bims-instec 2025-06-01 papers

bims-instec

Biomed News

on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration

Issue of 2025–06–01
fifteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury.
Petosemtamab, a Bispecific Antibody Targeting Epidermal Growth Factor Receptor (EGFR) and Leucine-Rich G Repeat-Containing Protein-Coupled Receptor (LGR5) Designed for Broad Clinical Applications.
BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in colorectal cancer.
Experimental toolkit to study the oncogenic role of WNT signaling in colorectal cancer.
The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets.
CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.
Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation.
Intestinal L-cell mechanoreception regulates hepatic lipid metabolism through GLP-1.
Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer.
BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer.
The Metabolic Landscape of Cancer Stem Cells: Insights and Implications for Therapy.
GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis.
Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells.
Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes.
From bench to bedside: the role of gastrointestinal stem cells in health and disease.

Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2417149122

The IL-18 receptor is expressed on murine small-intestinal enterochromaffin cells and executes a recovery program upon injury.

Nathaniel J Winsor, Derek K Tsang, Adrienne Ranger, Ojas Singh, Shawn Goyal, Dana J Philpott, Stephen E Girardin.

  Upon injury, epithelial-derived IL-18 is released and induces an inflammatory response in underlying IL18R1+ lamina propria cells. Notably, Il18r1 is also predicted to be expressed and functional in intestinal epithelial cells (IECs), since epithelial IL18R1 deficiency contributes to worsened outcomes upon inflammatory challenge. However, the nature of Il18r1+ IECs, and their subsequent role in epithelial-intrinsic IL-18 signaling is poorly characterized. Here, we show that, in the murine small intestine, the IL-18 receptor is expressed by rare IECs that we identified to be a subset of enterochromaffin cells (ECC). While these cells are the major producers of serotonin in the intestine, we found no evidence that IL-18 regulated serotonin metabolism or release. Rather, upon radiation-induced injury, Il18r1+ cells appeared in the crypt base and took on a revival stem cell (revSC) program, marked by mixed expression of YAP/TAZ and enteroendocrine genes signatures. Functionally, irradiated Il18-/- mice display reduced epithelial proliferation and altered differentiation in the small intestine, characterized by increased Paneth cells (PC) and elevated Wnt3 levels, which was partially recapitulated in Il18-/- ileal organoids. In sum, we identified an Il18r1+ population in the epithelium and revealed a role for IEC-intrinsic IL-18 signaling during injury.

Keywords:  IL-18 receptor; enterochromaffin cells; inflammasomes; intestinal injury; revival stem cells

DOI:  https://doi.org/10.1073/pnas.2417149122
Cancers (Basel). 2025 May 14. pii: 1665. [Epub ahead of print]17(10):

Petosemtamab, a Bispecific Antibody Targeting Epidermal Growth Factor Receptor (EGFR) and Leucine-Rich G Repeat-Containing Protein-Coupled Receptor (LGR5) Designed for Broad Clinical Applications.

Ante S Lundberg, Cecile A W Geuijen, Sally Hill, Jeroen J Lammerts van Bueren, Arianna Fumagalli, John de Kruif, Peter B Silverman, Josep Tabernero.

