinnis, Runmin Wei, Mary Keir, Orit Rozenblatt-Rosen, Michelle B Chen.
      The intestinal epithelium plays a critical role in health and disease, yet the impact of microenvironmental cues in diseased contexts, such as inflammatory bowel disease (IBD), remains poorly defined. To address this gap, we first benchmarked human colonic organoid injury models against IBD tissue and established a disease-relevant model of inflammation using inflammatory cytokines. Using this system, we built a dictionary of epithelial responses to 79 secreted niche factors at single cell resolution via donor-pooled, multiplexed single cell RNA-sequencing. The comprehensive nature of our atlas allowed us to map relationships between perturbations, infer the function of less characterized ligands, and identify cell type-specific perturbed pathways. Finally, we established the relevance of organoid-derived gene programs by mapping them to single cell and spatial atlases of human IBD tissue. Our resource offers a global view of epithelial responses to microenvironmental cues, offering insights into epithelial homeostasis and repair mechanisms in IBD.
    DOI:  https://doi.org/10.1038/s41467-025-68247-6
  14. Cell Rep. 2026 Jan 02. pii: S2211-1247(25)01480-9. [Epub ahead of print]45(1): 116708
    Single-cell resolution of an open chromatin signature in persister tumor cells.
    Mihai Gabriel Dumbrava, Wazim Mohammed Ismail, Leticia Sandoval, Amelia Mazzone, Syed Mohammed Musheer Aalam, Megan L Ritting, Xiaonan Hou, Yiwen Xie, Sierra Hamernick, Chunling Hu, Fergus J Couch, Shariska P Harrington, Scott H Kaufmann, Nagarajan Kannan, S John Weroha, Alexandre Gaspar-Maia.
      Cancer can recur when a subset of tumor cells, termed persister cells, survive therapy and re-enter the cell cycle. Through single-nucleus multi-omic profiling (single-nucleus RNA sequencing [snRNA-seq] and single-nucleus assay for transposase-accessible chromatin by sequencing [snATAC-seq]) of (1) non-malignant fallopian tubes and (2) treatment-naive and (3) neoadjuvant-chemotherapy-treated samples from patients with high-grade serous ovarian carcinoma (HGSOC), we identify a persister cell signature defining the chemotherapy-tolerant state. The chromatin features of the signature are detectable in residual tumors after treatment and in treatment-naive tumors from patients who later develop resistance. Further, the signature independently predicts chemotherapy response in metastatic HGSOC and patient-derived xenograft models. Cells enriched in the persister state display a subset of genes primed for expression before treatment, an altered cell cycle, and stress-response programs associated with poor clinical outcomes. These findings suggest that an intrinsic regulatory program primes tumor cells toward chemotherapy tolerance and reveal new vulnerabilities that can be targeted with chromatin-modifying agents to prevent cancer recurrence.
    Keywords:  CP: cancer; chemotherapy resistance; chromatin accessibility; high-grade serous ovarian carcinoma; open chromatin; patient-derived xenografts; persister cell signature; single-nucleus multi-omics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116708
  15. Exp Mol Med. 2026 Jan 07.
    Colorectal microenvironment determines the prognosis of colorectal cancer.
    Yeong Hak Bang, Ji Hye Choi, Kyunghee Park, Boram Lee, Kyung Yeon Han, Dae Hee Pyo, Yong Beom Cho, Tae-You Kim, Kyu Joo Park, Seung-Bum Ryoo, Sung-Bum Kang, Chang Sik Yu, Jaeim Lee, Kil-Yong Lee, Kyu-Tae Kim, Jin-Young Lee, Hoang Bao Khanh Chu, Nameeta Shah, Shashank Gupta, Pranali Sonpatki, Young-Joon Kim, Woong-Yang Park.
      Here we aimed to evaluate the feasibility of distinguishing colorectal microenvironments that support cancer cell growth from those that do not. We hypothesized that patients whose non-tumor-bearing tissue (NBT) obtained from the furthest margins of resected cancer specimens resembled the tumor had a poorer prognosis. Patients with colorectal cancer were divided into groups with tumor-supportive (TSM) or healthy microenvironments using bulk RNA sequencing data from 273 paired NBT and tumor samples. Patients in the TSM group exhibited significantly poorer 5-year recurrence-free survival and overall survival compared with those in the healthy microenvironment group. Pathway and 16S rRNA sequencing analyses revealed that NBT and tumors from the TSM group shared a microbiome composition, along with decreased pathway activity related to microvilli maintenance and flavonoid or vitamin metabolic processes. Single-cell RNA sequencing uncovered upregulated interactions between IL1Bhigh neutrophils and OLFM4+ epithelial cells in NBTs from the TSM group, as well as organized microniches in TSM tumors, featuring interactions between EMP1high epithelial cells, IL1Bhigh neutrophils and GZMKhigh CD8+ T cells. Collectively, the colorectal microenvironment can serve as a prognostic biomarker to effectively predict cancer invasiveness and tumor-promoting inflammation. Maintaining a healthy colorectal mucosal microenvironment, potentially through dietary intervention, is crucial.
    DOI:  https://doi.org/10.1038/s12276-025-01599-7
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