bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–01–19
ten papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells.
  2. New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice.
  3. LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.
  4. AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.
  5. Continuing anti-EGFR monoclonal antibody after secondary resection significantly prolongs overall survival for patients with metastatic colorectal cancer who were responsive to first-line anti-EGFR monoclonal antibody plus chemotherapy doublet.
  6. Identification of clinicopathological-specific driver gene and genetic subtyping of colorectal cancer.
  7. Light-dark shift promotes colon carcinogenesis through accelerated colon aging.
  8. First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer.
  9. DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.
  10. SATB2 Expression Affects Chemotherapy Metabolism and Immune Checkpoint Gene Expression in Colorectal Cancer.
  1. Dev Cell. 2025 Jan 02. pii: S1534-5807(24)00762-7. [Epub ahead of print]
    Fate mapping in mouse demonstrates early secretory differentiation directly from Lgr5+ intestinal stem cells.
    Isidora Banjac, Martti Maimets, Ingrid H C Tsang, Marius Dioli, Stine Lind Hansen, Kata Krizic, Raul Bardini Bressan, Cecilia Lövkvist, Kim B Jensen.
      The intestinal epithelium has a remarkably high turnover in homeostasis. It remains unresolved how this is orchestrated at the cellular level and how the behavior of stem and progenitor cells ensures tissue maintenance. To address this, we combined quantitative fate mapping in three complementary mouse models with mathematical modeling and single-cell RNA sequencing. Our integrated approach generated a spatially and temporally defined model of crypt maintenance based on two cycling populations: stem cells at the crypt-bottom and transit-amplifying (TA) cells above them. Subsequently, we validated the predictions from the mathematical model, demonstrating that fate decisions between the secretory and absorptive lineages are made within the stem cell compartment, whereas TA cell divisions contribute specifically to the absorptive lineage. These quantitative insights provide further direct evidence for crypt-bottom stem cells as the dominant driver of the intestinal epithelium replenishment.
    Keywords:  fate mapping; intestinal stem cells; mathematical modeling
    DOI:  https://doi.org/10.1016/j.devcel.2024.12.023
  2. ACS Pharmacol Transl Sci. 2025 Jan 10. 8(1): 97-112
    New Potent Inhibitor of Transforming Growth Factor-Beta (TGFβ) Signaling that is Efficacious against Microsatellite Stable Colorectal Cancer Metastasis in Combination with Immune Checkpoint Therapy in Mice.
    Daniele V F Tauriello, Elena Sancho, Daniel Byrom, Carolina Sanchez-Zarzalejo, Maria Salvany, Ana Henriques, Sergio Palomo-Ponce, Marta Sevillano, Xavier Hernando-Momblona, Joan A Matarin, Israel Ramos, Irene Ruano, Neus Prats, Eduard Batlle, Antoni Riera.
      Blockade of the TGFβ signaling pathway has emerged from preclinical studies as a potential treatment to enhance the efficacy of immune checkpoint inhibition in advanced colorectal cancer (CRC) and several other types of cancer. However, clinical translation of first-generation inhibitors has shown little success. Here, we report the synthesis and characterization of HYL001, a potent inhibitor of TGFβ receptor 1 (ALK5), that is approximately 9 times more efficacious than the structurally related compound galunisertib, while maintaining a favorable safety profile. HYL001 in combination with immune checkpoint blockade (anti-PD1) eradicates liver metastases generated in mice by microsatellite stable, aggressive colorectal cancer tumors at doses where galunisertib is ineffective.
    DOI:  https://doi.org/10.1021/acsptsci.4c00374
  3. J Clin Invest. 2025 Jan 14. pii: e186035. [Epub ahead of print]
    LIN28B-mediated PI3K/AKT pathway activation promotes metastasis in colorectal cancer models.