  Disease progression and treatment resistance in colorectal and other cancers are driven by a subset of cells within the tumor that have stem-cell-like properties and long-term tumorigenic potential. These stem-cell-like cells express the leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) and have characteristics similar to tissue-resident stem cells in normal adult tissues such as the colon. Organoid models of murine and human colorectal and other cancers contain LGR5-expressing (LGR5+) stem-cell-like cells and can be used to investigate the underlying mechanisms of cancer development, progression, therapy vulnerability, and resistance. A large biobank of organoids derived from colorectal cancer or adjacent normal tissue was developed. We performed a large-scale unbiased functional screen to identify bispecific antibodies (BsAbs) that preferentially inhibit the growth of colon tumor-derived, as compared to normal tissue-derived, organoids. We identified the most potent BsAb in the screen as petosemtamab, a Biclonics® BsAb targeting both LGR5 and the epidermal growth factor receptor (EGFR). Petosemtamab employs three distinct mechanisms of action: EGFR ligand blocking, EGFR receptor internalization and degradation in LGR5+ cells, and Fc-mediated activation of the innate immune system by antibody-dependent cellular phagocytosis (ADCP) and enhanced antibody-dependent cellular cytotoxicity (ADCC) (see graphical abstract). Petosemtamab has demonstrated substantial clinical activity in recurrent/metastatic head and neck squamous cell carcinoma (r/m HNSCC). The safety profile is generally favorable, with low rates of skin and gastrointestinal toxicity. Phase 3 trials are ongoing in both first-line programmed death-ligand 1-positive (PD-L1+) and second/third-line r/m HNSCC.

Keywords:  EGFR protein; LGR5 protein; bispecific antibody; cancer biology; cancer stem cell; colorectal cancer; head and neck cancer; petosemtamab

DOI:  https://doi.org/10.3390/cancers17101665
Mol Oncol. 2025 May 28.

BMP antagonist CHRDL2 enhances the cancer stem-cell phenotype and increases chemotherapy resistance in colorectal cancer.

Eloise Clarkson, Annabelle Lewis.

  Bone morphogenetic protein (BMP) antagonists have been increasingly linked to the development of colorectal cancer (CRC). BMP signalling operates in opposition to the WNT signalling pathway, which sustains stem-cell maintenance and self-renewal of the normal intestinal epithelium. Reduced BMP and elevated WNT signalling lead to expansion of the stem-cell compartment and the hyperproliferation of epithelial cells, a defining characteristic of CRC. Chordin-like-2 (CHRDL2) is a secreted BMP antagonist, with overexpression linked to poor prognosis and variants in the gene shown to be associated with an elevated CRC risk. However, the detailed mechanism by which CHRDL2 contributes to CRC is unknown. In this study, we explored the impact of CHRDL2 overexpression on CRC cells to investigate whether CHRDL2's inhibition of BMP signalling intensifies WNT signalling and enhances the cancer stem-cell phenotype and response to treatment. Our research approach combines 2D cancer cell lines engineered to inducibly overexpress CHRDL2 and 3D organoid models treated with extrinsic CHRDL2, complemented by RNA sequencing analysis. CHRDL2 was found to enhance the survival of organoids and CRC cells during chemotherapy and irradiation treatment due to activation of DNA damage response pathways. Organoids treated with secreted CHRDL2 exhibited elevated levels of stem-cell markers and reduced differentiation, as evidenced by diminished villi budding. RNA-seq analysis revealed that CHRDL2 increased the expression of stem-cell markers, WNT signalling and other well-established cancer-associated pathways through BMP inhibition. These findings collectively suggest that CHRDL2 overexpression could affect response to CRC therapy by enhancing DNA repair and the stem-cell potential of cancer cells, and its role as a biomarker should be further explored.

Keywords:  WNT signalling pathway; bone‐morphogenic protein; cancer stem cell; chordin‐like 2; colorectal cancer

DOI:  https://doi.org/10.1002/1878-0261.70064
Biochim Biophys Acta Rev Cancer. 2025 May 23. pii: S0304-419X(25)00096-4. [Epub ahead of print]1880(4): 189354

Experimental toolkit to study the oncogenic role of WNT signaling in colorectal cancer.

Pujarini Dash, Vikas Yadav, Biswajit Das, Shakti Ranjan Satapathy.

