bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–06–22
nine papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Protocol for sub-mucosal orthotopic injection of organoids into murine colon to study tumor growth and metastasis.
  2. Targeting the NAD+/SIRT1 axis: A metabolic strategy to overcome oxaliplatin resistance in colorectal cancer.
  3. Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models.
  4. Colorectal cancer cell line-derived organoid model with stem cell properties captures the regrowing state of residual cancer cells after neoadjuvant chemotherapy.
  5. Exercise alters transcriptional profiles of senescence and gut barrier integrity in intestinal crypts of aging mice.
  6. A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming.
  7. Tumor-derived CXCL5 promotes 5-fluorouracil resistance in colorectal cancer cells via p21 downregulation.
  8. NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT.
  9. ALDOC and PGK1 coordinately induce glucose metabolism reprogramming and promote development of colorectal cancer.
  1. STAR Protoc. 2025 Jun 12. pii: S2666-1667(25)00293-X. [Epub ahead of print]6(2): 103887
    Protocol for sub-mucosal orthotopic injection of organoids into murine colon to study tumor growth and metastasis.
    Sura Atatri, Marianne Meyers, Eliane Klein, Valentina Brunner, Markus Tschurtschenthaler, Elisabeth Letellier.
      Orthotopic mouse models of colorectal cancer (CRC) better recapitulate the physiological processes of tumor development and metastatic dissemination. Here, we provide a protocol for colonoscopy-guided transplantation of organoids into the murine colon. We describe the steps for preparing mouse organoids, equipment, and mice for injections, as well as performing colonoscopy-guided mucosal injections and providing subsequent care. This model can be used to investigate various experimental setups, including survival, metastatic potential, and the effects of treatments. For complete details on the use and execution of this protocol, please refer to Felchle et al.1.
    Keywords:  Cancer; Health Sciences; Model Organisms; Organoids
    DOI:  https://doi.org/10.1016/j.xpro.2025.103887
  2. World J Gastroenterol. 2025 Jun 07. 31(21): 106530
    Targeting the NAD+/SIRT1 axis: A metabolic strategy to overcome oxaliplatin resistance in colorectal cancer.
    Md Sadique Hussain, Vikash Jakhmola, Kavita Goyal, Arcot Rekha, Ayesha Sultana, Haider Ali, Gaurav Gupta.
      Oxaliplatin resistance remains a significant clinical challenge in colorectal cancer (CRC), highlighting the urgent need to identify novel molecular targets for therapeutic intervention. Recent findings by Niu et al have elucidated the role of the NAD+/SIRT1 axis in mediating oxaliplatin resistance through metabolic reprogramming. Their study demonstrated that oxaliplatin-induced DNA damage activates PARP, resulting in NAD+ depletion and subsequent downregulation of SIRT1. This reduction in SIRT1 levels enhances glycolysis, as evidenced by increased expression of PKM2 and LDHA, thereby conferring a metabolic advantage to resistant CRC cells. Conversely, restoration of SIRT1 expression reverses resistance, while pharmacological inhibition of glycolysis effectively sensitizes cells to oxaliplatin. These findings underscore the therapeutic potential of targeting the NAD+/SIRT1 pathway as a metabolic vulnerability in CRC. Future studies should investigate the clinical feasibility of combining SIRT1 agonists and glycolysis inhibitors with oxaliplatin to overcome drug resistance and improve patient outcomes.
    Keywords:  Chemotherapy; Colorectal cancer; Drug resistance; Glycolysis; SIRT1
    DOI:  https://doi.org/10.3748/wjg.v31.i21.106530
  3. Cancer Cell. 2025 Jun 10. pii: S1535-6108(25)00223-5. [Epub ahead of print]
    Cisplatin and temozolomide combinatorial treatment triggers hypermutability and immune surveillance in experimental cancer models.
    Pietro Paolo Vitiello, Benoit Rousseau, Rosaria Chilà, Paolo Battuello, Vito Amodio, Vittorio Battaglieri, Gaia Grasso, Sharon Scardellato, Achille Anselmo, Francesca Clemente, Giuseppe Rospo, Simona Lamba, Alice Bartolini, Federica Pisati, Claudio Tripodo, Noemi Congiusta, Mariangela Russo, Giovanni Crisafulli, Federica Di Nicolantonio, Giovanni Germano, Luis A Diaz, Alberto Bardelli.