    Alice E Shin, Kensuke Sugiura, Secunda W Kariuki, David A Cohen, Samuel P Flashner, Andres J Klein-Szanto, Noriyuki Nishiwaki, Dechokyab De, Neil Vasan, Joel T Gabre, Christopher J Lengner, Peter A Sims, Anil K Rustgi.
      Colorectal cancer (CRC) remains a leading cause of cancer death due to metastatic spread. LIN28B is overexpressed in 30% of CRCs and promotes metastasis, yet its mechanisms remain unclear. In this study, we genetically modified CRC cell lines to overexpress LIN28B, resulting in enhanced PI3K/AKT pathway activation and liver metastasis in mice. We developed genetically modified mouse models with constitutively active Pik3ca that form intestinal tumors progressing to liver metastases with an intact immune system, addressing the limitations of previous Pik3ca-mutant models, including long tumor latency, mixed histology, and lack of distant metastases. The PI3Kα-specific inhibitor alpelisib reduced migration and invasion in vitro and metastasis in vivo. We present the first comprehensive analysis of vertical inhibition of the PI3K/AKT pathway in CRC using FDA-approved drugs alpelisib and capivasertib (an AKT inhibitor) in combination with LY2584702 (an S6K inhibitor) in CRC cell lines and mouse- and patient-derived organoids (PDOs). Tissue microarrays from CRC patients confirmed that LIN28B and PI3K/AKT pathway activation correlate with CRC progression. These findings highlight the critical role of the LIN28B-mediated PI3K/AKT pathway in CRC metastasis, the therapeutic potential of targeted inhibition, and the promise of PDOs in precision medicine in metastatic CRC.
    Keywords:  Colorectal cancer; Gastroenterology; Mouse models; Oncogenes; Oncology
    DOI:  https://doi.org/10.1172/JCI186035
  4. Acta Pharm Sin B. 2024 Dec;14(12): 5305-5320
    AKR1C1 interacts with STAT3 to increase intracellular glutathione and confers resistance to oxaliplatin in colorectal cancer.
    Zhiwen Fu, Tingting Wu, Chen Gao, Lulu Wang, Yu Zhang, Chen Shi.
      Oxaliplatin (OXA), a platinum-based chemotherapeutic agent, remains a mainstay in first-line treatments for advanced colorectal cancer (CRC). However, the eventual development of OXA resistance represents a significant clinical challenge. In the present study, we demonstrate that the aldo-keto reductase 1C1 (AKR1C1) is overexpressed in CRC cells upon acquisition of OXA resistance, evident in OXA-resistant CRC cell lines. We employed genetic silencing and pharmacological inhibition strategies to establish that suppression of AKR1C1 restores OXA sensitivity. Mechanistically, AKR1C1 interacts with and activates the transcription factor STAT3, which upregulates the glutamate transporter EAAT3, thereby elevating intracellular glutathione levels and conferring OXA resistance. Alantolactone, a potent natural product inhibitor of AKR1C1, effectively reverses this chemoresistance, restricting the growth of OXA-resistant CRC cells both in vitro and in vivo. Our findings uncover a critical AKR1C1-dependent mechanism behind OXA resistance and propose a promising combinatorial therapeutic strategy to overcome this resistance in CRC.
    Keywords:  AKR1C1; Alantolactone; Chemoresistance; Colorectal cancer; Combination therapy; Glutathione; Natural product; Oxaliplatin resistance
    DOI:  https://doi.org/10.1016/j.apsb.2024.08.031
  5. Am J Cancer Res. 2024 ;14(12): 5909-5920
    Continuing anti-EGFR monoclonal antibody after secondary resection significantly prolongs overall survival for patients with metastatic colorectal cancer who were responsive to first-line anti-EGFR monoclonal antibody plus chemotherapy doublet.
    Yao-Yu Hsieh, Yu-Li Su, Feng-Che Kuan, Shu-Chuan Grace Chen, Chia-Lun Chang, Yu-Yun Shao, Ching-Wen Tsai, Yi-Hsin Liang.