  Colorectal cancer (CRC) is linked to the WNT/β-catenin signaling as its primary driver. Aberrant activation of WNT/β-catenin signaling is closely correlated with increased incidence, malignancy, poorer prognosis, and even higher cancer-related death. Research over the years has postulated various experimental models that have facilitated an understanding of the complex mechanisms underlying WNT signaling in CRC. In the present review, we have comprehensively summarized the in vitro, in vivo, patient-derived, and computational models used to study the role of WNT signaling in CRC. We discuss the use of CRC cell lines and organoids in capturing the molecular intricacies of WNT signaling and implementing xenograft and genetically engineered mouse models to mimic the tumor microenvironment. Patient-derived models, including xenografts and organoids, provide valuable insights into personalized medicine approaches. Additionally, we elaborated on the role of computational models in simulating WNT signaling dynamics and predicting therapeutic outcomes. By evaluating the advantages and limitations of each model, this review highlights the critical contributions of these systems to our understanding of WNT signaling in CRC. We emphasize the need to integrate diverse model systems to enhance translational research and clinical applications, which is the primary goal of this review.

Keywords:  Colorectal cancer; Computational models; Mouse models; Organoid models; WNT signaling

DOI:  https://doi.org/10.1016/j.bbcan.2025.189354
Cancer Cell. 2025 May 27. pii: S1535-6108(25)00212-0. [Epub ahead of print]

The pan-cancer proteome atlas, a mass spectrometry-based landscape for discovering tumor biology, biomarkers, and therapeutic targets.

Jaco C Knol, Mengge Lyu, Franziska Böttger, Madalena Nunes Monteiro, Thang V Pham, Frank Rolfs, Andrea Vallés-Martí, Tim Schelfhorst, Richard R de Goeij-de Haas, Irene V Bijnsdorp, Shuaiyao Wang, Fangfei Zhang, Jun A, Bart A Westerman, Barbara Sitek, Janne Lehtiö, Jan Koster, Jan N M IJzermans, Hanneke W M van Laarhoven, Maarten F Bijlsma, Jan Paul Medema, Alex A Henneman, Sander R Piersma, Ruud H Brakenhoff, Jacqueline Cloos, Valentina Cordo', Daphne de Jong, Geert Kazemier, Danijela Koppers-Lalic, Mariette Labots, Tessa Y S Le Large, John W M Martens, Jules P P Meijerink, Madiha Mumtaz, Chantal Scheepbouwer, Robby E Kibbelaar, David P Noske, Renske D M Steenbergen, Nicole C T van Grieken, Winan van Houdt, Elisa Giovannetti, Geert J L H van Leenders, Jos Jonkers, Tong Liu, Meisi Yan, Xiaolu Zhan, Tiannan Guo, Connie R Jimenez.

  Most cancer proteomics studies to date have focused on a single cancer type. We report The Pan-Cancer Proteome Atlas (TPCPA) based on data-independent acquisition mass spectrometry, to better understand cancer biology and identify therapeutic targets and biomarkers. TPCPA includes 9,670 proteins derived from 999 primary tumors representing 22 cancer types. We describe pan-cancer and cancer type-enriched proteins with extensive external annotation, prioritizing candidate drug targets and biomarkers. Relevant for proteolysis-targeting chimeras, we identify E3-ubiquitin ligases highly expressed in specific tumor types, including HERC5 (esophageal cancer) and RNF5 (liver cancer). Co-expression analysis reveals 13 modules, including unexpected hub proteins as potential drug targets (e.g., GFPT1, LRPPRC, PINK1, DOCK2, and PTPN6). Analysis of 195 colorectal cancers identifies protein markers for RNA-based consensus molecular subtypes (CMSs) and two immune subtypes with prognostic value. We report a cancer type classifier for identification of cancers of unknown primary origin. All TPCPA data can be queried in a dedicated web resource.

Keywords:  bioinformatics; biomarker/ target; colorectal cancer subtypes; mass spectrometry; multi-cancer (sub)type classification; pan-cancer; proteome

DOI:  https://doi.org/10.1016/j.ccell.2025.05.003
Proc Natl Acad Sci U S A. 2025 Jun 03. 122(22): e2502876122

CRISPR screen reveals a simultaneous targeted mechanism to reduce cancer cell selenium and increase lipid oxidation to induce ferroptosis.

