bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–11–09
fourteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Lymph node environment drives FSP1 targetability in metastasizing melanoma.
  2. WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer.
  3. Targeting FSP1 triggers ferroptosis in lung cancer.
  4. Epigenetically driven and early immune evasion in colorectal cancer evolution.
  5. TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
  6. Integrative multi-omics of matched primary and liver metastatic colorectal cancer organoids identifies putative molecular targets.
  7. Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.
  8. Clinical implications of whole genome sequencing in metastatic colorectal cancer.
  9. Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
  10. Cytoplasmic p21 promotes stemness of colon cancer cells via activation of the NFκB pathway.
  11. Effect of chemotherapy on passenger mutations in metastatic colorectal cancer.
  12. Neutrophil extracellular traps regulate LDHA expression to promote colorectal cancer liver metastasis.
  13. A novel paradigm for single-cell annotation in stem cell research.
  14. Timing and mechanisms of immune evasion in colorectal cancers.
  1. Nature. 2025 Nov 05.
    Lymph node environment drives FSP1 targetability in metastasizing melanoma.
    Mario Palma, Milena Chaufan, Cort B Breuer, Sebastian Müller, Marie Sabatier, Cameron S Fraser, Krystina J Szylo, Mahsa Yavari, Alanis Carmona, Mayher Kaur, Luiza Martins Nascentes Melo, Feyza Cansiz, June Monge-Lorenzo, Midori Flores, Eikan Mishima, Toshitaka Nakamura, Bettina Proneth, Marcos Labrado, Yanshan Liang, Nicole Cayting, Lan Zheng, Tatiana Cañeque, Ludovic Colombeau, Adam Wahida, José Pedro Friedmann Angeli, Alpaslan Tasdogan, Sheng Hui, Raphaël Rodriguez, Marcus Conrad, Nathan E Reticker-Flynn, Jessalyn M Ubellacker.
      Ferroptosis has emerged as an actionable target to eliminate therapy-resistant and metastatic cancers1. However, which ferroptosis surveillance systems may offer a therapeutic window to leverage redox maladaptation in cancer remains unclear. In melanoma, glutathione peroxidase 4 (GPX4) impedes ferroptosis during haematogenous metastasis, but is dispensable during lymphatic metastasis2. Here, using a metastatic mouse melanoma model selected for lymph node metastasis, we show that lymph-node-derived metastatic cells exhibit markedly diminished expression of glutamate-cysteine ligase (GCLC) and reduced glutathione (GSH) levels relative to their parental counterparts. This metabolic shift occurs within the hypoxic lymphatic niche. Under comparable low-oxygen conditions, GPX4 undergoes ubiquitination and proteasomal degradation. In response, lymph node metastatic cells acquire increased reliance on ferroptosis suppressor protein 1 (FSP1), which is localized with perinuclear lysosomes. These findings reveal that the reduced reliance on the GPX4 axis enables melanoma cells to shift toward FSP1 dependency. Notably, intratumoural monotherapy with selective FSP1 inhibitors (viFSP1 and FSEN1) effectively suppresses melanoma growth in lymph nodes, but not in subcutaneous tumours, emphasizing a microenvironment-specific dependency on FSP1. Thus, targeting FSP1 in the lymph nodes holds strong potential for blocking melanoma progression.
    DOI:  https://doi.org/10.1038/s41586-025-09709-1
  2. EMBO Rep. 2025 Nov 04.
    WNT signalling promotes NF-κB activation and drug resistance in KRAS-mutant colorectal cancer.
    Bojie Cong, Evangelia Stamou, Kathryn Pennel, Teena Thakur, Molly Mckenzie, Amna Matly, Kathryn Gilroy, Harshit Shah, Sindhura Gopinath, Joanne Edwards, Ross Cagan.