      The combination of anti-epidermal growth factor receptor (EGFR) monoclonal antibodies (mAb) and doublet chemotherapy is the standard first-line treatment for patients with wild-type RAS/BRAF metastatic colorectal cancer (mCRC). Some patients may require secondary resection after first-line treatment. However, it remains unclear whether targeted therapy should be continued after liver resection. To investigate whether targeted therapy can be spared after secondary resection, we retrospectively analyzed data from the Taiwan National Health Insurance Research Database for patients with wild-type KRAS mCRC who received first-line anti-EGFR mAb plus doublet chemotherapy. Between 2013 and 2018, 5694 mCRC patients were screened, with 174 meeting the eligibility criteria and being enrolled in this study. Among them, 153 patients continued anti-EGFR mAb after secondary resection. These patients demonstrated a significant improvement in overall survival (OS) but not in time to treatment failure. Postresection anti-EGFR mAb conferred OS benefits compared to no anti-EGFR mAb (43.17 vs. 31.41 months; P = 0.0064). When stratified by assessment period, OS was longer in patients assessed between 2016 and 2018 than in those assessed between 2012 and 2015 (not reached vs. 39.87 months; P = 0.1819). However, no significant difference was observed in time to treatment failure when stratified by assessment period or primary tumor location. A multivariate analysis revealed that postresection anti-EGFR mAb was an independent predictor of prolonged OS. In conclusion, for mCRC patients who have undergone secondary resection after first-line anti-EGFR mAb plus doublet chemotherapy, continuing anti-EGFR mAb may significantly extend OS, regardless of the primary tumor location.
    Keywords:  Metastatic colorectal cancer; doublet chemotherapy; epidermal growth factor receptor; monoclonal antibody; secondary surgery
    DOI:  https://doi.org/10.62347/MUCQ4129
  6. Cancer Sci. 2025 Jan 11.
    Identification of clinicopathological-specific driver gene and genetic subtyping of colorectal cancer.
    Jianjiong Li, Chunnian Wang, Changshun Yang, Hua Bao, Ningyou Li, Xianqiang Huang, Wei Gong, Xinyue Hong, Jiani C Yin, Jiaohui Pang, Meifu Gan, Danping Yuan.
      This study analyzed targeted sequencing data from 6530 tissue samples from patients with metastatic Chinese colorectal cancer (CRC) to identify low mutation frequency and subgroup-specific driver genes, using three algorithms for overall CRC as well as across different clinicopathological subgroups. We analyzed 425 cancer-related genes, identifying 101 potential driver genes, including 36 novel to CRC. Notably, some genes demonstrated subgroup specificity; for instance, ERBB4 was found as a male-specific driver gene and mutations of ERBB4 only influenced the prognosis of male patients with CRC. This sex disparity of ERBB4 was validated in an independent large-scale Memorial Sloan Kettering Cancer Center CRC cohort with 2444 samples. Furthermore, using network-based stratification based on protein-protein interaction, we classified the microsatellite stable (MSS) and unstable (MSI) CRCs into six and three major subtypes, respectively, each showing unique phenotypes and prognoses. In MSS CRC, cluster 5 (APCAMER1-KRAS) and cluster 2 (RNF43-BRAF-PIK3CA) were predominant, and cluster 5 showed a superior overall survival compared with cluster 2. This extensive heterogeneity in driver gene mutations underscores the complexity of CRC and suggests significant implications for treatment and prognostic assessments.
    Keywords:  classification; colorectal cancer; driver gene; genetic heterogeneity; protein–protein interaction
    DOI:  https://doi.org/10.1111/cas.16432
  7. iScience. 2025 Jan 17. 28(1): 111560
    Light-dark shift promotes colon carcinogenesis through accelerated colon aging.