Sophia M Lamperis, Kaylin M McMahon, Andrea E Calvert, Jonathan S Rink, Karthik Vasan, Madhura R Pandkar, Eliana U Crentsil, Zachary R Chalmers, Natalie R McDonald, Cameron J Kosmala, Marcelo G Bonini, Daniela Matei, Leo I Gordon, Navdeep S Chandel, C Shad Thaxton.

  Ferroptosis is a cell death mechanism distinguished by its dependence on iron-mediated lipid oxidation. Cancer cells highly resistant to conventional therapies often demonstrate lipid metabolic and redox vulnerabilities that sensitize them to cell death by ferroptosis. These include a unique dependency on the lipid antioxidant selenoenzyme, glutathione peroxidase 4 (GPx4), that acts as a ferroptosis inhibitor. Synthetic high-density lipoprotein-like nanoparticle (HDL NP) targets the high-affinity HDL receptor scavenger receptor class B type 1 (SR-B1) and regulates cell and cell membrane lipid metabolism. Recently, we reported that targeting cancer cell SR-B1 with HDL NP depleted cell GPx4, which is accompanied by increased cell membrane lipid peroxidation and cancer cell death. These data suggest that HDL NP may induce ferroptosis. Thus, we conducted an unbiased CRISPR-based positive selection screen and target validation studies in ovarian clear cell carcinoma (OCCC) cell lines to ascertain the mechanism through which HDL NP regulates GPx4 and kills cancer cells. The screen revealed two genes, acyl-CoA synthetase long chain family member 4 (ACSL4) and thioredoxin reductase 1 (TXNRD1), whose loss conferred resistance to HDL NP. Validation of ACSL4 supports that HDL NP induces ferroptosis as the predominant mechanism of cell death, while validation of TXNRD1 revealed that HDL NP reduces cellular selenium and selenoprotein production, most notably, GPx4. Accordingly, we define cancer cell metabolic targets that can be simultaneously actuated by a multifunctional, synthetic HDL NP ligand of SR-B1 to kill cancer cells by ferroptosis.

Keywords:  cancer; cell death; ferroptosis; lipids; nanoparticles

DOI:  https://doi.org/10.1073/pnas.2502876122
Discov Oncol. 2025 May 27. 16(1): 935

Butyrate confers colorectal cancer cell resistance to anti-PD-1 therapy by promoting CPT1A-mediated fatty acid oxidation.

Ran Zhu, Shujiang Gu, Yuan Tao, Yan Zhang.

  Immunotherapy including anti-PD-1 demonstrated therapeutic promise to colorectal cancer (CRC) patients, but tumor cell resistance limits their efficacy. Butyrate may influence therapeutic outcomes by modulating tumor metabolism, but it remains unclear whether butyrate influences CRC cell resistance to anti-PD-1 therapy. We aimed to investigate whether butyrate promotes resistance to anti-PD-1 therapy in CRC and underlying metabolic and immunologic mechanisms. CRC murine models were established by subcutaneously inoculating MC38 cells or butyrate/anti-PD-1-administered tumor cells of mice, followed by treatment with butyrate, anti-PD-1, or a combination. Therapeutic efficacy was assessed by tumor growth and survival outcomes. In vitro, HCT116 cells were exposed to monotherapy or co-therapy regimens. Carnitine Palmitoyltransferase 1A (CPT1A) knockdown was conducted by shRNA transfection both in vivo and in vitro. Fatty acid oxidation (FAO) was determined by oxygen consumption rate and CPT1A expression. CD8+ T cell cytotoxicity assays and CD8 expression in tumors were performed to evaluate immune cell infiltration. The addition of butyrate into anti-PD-1 treatment combination did not improve survival or reduce tumor volume compared to anti-PD-1 alone, with a marked activation of CPT1A observed in treated tumor tissues. Butyrate significantly elevated FAO, contributing to elevated oxygen consumption rate and reduced CD8+ T cell cytotoxicity. However, in sh-CPT1A models, the combination therapy significantly improved antitumor efficacy and restored CD8+ T cell infiltration. Furthermore, CRC patient samples resistant to anti-PD-1 therapy exhibited elevated CPT1A levels. Butyrate-induced CPT1A-mediated FAO promotes resistance to anti-PD-1 therapy in CRC, suggesting that targeting CPT1A might enhance the efficacy of immunotherapy.