      Approximately 40% of colorectal cancer (CRC) cases are characterised by KRAS mutations, rendering them insensitive to most therapies. While the reasons for this resistance remain incompletely understood, one key aspect is genetic complexity: in CRC, oncogenic KRAS is most commonly paired with mutations that alter WNT and P53 activities ("RAP"). Here, we demonstrate that elevated WNT activity upregulates canonical NF-κB signalling in both Drosophila and human RAS mutant tumours. This upregulation was enhanced by P53 loss and required immune-associated factors Toll-1 and Toll-9. These changes reduced efficacy of Ras pathway-targeting drugs such as trametinib due to NF-κB-dependent enhancement of the glucuronidation detoxifying pathway, likely through modulating gene transcription and glucose uptake. Inhibiting WNT activity pharmacologically suppressed trametinib resistance in RAP tumours and more genetically complex 'patient avatar' models. The efficacy of WNT/MEK drug inhibitor combinations was further enhanced by targeting brm, shg, ago, rhoGAPp190, and upf1, potential biomarkers for patients responsive to this dual therapeutic approach. These findings shed light on how genetic complexity impacts drug resistance and a strategy to overcome it.
    Keywords:   Drosophila ; Colorectal Cancer; Glucuronidation; NF-κB; WNT
    DOI:  https://doi.org/10.1038/s44319-025-00588-1
  3. Nature. 2025 Nov 05.
    Targeting FSP1 triggers ferroptosis in lung cancer.
    Katherine Wu, Alec J Vaughan, Jozef P Bossowski, Yuan Hao, Aikaterini Ziogou, Seon Min Kim, Tae Ha Kim, Mari N Nakamura, Ray Pillai, Mariana Mancini, Sahith Rajalingam, Mingqi Han, Toshitaka Nakamura, Lidong Wang, Suckwoo Chung, Diane Simeone, David Shackelford, Yun Pyo Kang, Marcus Conrad, Thales Papagiannakopoulos.
      Emerging evidence indicates that cancer cells are susceptible to ferroptosis, a form of cell death that is triggered by uncontrolled lipid peroxidation1-3. Despite broad enthusiasm about harnessing ferroptosis as a novel anti-cancer strategy, whether ferroptosis is a barrier to tumorigenesis and can be leveraged therapeutically remains unknown4,5. Here, using genetically engineered mouse models of lung adenocarcinoma, we performed tumour-specific loss-of-function studies of two key ferroptosis suppressors, GPX46,7 and ferroptosis suppressor protein 1 (FSP1)8,9, and observed increased lipid peroxidation and robust suppression of tumorigenesis, suggesting that lung tumours are highly sensitive to ferroptosis. Furthermore, across multiple pre-clinical models, we found that FSP1 was required for ferroptosis protection in vivo, but not in vitro, underscoring a heightened need to buffer lipid peroxidation under physiological conditions. Lipidomic analyses revealed that Fsp1-knockout tumours had an accumulation of lipid peroxides, and inhibition of ferroptosis with genetic, dietary or pharmacological approaches effectively restored the growth of Fsp1-knockout tumours in vivo. Unlike GPX4, expression of FSP1 (also known as AIFM2) was prognostic for disease progression and poorer survival in patients with lung adenocarcinoma, highlighting its potential as a viable therapeutic target. To this end, we demonstrated that pharmacologic inhibition of FSP1 had significant therapeutic benefit in pre-clinical lung cancer models. Our studies highlight the importance of ferroptosis suppression in vivo and pave the way for FSP1 inhibition as a therapeutic strategy for patients with lung cancer.
    DOI:  https://doi.org/10.1038/s41586-025-09710-8
  4. Nat Genet. 2025 Nov 05.
    Epigenetically driven and early immune evasion in colorectal cancer evolution.
    Eszter Lakatos, Vinaya Gunasri, Luis Zapata, Jacob Househam, Timon Heide, Nicholas Trahearn, Ottilie Swinyard, Luis Cisneros, Claire Lynn, Maximilian Mossner, Chris Kimberley, Inmaculada Spiteri, George D Cresswell, Gerard Llibre-Palomar, Miriam Mitchison, Carlo C Maley, Marnix Jansen, Manuel Rodriguez-Justo, John Bridgewater, Ann-Marie Baker, Andrea Sottoriva, Trevor A Graham.