    Deepak Sharma, Phillip A Engen, Abu Osman, Darbaz Adnan, Maliha Shaikh, Mostafa K Abdel-Reheem, Ankur Naqib, Stefan J Green, Bruce Hamaker, Christopher B Forsyth, Lin Cheng, Ali Keshavarzian, Khashayarsha Khazaie, Faraz Bishehsari.
      Colorectal cancer (CRC) is the third most common cancer worldwide, with rising prevalence among younger adults. Several lifestyle factors, particularly disruptions in circadian rhythms by light-dark (LD) shifts, are known to increase CRC risk. Epidemiological studies previously showed LD-shifts are associated with increased risk of CRC. To explore the mechanisms and interactions between LD-shift and intestinal aging, we investigated how the combination of LD-shifts and aging impacts colon carcinogenesis development. Our data showed that LD-shifts and aging increased colon tumorigenesis. Notably, LD-shift accelerated intestinal aging by altering aging-related pathways, such as intestinal barrier damage, accompanied by dysbiotic changes in the intestinal microbiota that negatively impacts barrier stability. The increased carcinogenesis and intestinal aging were preceded by enrichment in host-microbiome features that are strongly regulated by the circadian clock. Overall, our results suggest that LD-shifts, increasingly prevalent among young adults, contribute to both intestinal aging and the development of colon carcinogenesis.
    Keywords:  Cancer; Cell biology
    DOI:  https://doi.org/10.1016/j.isci.2024.111560
  8. Nat Cancer. 2025 Jan 16.
    First-in-class ultralong-target-residence-time p38α inhibitors as a mitosis-targeted therapy for colorectal cancer.
    Ramona Rudalska, Jule Harbig, Michael Forster, Pascal Woelffing, Aylin Esposito, Mark Kudolo, Adelina Botezatu, Vanessa Haller, Nicole Janssen, Samuel Holzmayer, Philipp Nahidino, Omelyan Trompak, Tatu Pantsar, Thales Kronenberger, Can Yurttas, Elke Rist, Alexander N R Weber, Marc H Dahlke, German Ott, Alfred Koenigsrainer, Ulrich Rothbauer, Melanie Maerklin, Thomas Muerdter, Matthias Schwab, Stephan Singer, Lars Zender, Stefan Laufer, Daniel Dauch.
      Colorectal cancer (CRC) constitutes the second leading cause of cancer-related death worldwide and advanced CRCs are resistant to targeted therapies, chemotherapies and immunotherapies. p38α (Mapk14) has been suggested as a therapeutic target in CRC; however, available p38α inhibitors only allow for insufficient target inhibition. Here we describe a unique class of p38α inhibitors with ultralong target residence times (designated ULTR-p38i) that robustly inhibit p38α downstream signaling and induce distinct biological phenotypes. ULTR-p38i monotherapy triggers an uncontrolled mitotic entry by activating Cdc25 and simultaneously blocking Wee1. Consequently, CRC cells undergo mitotic catastrophe, resulting in apoptosis or senescence. ULTR-p38i exhibit high selectivity, good pharmaco-kinetic properties and no measurable toxicity with strong therapeutic effects in patient-derived CRC organoids and syngeneic CRC mouse models. Conceptually, our study suggests ultralong-target-residence-time kinase inhibitors as an alternative to covalent inhibitors, which, because of the lack of cysteine residues, cannot be generated for many kinase cancer targets.
    DOI:  https://doi.org/10.1038/s43018-024-00899-7
  9. Cell Death Dis. 2025 Jan 14. 16(1): 16
    DNA replication stress underpins the vulnerability to oxidative phosphorylation inhibition in colorectal cancer.
    Xiao Hong Zhao, Man Man Han, Qian Qian Yan, Yi Meng Yue, Kaihong Ye, Yuan Yuan Zhang, Liu Teng, Liang Xu, Xiao-Jing Shi, Ting La, Yu Chen Feng, Ran Xu, Vinod K Narayana, David P De Souza, Lake-Ee Quek, Jeff Holst, Tao Liu, Mark A Baker, Rick F Thorne, Xu Dong Zhang, Lei Jin.