Keywords:  Anti-PD-1 therapy; Butyrate; CPT1A; Colorectal cancer; Fatty acid oxidation; Immune resistance

DOI:  https://doi.org/10.1007/s12672-025-02686-x
Sci Adv. 2025 May 30. 11(22): eadv3201

Intestinal L-cell mechanoreception regulates hepatic lipid metabolism through GLP-1.

Luyang Gao, Ke Yang, Yawen Zhao, Jinshan Zhang, Shaohua Jiang, Rujiao Zhang, Wenxin He, Yuhang Zhao, Qianqian Ye, Geyang Xu.

Glucagon-like peptide-1 (GLP-1), secreted by intestinal L cells, is essential for lowering postprandial glucose levels and regulating hepatic lipid metabolism.We investigate the effects of manipulating Piezo1 in L cells on hepatic lipid metabolism. We found that normal and high-fat diet-fed L cell-specific Piezo1 knockout (IntL-Piezo1-/-) mice exhibited reduced circulating GLP-1 levels, increased hepatic lipid accumulation, decreased β-catenin expression, and elevated lipogenesis-related genes and proteins, including SREBP1c, PPARγ, FASN, and ACC. Treatment with exendin-4 improved fatty liver in IntL-Piezo1-/- mice by stimulating β-catenin and inhibiting de novo lipogenesis. Intestinal bead implantation stimulated GLP-1 release and inhibited lipid synthesis in livers of diet-induced obese mice but not in IntL-Piezo1-/- mice. In primary hepatocytes derived from IntL-Piezo1-/- mice, lipid accumulation and enhanced fatty acid synthesis were associated with reduced β-catenin expression and impaired nuclear translocation. Exendin-4 treatment alleviated lipid accumulation, which was blocked by the β-catenin inhibitor nitazoxanide. L-cell mechanoreception is vital for regulating hepatic lipid metabolism through GLP-1.

DOI: https://doi.org/10.1126/sciadv.adv3201
J Exp Clin Cancer Res. 2025 05 28. 44(1): 164

Acetylation-induced degradation of ECHS1 enhances BCAA accumulation and proliferation in KRAS-mutant colorectal cancer.

Zhenkang Li, Zhengyu Liu, Mingdao Lin, Huayang Pan, Yuechen Liu, Yang Liu, Yuwen Xie, Jinchao Zhang, Shenyuan Guan, Yongsheng Li, Mulan Zhu, Yuan Fang, Zhiyong Shen, Haijun Deng.

   BACKGROUND: Branched-chain amino acid (BCAA) metabolism is dysregulated in colorectal cancer (CRC), with elevated plasma BCAA levels significantly associated with an increased risk of developing the disease. However, whether BCAAs directly promote CRC progression and their underlying mechanisms remain unclear.
METHODS: In this study, we investigated the metabolic alterations in KRAS-mutant CRC. We examined the effects of restricting BCAA supply on the proliferation and metastasis of KRAS-mutant CRC cells both in vitro and in vivo.
RESULTS: We found that in KRAS-mutant CRC, BCAAs and their metabolic products accumulate markedly. Restricting the BCAA supply specifically inhibits the proliferation of KRAS-mutant CRC cells but does not affect metastasis. In these cancer cells, enoyl-CoA hydratase-1 (ECHS1), a key enzyme in BCAA metabolism, is downregulated. Furthermore, BCAAs enhance the acetylation of lysine 204 on ECHS1, impairing its ability to bind enoyl-CoA and reducing its catalytic activity. This modification triggers the ubiquitination of ECHS1 and its subsequent degradation, diminishing BCAA catabolism and leading to its cellular accumulation. This accumulation activates the mTORC1 signaling pathway, which induces the transcriptional activation of downstream target proteins and promotes the malignant progression of CRC.
CONCLUSIONS: Limiting BCAA intake not only suppresses tumor growth in KRAS-mutant CRC but also enhances the efficacy of the KRAS G12D inhibitor MRTX1133 and the monoclonal antibody bevacizumab. Our findings reveal a previously unknown regulatory mechanism of ECHS1 in CRC and offer new potential therapeutic targets.