      Hypermutation induced by mismatch repair (MMR) inactivation leads to immune surveillance in colorectal cancer (CRC) and in several other malignancies. We investigated the impact of a rationally designed chemotherapy combination on the generation of hypermutation and immunogenicity in otherwise immune-refractory CRC and breast cancer mouse models. Combinatorial treatment with cisplatin (CDDP) and temozolomide (TMZ) induces an adaptive downregulation of MMR, resulting in chemotherapy-dependent hypermutability and increase in predicted neoantigens. This combination specifically alters the immune fitness of the tumors, ultimately leading to CD8+ T cell-mediated immune surveillance, immunoediting of chemotherapy-induced neoantigens, and durable immunological memory. Treatment with CDDP and TMZ also remodels the innate immune microenvironment and induces long-lasting responses and complete rejections when combined with anti-PD-1 therapy in mice. The same effects are not observed using the clinically approved combination of 5-fluorouracil, oxaliplatin, and irinotecan (FOLFOXIRI). Treatment-induced hypermutation can enhance anti-tumor immune responses, offering additional avenues for cancer treatment.
    Keywords:  chemotherapy; cisplatin; colorectal cancer; cytotoxic chemotherapy; immune checkpoint blockade; immune rewiring; immune surveillance; mismatch repair modulation; neoantigens; temozolomide
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.014
  4. Cell Death Discov. 2025 Jun 20. 11(1): 282
    Colorectal cancer cell line-derived organoid model with stem cell properties captures the regrowing state of residual cancer cells after neoadjuvant chemotherapy.
    Kiyotaka Nakano, Eiji Oki, Masaki Yamazaki, Masami Suzuki, Shigeto Kawai, Takanori Fujita, Atsuhiko Kato, Yoko Zaitsu, Tomoko Jogo, Chie Kato, Takeshi Watanabe, Eri Hashimoto, Chiyoko Nishime, Etsuko Fujii, Koji Ando, Genta Nagae, Norifumi Harimoto, Mitsuhiko Ota, Hiroshi Saeki, Hiroyuki Aburatani, Yoshihiko Maehara, Tatsumi Yamazaki.
      The effectiveness of colorectal cancer (CRC) therapy is limited owing to the absence of treatments targeting drug-tolerant residual cancer cells. Although neoadjuvant therapy is effective, pathological examination of residual tumors has revealed the presence of small clusters of LGR5-positive cancer cells in the fibrous tissue. Here, we established a colorectal cancer cell line-derived organoid (CCD-organoid) regrowth model using a patient-derived cell line with cancer stem cell properties and demonstrated that it displayed the morphological characteristics of small clusters in clinical tissues. Time course analysis of single-cell RNA sequencing of the CCD-organoid regrowth model revealed various states and dynamic alterations within non-cycling cells. We identified subpopulations highly expressing protein translation-related genes RPL17 and EEF1G. To identify key signals for the transition of residual cancer cells to regrowth, we evaluated inhibitors targeting pathways such as the Wnt pathway, reactive oxygen species pathway, and RNA polymerase I pathway, highlighted in the single-cell RNA sequencing analysis. Only the polymerase I-inhibitor BMH-21 significantly reduced tumor growth both in vitro and in vivo, indicating the critical cell subpopulation driving recurrence. Our results demonstrate the possibility of a unique therapeutic target for CRC treatment targeting drug-tolerant residual cancer cells.
    DOI:  https://doi.org/10.1038/s41420-025-02567-w
  5. NPJ Aging. 2025 Jun 13. 11(1): 51
    Exercise alters transcriptional profiles of senescence and gut barrier integrity in intestinal crypts of aging mice.
    Hyeonuk Jeon, Siyeon Lee, Yumin Kim, Yeongmin Kim, Soyeon Shin, Yoseob Lee, Minki Kim, Eunbin Ko, Eunsu Lee, Brian Min Song, Hojeong Choi, Nahee Hwang, Se-Eun Han, Byungjin Hwang, Jae-Woo Kim, Chang-Myung Oh, Sungsoon Fang.
      Senescence is the gradual process of aging in tissues and cells, and a primary cause of aging-associated diseases. Among them, intestinal stem cells (ISCs) experience exhaustion during aging, leading to reduced regenerative capacity in the intestinal crypt, which impairs intestinal function and contributes to systemic health issues. Given the critical role ISCs play in maintaining intestinal homeostasis, preventing their senescence is essential for preserving intestinal function. Among the various strategies proposed to slow cellular senescence, regular exercise has emerged as one of the most well-known and widely accepted interventions. Here, we examined how exercise affects the small intestine in an aging mouse model. Using single-cell RNA sequencing, we found that signaling pathways and gene expression related to DNA replication and cell cycle progression were upregulated in ISCs. Additionally, genes promoting ribosome biogenesis showed increased expression in both ISCs and transit amplifying cells. Exercise also recovered Wnt signaling inhibition, potentially influencing ISC differentiation. Furthermore, exercise increased Reg3g expression in Paneth cells and improved gut barrier function, contrasting with findings from a diet-induced obese mouse model. This suggests that regular exercise helps inhibit the aging of ISCs in multiple ways, contributing to the maintenance of intestinal homeostasis.