      Immune system control is a principal hurdle in cancer evolution. The temporal dynamics of immune evasion remain incompletely characterized, and how immune-mediated selection interrelates with epigenome alteration is unclear. Here we infer the genome- and epigenome-driven evolutionary dynamics of tumor-immune coevolution within primary colorectal cancers (CRCs). We utilize a multiregion multiomic dataset of matched genome, transcriptome and chromatin accessibility profiling from 495 single glands (from 29 CRCs) supplemented with high-resolution spatially resolved neoantigen sequencing data and multiplexed imaging of the tumor microenvironment from 82 microbiopsies within 11 CRCs. Somatic chromatin accessibility alterations contribute to accessibility loss of antigen-presenting genes and silencing of neoantigens. Immune escape and exclusion occur at the outset of CRC formation, and later intratumoral differences in immuno-editing are negligible or exclusive to sites of invasion. Collectively, immune evasion in CRC follows a 'Big Bang' evolutionary pattern, whereby it is acquired close to transformation and defines subsequent cancer-immune evolution.
    DOI:  https://doi.org/10.1038/s41588-025-02349-1
  5. Nat Genet. 2025 Nov 07.
    TGF-β builds a dual immune barrier in colorectal cancer by impairing T cell recruitment and instructing immunosuppressive SPP1+ macrophages.
    Ana Henriques, Maria Salvany-Celades, Paula Nieto, Sergio Palomo-Ponce, Marta Sevillano, Xavier Hernando-Momblona, Emily Middendorp-Guerra, Montserrat Llanses Martinez, Elisabeth Marjolein Haak, Juan Nieto, Ginevra Caratú, Domenica Marchese, Max Ruiz Gil, Sebastien Tosi, Theresa Suckert, Jordi Badia-Ramentol, Adrià Caballé-Mestres, Carolina Sanchez-Zarzalejo, Lidia Mateo, Daniele V F Tauriello, Antoni Riera, Elena Sancho, Camille Stephan-Otto Attolini, Alejandro Prados, Holger Heyn, Eduard Batlle.
      Transforming growth factor β (TGF-β) signaling in the tumor microenvironment predicts resistance to immune checkpoint blockade (ICB). While TGF-β inhibition enhances ICB efficacy in murine cancer models, clinical trials have yet to demonstrate benefit, underscoring the need to better understand its immunoregulatory roles across disease contexts. Using mouse models of advanced colorectal cancer and patient-derived data, we demonstrate that TGF-β impairs antitumor immunity at multiple levels in liver metastases. It acts directly on T cells to block recruitment of peripheral memory CD8+ T cells, thereby limiting the effectiveness of ICB. Concurrently, TGF-β instructs tumor-associated macrophages to suppress clonal expansion of newly arrived T cells by inducing SPP1 expression. This extracellular matrix protein promotes collagen deposition and accumulation of tumor-associated macrophages and fibroblasts, ultimately driving ICB resistance. Our findings reveal how TGF-β coordinates immunosuppressive mechanisms across innate and adaptive immune compartments to promote metastasis, offering new avenues to improve immunotherapy in colorectal cancer.
    DOI:  https://doi.org/10.1038/s41588-025-02380-2
  6. Transl Oncol. 2025 Nov 04. pii: S1936-5233(25)00323-7. [Epub ahead of print]63 102592
    Integrative multi-omics of matched primary and liver metastatic colorectal cancer organoids identifies putative molecular targets.
    Chae-Young Kim, Soon-Chan Kim, Rumi Shin, Min Jung Kim, Seung-Yong Jeong, Ji Won Park, Ja-Lok Ku.
      Hepatic metastasis from colorectal cancer (CRC) mainly accounts for the dismal prognosis of advanced CRC. Metastasized tumor cells exhibit strong resistance to commonly used systemic chemotherapy, which causes the high mortality of colorectal liver metastasis (CLM) patients. Although previous studies using biological resources have suggested multiple metastatic factors, molecular integration into chemotherapeutic responses is seldom studied. In this study, we established five pairs of CLM organoids, which were subjected to a multi-omics approach including genetic, transcriptional, exosomal miRNA and pharmacological analyses. These multi-omics layers were interlinked through machine learning analysis to construct a drug response prediction model. Our approach not only recapitulated druggable molecular targets that were specifically dysregulated in LM organoids but also potentially revealed a statistical connection to systemic therapy regimens.