Keywords:  Acetylation; BCAAs; Colorectal cancer; KRAS

DOI:  https://doi.org/10.1186/s13046-025-03399-3
Oncogene. 2025 May 28.

BRD4 regulates PAI-1 expression in tumor-associated macrophages to drive chemoresistance in colorectal cancer.

Dun Pan, Jinfeng Hu, Guo Li, Xuming Gao, Jie Wang, Leisi Jiang, Hong Lin, Yulin Chen, Yanheng Chen, Yiran Zheng, Junjin Lin, Min Zheng, Hui Chen, Lin-Feng Chen, Xiangming Hu.

Tumor-associated macrophages (TAMs) in the tumor microenvironment play a key role in drug resistance, but the mechanisms underlying TAM polarization and its role in drug resistance remain unclear. Here, we identified BRD4 as a critical factor in TAM polarization and drug resistance in colorectal cancer (CRC). BRD4 deficiency in macrophages impaired M2-like TAM polarization, and tumors from myeloid-lineage specific Brd4 conditional knockout (Brd4-CKO) mice displayed a reduction in infiltrating M2-like TAMs and an enhanced anti-tumor microenvironment. Colon cancer cells treated with conditioned medium from polarized Brd4-deficient TAMs, as well as tumors in Brd4-CKO mice, were more sensitive to oxaliplatin. RNA-seq and cytokine microarray analysis revealed that mRNA and protein levels of PAI-1 were significantly decreased in Brd4-deficient polarized TAMs. BRD4 was recruited to the promoter of Serpine1, promoting SMAD-dependent PAI-1 expression. Supplementing Brd4-deficient TAMs with recombinant PAI-1 hampered the sensitivity of colon cancer cells to oxaliplatin. Moreover, PAI-1 inhibitor and oxaliplatin synergistically suppressed the growth of colon tumors. Clinically, the expression levels of BRD4 in TAMs and PAI-1 in tumors were elevated in CRC patients with chemoresistance, correlating with shorter recurrence-free survival. Collectively, our findings uncover a novel role for BRD4 in TAM polarization and drug resistance via PAI-1 upregulation, suggesting the BRD4/PAI-1 axis as a potential prognostic marker and therapeutic target in CRC.

DOI: https://doi.org/10.1038/s41388-025-03453-6
Cells. 2025 05 15. pii: 717. [Epub ahead of print]14(10):

The Metabolic Landscape of Cancer Stem Cells: Insights and Implications for Therapy.

Martina Milella, Monica Rutigliano, Savio Domenico Pandolfo, Achille Aveta, Felice Crocetto, Matteo Ferro, Antonio d'Amati, Pasquale Ditonno, Giuseppe Lucarelli, Francesco Lasorsa.

  Cancer stem cells (CSCs) are a subpopulation with self-renewal and differentiation capacities believed to be responsible for tumor initiation, progression, and recurrence. These cells exhibit unique metabolic features that contribute to their stemness and survival in hostile tumor microenvironments. Like non-stem cancer cells, CSCs primarily rely on glycolysis for ATP production, akin to the Warburg effect. However, CSCs also show increased dependence on alternative metabolic pathways, such as oxidative phosphorylation (OXPHOS) and fatty acid metabolism, which provide necessary energy and building blocks for self-renewal and therapy resistance. The metabolic plasticity of CSCs enables them to adapt to fluctuating nutrient availability and hypoxic conditions within the tumor. Recent studies highlight the importance of these metabolic shifts in maintaining the CSC phenotype and promoting cancer progression. The CSC model suggests that a small, metabolically adaptable subpopulation drives tumor growth and therapy resistance. CSCs can switch between glycolysis and mitochondrial metabolism, enhancing their survival under stress and dormant states. Targeting CSC metabolism offers a promising therapeutic strategy; however, their adaptability complicates eradication. A multi-targeted approach addressing various metabolic pathways is essential for effective CSC elimination, underscoring the need for further research into specific CSC markers and mechanisms that distinguish their metabolism from normal stem cells for successful therapeutic intervention.