    DOI:  https://doi.org/10.1038/s41514-025-00242-z
  6. Bioact Mater. 2025 Oct;52 73-91
    A dual-targeting strategy to inhibit colorectal cancer liver metastasis via tumor cell ferroptosis and cancer-associated fibroblast reprogramming.
    Ziying Wu, Xiewei Lin, Yao Ying, Gaowei Fan, Junyao Shi, Xiaoqing Zheng, Ben Hu, Hungchen Che, Huiyang Chen, Weilong Yang, Xindi Fan, Ke Mo, Junming Wu, Zhien Lan, Zhiqiang Yu, Shengtao Wang, Chunhui Cui.
      Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with liver metastasis posing a significant therapeutic challenge. Within the "seed and soil" paradigm, disrupting both tumor cells and their supportive microenvironment is essential to suppress disease progression. Here, we utilized single-cell transcriptomics of clinical CRC samples identified NOX4+ (NADPH oxidase 4 positive) cancer-associated fibroblasts (CAFs) and CXCR4+ (C-X-C motif chemokine receptor 4 positive)/GPX4+ (glutathione peroxidase 4 positive) tumor cells as critical drivers of metastasis. Consequently, a dual-targeted nanosystem was thus devised to induce ferroptosis in tumor cells and reprogram CAFs. This strategy integrates a ferroptosis inducer encapsulated within the cancer cell membrane and a CXCR4-NOX4 inhibitor loaded onto a hybrid membrane composed of cancer cells and CAFs, thereby achieving dual synergistic effects: ferroptotic eradication of malignant cells and induction of CAFs quiescence. In orthotopic, liver metastasis, and patient-derived tumor xenograft humanized immune mouse models, these nanoparticles significantly suppressed tumor growth, mitigated immunosuppressive signaling, and augmented antitumor immune responses, while maintaining favorable biocompatibility. These findings highlight the potential of simultaneously targeting ferroptosis in tumor cells and CAFs reprogramming in the tumor microenvironment to overcome liver metastasis of CRC.
    Keywords:  Cancer-associated fibroblasts; Colorectal cancer liver metastasis; Dual-targeted nanosystem; Ferroptosis; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bioactmat.2025.05.025
  7. Med Oncol. 2025 Jun 13. 42(7): 257
    Tumor-derived CXCL5 promotes 5-fluorouracil resistance in colorectal cancer cells via p21 downregulation.
    Wanjun Xu, Jianjun Wang, Wencan Han, Jinmin Sun, Xuemei Yang, Xiaomin Li, Dongsheng Pei.
      The efficacy of 5-fluorouracil treatment for colorectal cancer (CRC) is substantially compromised by drug resistance, although the underlying mechanisms remain unclear. In this research, we aimed to explore the role and mechanism of action of CXC motif chemokine ligand 5 (CXCL5) in 5-fluorouracil resistance. RNA sequencing was conducted to detect abnormally expressed genes in the 5-fluorouracil-resistant colon cancer cell line, HCT8-5FU. CXCL5 expression in CRC tissues and cell lines was evaluated using RT-qPCR, western blotting, and immunohistochemistry. In vivo and in vitro assays were conducted to evaluate the role of CXCL5 in the promotion of CRC progression. Mass spectrometry and co-immunoprecipitation were employed to investigate the role of CXCL5 in CRC development and 5-fluorouracil resistance. Immunofluorescence and western blot analyses were employed to determine the subcellular localization of CXCL5 and its associated signaling pathways. CXCL5 expression was elevated in both CRC tissues and cell lines. CXCL5 promoted CRC cell growth and resistance to 5-fluorouracil in both in vitro and in vivo settings. Mechanistically, CXCL5 may modulate the MDM2/p53 axis to inhibit p21 by binding to RALY. In this study, CXCL5 accelerated CRC progression and increased CRC cell resistance to 5-fluorouracil via the inhibition of p21 expression. Thus, CXCL5 is a potential target for CRC therapeutic strategies.