    Keywords:  Colorectal liver metastasis; Drug screening; Exosomal miRNA; Multi-omics; Organoid; Prediction model
    DOI:  https://doi.org/10.1016/j.tranon.2025.102592
  7. Adv Sci (Weinh). 2025 Nov 06. e11744
    Proteogenomic Characterization Reveals Metabolic Vulnerabilities and Aberrant Phosphorylation in Colorectal Metastasis to Liver.
    Wensi Zhao, Lei Zhao, Yannan Lian, Zhiwei Liu, Yaqi Li, Xuege Wang, Mingya Zhang, Ni Li, Jingli Guo, Danqing Shen, Shaobo Mo, Jiahao Li, Linhui Zhai, Jiahui Ni, Sangkyu Lee, Bin Liu, Jing Li, Fei Wang, Junjie Peng, Jun Qin, Minjia Tan.
      Colorectal liver metastasis (CRLM) is one of the leading death causes among colorectal cancer (CRC) patients, yet its underlying molecular events remain poorly understood, particularly at the proteomic and phosphoproteomic levels. A proteogenomic analysis combining genomics, transcriptomics, proteomics, and phosphoproteomics is performed on 102 samples from 34 treatment-naïve CRLM patients, including primary CRC, adjacent normal colorectal, and matched liver metastasis tissues. CRC cell lines, organoids, mouse models, and an independent patient cohort are used to validate the findings. Proteomics and phosphoproteomics show profoundly dysregulated pathways in liver metastasis tissues, notably disruptions in carbon metabolism. Functional validation using CRC organoids and mouse models demonstrates that the one-carbon metabolism enzyme SHMT1 promotes CRC tumorigenesis and metastasis via formate-mediated AMPK inhibition, whereas PIM kinase-dependent NDRG1 Ser330 phosphorylation exacerbates liver metastasis by promoting ubiquitin-dependent degradation of NDRG1. Unsupervised clustering identifies two proteomic subtypes of liver metastasis samples with distinct clinical outcomes: a poor-prognosis C1 (metabolism) subtype and a better-prognosis C2 (RNA function) subtype. Considering expression frequency, specificity, and functional relevance, FTCD, GPD1, SOD2, and EIF4B Ser422 phosphorylation are further identified and validated as subtype prognostic biomarkers. This study provides critical insights into the molecular mechanisms underlying CRLM and offers resources for high-risk metastatic CRC.
    Keywords:  SHMT1; biomarker; colorectal liver metastasis; phosphoproteomics; proteomic subtype; proteomics
    DOI:  https://doi.org/10.1002/advs.202511744
  8. Oncogene. 2025 Nov 07.
    Clinical implications of whole genome sequencing in metastatic colorectal cancer.
    Lidwien P Smabers, Hilde H Nienhuis, Wendy W J de Leng, Paul Roepman, Ilcan Ö A Ciftcibasi, G Emerens Wensink, Maarten A Huismans, Liselot B J Valkenburg-van Iersel, Geert A Cirkel, Elske C Gootjes, Henk M W Verheul, Frank J Jeurissen, Guus M Bol, Onno Kranenburg, Miriam Koopman, Edwin Cuppen, Jeanine M L Roodhart.
      Whole genome sequencing (WGS) provides complete genetic information in one test, supporting the shift towards individualized metastatic colorectal cancer (mCRC) treatment. Although WGS is validated as a diagnostic test, the potential clinical implications for mCRC remain unknown. We evaluated the clinical consequences of WGS in 96 mCRC patients. Clinically actionable biomarkers were identified by a molecular biologist and medical oncologist, with added value defined as biomarkers undetected by standard diagnostics. We evaluated how these biomarkers informed treatment decisions. We used patient-derived organoids (PDOs) to test drug sensitivity to MET, MEK, and CDK4/6 inhibitors, translating genomic findings into functional evidence. WGS yields biomarkers with clinical implications in 81% of patients, with 49% (N = 47/96) identified by WGS that were not detected by guideline-based diagnostics, and 40% (N = 38/96) not detected by applied diagnostics. The proportion of patients receiving biomarker-based treatment has increased from 11% to at least 24% by WGS. PDOs with actionable biomarkers showed clear differential response to different biomarker-based treatments. WGS enables considerably more personalized therapeutic interventions and represents a promising approach in advancing precision oncology for mCRC patients. PDO pre-screening can refine therapy by identifying (in)effective treatments in a patient-specific context, to accelerate the development of personalized treatment.