      Mitochondrial oxidative phosphorylation (OXPHOS) is a therapeutic vulnerability in glycolysis-deficient cancers. Here we show that inhibiting OXPHOS similarly suppresses the proliferation and tumorigenicity of glycolytically competent colorectal cancer (CRC) cells in vitro and in patient-derived CRC xenografts. While the increased glycolytic activity rapidly replenished the ATP pool, it did not restore the reduced production of aspartate upon OXPHOS inhibition. This shortage in aspartate, in turn, caused nucleotide deficiencies, leading to S phase cell cycle arrest, replication fork stalling, and enrichment of the p53 pathway, manifestations of replication stress. The addition of purine nucleobases adenine and guanine along with the pyrimidine nucleoside uridine restored replication fork progression and cell proliferation, whereas the supplementation of exogenous aspartate recovered the nucleotide pool, demonstrating a causal role of the aspartate shortage in OXPHOS inhibition-induced nucleotide deficiencies and consequently replication stress and reductions in proliferation. Moreover, we demonstrate that glutamic-oxaloacetic transaminase 1 (GOT1) is critical for maintaining the minimum aspartate pool when OXPHOS is inhibited, as knockdown of GOT1 further reduced aspartate levels and rendered CRC cells more sensitive to OXPHOS inhibition both in vitro and in vivo. These results propose GOT1 targeting as a potential avenue to sensitize cancer cells to OXPHOS inhibitors, thus lowering the necessary doses to efficiently inhibit cancer growth while alleviating their adverse effects.
    DOI:  https://doi.org/10.1038/s41419-025-07334-4
  10. Clin Colorectal Cancer. 2024 Dec 18. pii: S1533-0028(24)00119-1. [Epub ahead of print]
    SATB2 Expression Affects Chemotherapy Metabolism and Immune Checkpoint Gene Expression in Colorectal Cancer.
    Barry Maguire, Batuhan Kisakol, Jochen H M Prehn, John P Burke.
       BACKGROUND: Special AT-rich binding protein-2 (SATB2) is a nuclear matrix associated protein regulating gene expression which is normally expressed in colonic tissue. Loss of SATB2 expression in colorectal cancer (CRC) has negative implications for prognosis and has been associated with chemotherapy resistance. Furthermore, recent evidence suggests SATB2 may influence immune checkpoint (IC) expression. We hypothesized that SATB2 expression may be associated with altered expression of chemotherapy resistance associated and IC genes.
    METHODS: Clinicopathologic and gene expression data were extracted from The Cancer Genome Atlas PanCancer Atlas. SATB2 expression was compared by clinicopathologic characteristic and by using multivariate regression analysis to explore associations with chemotherapy and IC gene expression.
    RESULTS: About 553 patients were included for analysis. Lower quartile SATB2 expression was associated with worse disease specific survival (P = .04). MSI (P < .001) and mucinous (P < .001) tumors were associated with reduced SATB2 expression independently. SATB2 varied by consensus molecular subtype (P < .001) and was lowest in CMS1. On multivariate analysis, SATB2 was negatively associated with 5-FU related metabolism genes, while more complex but significant relationships were seen with oxaliplatin and irinotecan related genes. Low SATB2 expression was associated with increased expression of PD-1, PD-L1, TIM-3 and CTLA-4 IC genes.
    CONCLUSION: The positive prognostic influence of SATB2 expression is reaffirmed in this study. This effect may be explained by the negative association between SATB2 and 5-FU-resistance related gene expression. Enhanced IC gene expression in SATB2 low cases suggests a potential role for IC inhibition in this setting, but further study is required.
    Keywords:  5-fluorouracil; CMS1; PD-1; PD-L1; Prognosis
    DOI:  https://doi.org/10.1016/j.clcc.2024.12.004
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