    Keywords:  5-fluorouracil; CXCL5; Colorectal cancer; p21
    DOI:  https://doi.org/10.1007/s12032-025-02801-6
  8. Oncogenesis. 2025 Jun 17. 14(1): 19
    NUCKS1 promotes invasion and metastasis of colorectal cancer by stabilizing HDAC2 and activating AKT.
    Liaoliao Zhu, Ting Zhao, Haichuan Su, Junqiang Li, Xiangjing Shen, Liang Zhang, Jun Chen, Yang Song.
      Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) functions as an oncogene in colorectal cancer (CRC), promotes the progression of CRC, and is associated with poor prognosis in patients. Studies have found that NUCKS1 promotes tumor cell metastasis, yet its role in CRC invasion and metastasis remains unclear. Our findings revealed higher NUCKS1 expression in metastatic CRC compared to non-metastatic samples. Upregulation of NUCKS1 expression promoted the migration and invasion of CRC cells, while knockdown of NUCKS1 significantly inhibited the migration and invasion of CRC cells. Mechanistically, NUCKS1 was initially found to upregulate HDAC2 expression by inhibiting the lysosomal pathway, activating AKT, and thus promoting CRC invasion and metastasis. Moreover, HDAC2 inhibitor Santacruzamate A or AKT inhibitor LY294002 rescued the migration and invasion of CRC cells caused by NUCKS1 overexpression. In vivo, by injecting CRC cells into the tail vein of a nude mouse model, we found that overexpression of NUCKS1-induced lung and liver metastasis was suppressed by HDAC2 knockdown or intraperitoneal administration of the HDAC2 inhibitor Santacruzamate A. Meanwhile, AKT inhibitor LY294002 significantly inhibited lung and liver metastasis caused by overexpression of HDAC2. The expression levels of NUCKS1, HDAC2, and phosphorylated AKT were significantly positively correlated in human CRC tissues. These findings suggest that NUCKS1 contributes to CRC invasion and metastasis by stabilizing HDAC2 and activating AKT, highlighting NUCKS1 and HDAC2 as potential therapeutic targets for CRC.
    DOI:  https://doi.org/10.1038/s41389-025-00562-5
  9. Mol Med. 2025 Jun 15. 31(1): 239
    ALDOC and PGK1 coordinately induce glucose metabolism reprogramming and promote development of colorectal cancer.
    Liyong Huang, Yixin Tong, Xu Li, Wei Wang, Zhen Wang, Bingchen Chen, Jifu E, Ruzhen Zhou, Hantao Wang, Jinghu He.
      Colorectal cancer (CRC) remains a significant health challenge globally, demanding a comprehensive understanding of its molecular underpinnings for effective management. In this study, we investigated the role of Aldolase C (ALDOC), a glycolytic enzyme, in CRC pathogenesis. Transcriptomic analysis of CRC tissues from The Cancer Genome Atlas (TCGA) revealed a substantial upregulation of ALDOC, correlating with adverse clinical outcomes. Immunohistochemical (IHC) staining of locally collected patient-derived tissues corroborated these findings, demonstrating elevated ALDOC expression in tumor tissues, particularly in advanced stages. Functional studies elucidated the regulatory role of ALDOC in CRC cell phenotypes. ALDOC knockdown significantly inhibited cell proliferation, induced apoptosis, arrested cell cycle progression, and suppressed cell migration in vitro. Moreover, in vivo studies using xenograft models confirmed that ALDOC knockdown attenuated tumor growth. Mechanistically, ALDOC was found to interact with hypoxia-inducible factor 1 alpha (HIF1A) and enhance its transcriptional activity on phosphoglycerate kinase 1 (PGK1), a key glycolytic enzyme. Dual-luciferase reporter assays and chromatin immunoprecipitation experiments validated the ALDOC-mediated transcriptional activation of PGK1. Further functional rescue experiments revealed a synergistic interplay between ALDOC and PGK1 in regulating CRC cell phenotypes. Additionally, ALDOC was implicated in promoting aerobic glycolysis in CRC cells, potentially through PGK1 regulation. Collectively, our findings unveil ALDOC as a critical regulator of CRC pathogenesis, offering insights into its potential as a therapeutic target and highlighting the ALDOC/PGK1 axis as a promising avenue for further investigation in CRC.
    Keywords:  ALDOC; Colorectal cancer; Glycolysis; Molecular mechanism; PGK1
    DOI:  https://doi.org/10.1186/s10020-025-01252-z
This page is being maintained by Thomas Krichel. It was last updated on 2025‒06‒23 at 9:49.