    DOI:  https://doi.org/10.1038/s41388-025-03618-3
  9. Cancer Cell. 2025 Nov 06. pii: S1535-6108(25)00448-9. [Epub ahead of print]
    Decoding the spatial dynamics of tumor and immune cell interactions in solid cancers.
    Eleanor Minogue, Pilar Baldominos, Lauren Hsu, Marcia C Haigis, Judith Agudo.
      The spatial landscape of the tumor immune microenvironment (TIME) is under significant investigation as a driver of immunotherapy resistance in solid tumors. Most work centers on constituent immune cells within intra-tumoral niches, overlooking tumor cell phenotypes. Yet cancer cells shape their milieu by multiple modalities, including secreting and depleting metabolites. Here, we argue that integrating cancer cell phenotypic heterogeneity into spatial analyses is essential to reveal the mechanisms that generate TIME diversity and to better address resistance to immunotherapy.
    DOI:  https://doi.org/10.1016/j.ccell.2025.10.007
  10. Mol Oncol. 2025 Nov 03.
    Cytoplasmic p21 promotes stemness of colon cancer cells via activation of the NFκB pathway.
    Arnatchai Maiuthed, Kerstin Huebner, Katharina Erlenbach-Wuensch, Chuanpit Hampel, Daniela Thalheim, Adriana Vial-Roehe, Bodee Nutho, Susanne Merkel, Arndt Hartmann, Pithi Chanvorachote, Regine Schneider-Stock.
      Cancer stem cells (CSCs) drive tumor initiation, metastasis, and therapy resistance. The role of cytoplasmic cyclin-dependent kinase inhibitor 1A (CDKN1A, p21) in CSC biology remains unclear. Since cytoplasmic p21 correlated with advanced stage and metastasis in colorectal cancer (CRC) patients, we investigated its causal role in CSC features in vitro and in vivo. Cytoplasmic p21 increased spheroid formation and CD133 expression in a mechanism partly dependent on AKT activation. Phosphomimetic p21 (p21T145D) enhanced spheroid growth, CD133, and stemness factors (Oct3/4, Nanog, Sox2), whereas nuclear p21 (p21T145A) reduced them. Immunoprecipitation, proximity ligation assays, and in silico modeling demonstrated that cytoplasmic p21 interacts with the NFκB-IκB complex, promoting NFκB release and activation. Consequently, NFκB targets BCL-xL and COX2 were upregulated in p21T145D- and AKTT308D,S473D CRC cells in vitro and in a chorioallantoic membrane (CAM) model, supporting their role as downstream effectors of cytoplasmic p21. Our findings uncover a new function of cytoplasmic p21 in regulating CSC properties through NFκB modulation. Screening p21 subcellular localization may stratify CRC patients with high metastatic risk providing a basis for CSC-targeted therapeutic strategies.
    Keywords:  BCL‐xL; CAM model; CD133; IκB; NFκB; stem cells
    DOI:  https://doi.org/10.1002/1878-0261.70150
  11. Mol Oncol. 2025 Nov 05.
    Effect of chemotherapy on passenger mutations in metastatic colorectal cancer.
    Marium T Siddiqui, Matthew A Cottam, Muhammad Bilal Mirza, Keeli B Lewis, Kristen K Ciombor, Mary Kay Washington, Kamran Idrees.