Keywords:  cancer; markers; stem cells; treatment

DOI:  https://doi.org/10.3390/cells14100717
Mol Cancer. 2025 May 26. 24(1): 151

GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis.

Linfei Huang, Meng Wei, Huilong Li, Mingxin Yu, Luming Wan, Ruzhou Zhao, Qi Gao, Lijuan Sun, Xufeng Hou, Yunhai Mo, Qing Huang, Lan Zhen, Xiaopan Yang, Jingfei Li, Nan Wang, Chundong Zhang, Haoran Jin, Li Zhou, Yixin Xu, Haotian Lin, Xuhui Zhang, Boan Li, Yue Han, Jing Yuan, Rui Zhang, Feixiang Wu, Hui Zhong, Congwen Wei.

  Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.

Keywords:  Colorectal cancer; Exosome; Golgi protein 73; Metastasis

DOI:  https://doi.org/10.1186/s12943-025-02350-6
Nat Commun. 2025 May 27. 16(1): 4884

Spike-in enhanced phosphoproteomics uncovers synergistic signaling responses to MEK inhibition in colon cancer cells.

Mirjam van Bentum, Bertram Klinger, Anja Sieber, Sheyda Naghiloo, Henrik Zauber, Nadine Lehmann, Mohamed Haji, Sylvia Niquet, Philipp Mertins, Nils Blüthgen, Matthias Selbach.

Targeted kinase inhibitors are a cornerstone of cancer therapy, but their success is often hindered by the complexity of cellular signaling networks that can lead to resistance. Overcoming this challenge necessitates a deep understanding of cellular signaling responses. While standard global phosphoproteomics offers extensive insights, lengthy processing times, the complexity of data interpretation, and frequent omission of crucial phosphorylation sites limit its utility. Here, we combine data-independent acquisition (DIA) with spike-in of synthetic heavy stable isotope-labeled phosphopeptides to facilitate the targeted detection of particularly informative phosphorylation sites. Our spike-in enhanced detection in DIA (SPIED-DIA) approach integrates the improved sensitivity of spike-in-based targeted detection with the discovery potential of global phosphoproteomics into a simple workflow. We employed this method to investigate synergistic signaling responses in colorectal cancer cell lines following MEK inhibition. Our findings highlight that combining MEK inhibition with growth factor stimulation synergistically activates JNK signaling in HCT116 cells. This synergy emphasizes the therapeutic potential of concurrently targeting MEK and JNK pathways, as evidenced by the significantly impaired growth of HCT116 cells when treated with both inhibitors. Our results demonstrate that SPIED-DIA effectively identifies synergistic signaling responses in colorectal cancer cells, presenting a valuable tool for uncovering new therapeutic targets and strategies in cancer treatment.

DOI: https://doi.org/10.1038/s41467-025-59404-y
Nat Commun. 2025 May 30. 16(1): 5043

Multi-tissue expression and splicing data prioritise anatomical subsite- and sex-specific colorectal cancer susceptibility genes.

Emma Hazelwood, Daffodil M Canson, Benedita Deslandes, Xuemin Wang, Pik Fang Kho, Danny Legge, Andrei-Emil Constantinescu, Matthew A Lee, D Timothy Bishop, Andrew T Chan, Stephen B Gruber, Jochen Hampe, Loic Le Marchand, Michael O Woods, Rish K Pai, Stephanie L Schmit, Jane C Figueiredo, Wei Zheng, Jeroen R Huyghe, Neil Murphy, Marc J Gunter, Tom G Richardson, Vicki L J Whitehall, Emma E Vincent, Dylan M Glubb, Tracy A O'Mara.