      Metastatic colorectal cancer (mCRC), particularly microsatellite stable (MSS) cases, often exhibits limited responsiveness to immunotherapy, leaving chemotherapy as the primary treatment option. While chemotherapy effectively targets tumor cells, its impact on the broader mutational landscape, including passenger mutations in large genes such as Titin (TTN), remains poorly understood. Passenger mutations, traditionally deemed biologically inert, may reflect tumor mutational burden (TMB) and influence treatment outcomes. In our study involving whole exome sequencing of paired primary and metastatic tumor samples from 22 mCRC patients, recurrent driver mutations in APC, KRAS, and TP53 were consistently observed. However, passenger mutations in large genes, particularly TTN, were notably enriched in chemonaïve specimens and associated with higher TMB. Chemotherapy-treated samples exhibited a significant reduction in these mutations, suggesting selective depletion of hypermutated subclones. Our findings demonstrate that chemotherapy may selectively reduce passenger mutations in mCRC, potentially influencing the persistence of hypermutated subclones. This highlights the potential role of passenger mutation patterns and TMB as biomarkers for treatment response and raises the hypothesis that they could help guide immunotherapy considerations for patients with MSS mCRC.
    Keywords:  chemotherapy; colorectal cancer; metastasis; passenger mutations; whole exome sequencing
    DOI:  https://doi.org/10.1002/1878-0261.70154
  12. J Transl Med. 2025 Nov 03. 23(1): 1208
    Neutrophil extracellular traps regulate LDHA expression to promote colorectal cancer liver metastasis.
    Nana Li, Shifeng Yang, Congxue Hu, Jie Zheng, Hao Yang, Tianming Jiang, Xiaodong Li, Qixiang Han, Xinyu Zhang, Yanmei Yang, Sajid Khan, Boshi Sun.
      Metastasis is the most common cause of colorectal cancer (CRC)-related death. Neutrophil extracellular traps (NETs) promote tumor progression and distant metastasis. This study aimed to explore the role of NETs in CRC liver metastasis. Through analysis of publicly available single-cell transcriptome sequencing databases, in vitro experiments and nude mouse liver xenograft model experiments, we revealed that NETs promote CRC metastatic progression. Using scRNA-Seq technology, we showed that NETs marker expression was higher in metastatic lesions than in primary tumors. NET marker expression was high in colorectal cancer tissues and correlated with advanced tumor pathological grade. In addition, treatment with NETs enhanced the proliferation, migration and invasion of CRC cells in vitro by inducing EMT, as indicated by downregulation of E-cadherin and upregulation of N-cadherin and Vimentin. Cell-cell communication analysis revealed that NETs are related to the PI3K/AKT pathway and regulate the expression of LDHA, a key enzyme in glucose metabolism. In vitro, treatment with NETs promoted LDHA production and cell invasion and migration in CRC, while knockdown of LDHA suppressed EMT. Further, inhibition of LDHA expression or NET formation effectively inhibited NET-induced liver metastasis. In summary, this study elucidates the mechanism by which NETs regulate LDHA expression to promote CRC liver metastasis.
    Keywords:  Colorectal cancer; Lactate; Metastasis; Neutrophil extracellular trap; scRNA-Seq
    DOI:  https://doi.org/10.1186/s12967-025-07174-y
  13. Stem Cell Reports. 2025 Nov 06. pii: S2213-6711(25)00311-X. [Epub ahead of print] 102707
    A novel paradigm for single-cell annotation in stem cell research.
    Trevor Atkeson, Sean B Wilson, Elias R Ruiz-Morales, Melissa H Little, Roser Vento-Tormo, Drew Neavin, Joseph E Powell.
      Stem cell-derived models are a powerful tool for studying biology and are increasingly paving the way for cell-based therapies. However, understanding precisely which cell types are present and how closely they recapitulate in vivo cells remains challenging. Single-cell genomics, coupled with annotation methods, provides a framework for evaluating the congruence of stem cells with in vivo biology. Here, we explore approaches to cell annotation and discuss the challenges of implementing these methods in stem cell-derived models. We provide recommendations for the application of these methods, as well as our vision for the future of stem cell annotation using cell manifolds.
    Keywords:  AI; cell annotation; cellular genomics; hPSCs; single cell
    DOI:  https://doi.org/10.1016/j.stemcr.2025.102707
  14. Nat Genet. 2025 Nov 07.
    Timing and mechanisms of immune evasion in colorectal cancers.
      
    DOI:  https://doi.org/10.1038/s41588-025-02348-2
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