Genome-wide association studies have suggested numerous colorectal cancer (CRC) susceptibility genes, but their causality and therapeutic potential remain unclear. To prioritise causal associations between gene expression/splicing and CRC risk (52,775 cases; 45,940 controls), we perform a transcriptome-wide association study (TWAS) across six tissues with Mendelian randomisation and colocalisation, integrating sex- and anatomical subsite-specific analyses. Here we reveal 37 genes with robust causal links to CRC risk, ten of which have not previously been reported by TWAS. Most likely causal genes with evidence of cancer cell dependency show elevated expression linked to risk, suggesting therapeutic potential. Notably, SEMA4D, encoding a protein targeted by an investigational CRC therapy, emerges as a key risk gene. We also identify a female-specific association with CRC risk for CCM2 expression and subsite-specific associations, including LAMC1 with rectal cancer risk. These findings offer valuable insights into CRC molecular mechanisms and support promising therapeutic avenues.

DOI: https://doi.org/10.1038/s41467-025-60275-6
Inflamm Regen. 2025 May 28. 45(1): 15

From bench to bedside: the role of gastrointestinal stem cells in health and disease.

Xiaopeng Bai, Eikichi Ihara, Yoshimasa Tanaka, Yosuke Minoda, Masafumi Wada, Yoshitaka Hata, Mitsuru Esaki, Haruei Ogino, Takatoshi Chinen, Yoshihiro Ogawa.

  The gastrointestinal (GI) tract constitutes a sophisticated system integral to digestion, nutrient absorption, and overall health, with its functionality predominantly hinging on the distinctive properties of diverse stem cell types. This review systematically investigates the pivotal roles of stem cells across the esophagus, stomach, small intestine, and colon, emphasizing their crucial contributions to tissue homeostasis, repair mechanisms, and regeneration. Each segment of the GI tract is characterized by specialized stem cell populations that exhibit distinct functional attributes, highlighting the necessity for tailored therapeutic approaches in the management of gastrointestinal disorders.Emerging research has shed light on the functional heterogeneity of GI stem cells, with ISCs in the small intestine displaying remarkable turnover rates and regenerative potential, whereas colonic stem cells (CSCs) are essential for the preservation of the colonic epithelial barrier. The intricate interplay between stem cells and their microenvironment-or niche-is fundamentally important for their functionality, with critical signaling pathways such as Wnt and Notch exerting substantial influence over stem cell behavior. The advent of organoid models derived from GI stem cells offers promising avenues for elucidating disease mechanisms and for the preclinical testing of novel therapeutic interventions.Despite notable advancements in foundational research on GI stem cells, the translation of these scientific discoveries into clinical practice remains limited. As of 2025, Japan's clinical GI disease guidelines do not endorse any stem cell-based therapies, underscoring the existing disconnect between research findings and clinical application. This scenario accentuates the urgent need for sustained efforts to bridge this divide and to cultivate innovative strategies that synergize stem cell technology with conventional treatment modalities.Future investigations should be directed toward unraveling the mechanisms that underpin stem cell dysfunction in various gastrointestinal pathologies, as well as exploring combination therapies that harness the regenerative capacities of stem cells in conjunction with immunomodulatory treatments. By fostering collaborative endeavors between basic researchers and clinical practitioners, we can deepen our understanding of GI stem cells and facilitate the translation of this knowledge into effective therapeutic interventions, ultimately enhancing patient outcomes in gastrointestinal diseases.

Keywords:  Cancer stem cells; Gastrointestinal stem cells; Signaling pathways; Therapeutic applications; Tissue regeneration

DOI:  https://doi.org/10.1186/s41232-025-00378-1