bims-instec 2025-02-16 papers

bims-instec

Biomed News

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

Issue of 2025–02–16
twelve papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Lactate controls cancer stemness and plasticity through epigenetic regulation.
Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer.
Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors.
Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation.
Immunosensitivity cuts across mismatch repair status in colorectal cancer.
EpCAM deficiency causes the premature ageing of intestinal stem cells via EGFR/SP1/mTORC1 pathway.
Identification of Lipid Species Signatures in FOLFOXIRI-Resistant Colorectal Cancer Cells.
Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells.
Comparative analysis of senescence induction by different chemotherapeutic agents in HCT116 colon cancer cells.
Oxidative High Mobility Group Box-1 Accelerates Mitochondrial Transfer from Mesenchymal Stem Cells to Colorectal Cancer Cells Providing Cancer Cell Stemness.
Topological segregation of stress sensors along the gut crypt-villus axis.
Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.

Cell Metab. 2025 Feb 04. pii: S1550-4131(25)00002-6. [Epub ahead of print]

Lactate controls cancer stemness and plasticity through epigenetic regulation.

Nguyen T B Nguyen, Sira Gevers, Rutger N U Kok, Lotte M Burgering, Hannah Neikes, Ninouk Akkerman, Max A Betjes, Marlies C Ludikhuize, Can Gulersonmez, Edwin C A Stigter, Yvonne Vercoulen, Jarno Drost, Hans Clevers, Michiel Vermeulen, Jeroen S van Zon, Sander J Tans, Boudewijn M T Burgering, Maria J Rodríguez Colman.

  Tumors arise from uncontrolled cell proliferation driven by mutations in genes that regulate stem cell renewal and differentiation. Intestinal tumors, however, retain some hierarchical organization, maintaining both cancer stem cells (CSCs) and cancer differentiated cells (CDCs). This heterogeneity, coupled with cellular plasticity enabling CDCs to revert to CSCs, contributes to therapy resistance and relapse. Using genetically encoded fluorescent reporters in human tumor organoids, combined with our machine-learning-based cell tracker, CellPhenTracker, we simultaneously traced cell-type specification, metabolic changes, and reconstructed cell lineage trajectories during tumor organoid development. Our findings reveal distinctive metabolic phenotypes in CSCs and CDCs. We find that lactate regulates tumor dynamics, suppressing CSC differentiation and inducing dedifferentiation into a proliferative CSC state. Mechanistically, lactate increases histone acetylation, epigenetically activating MYC. Given that lactate's regulation of MYC depends on the bromodomain-containing protein 4 (BRD4), targeting cancer metabolism and BRD4 inhibitors emerge as a promising strategy to prevent tumor relapse.

Keywords:  cancer metabolism; cell plasticity; cell types; cell-cell interactions; differentiation; heterogeneity; live imaging; organoids; single-cell tracking; stem cells

DOI:  https://doi.org/10.1016/j.cmet.2025.01.002
Nat Genet. 2025 Feb;57(2): 402-412

Oncofetal reprogramming drives phenotypic plasticity in WNT-dependent colorectal cancer.

Slim Mzoughi, Megan Schwarz, Xuedi Wang, Deniz Demircioglu, Gulay Ulukaya, Kevin Mohammed, Habiba Zorgati, Denis Torre, Lewis E Tomalin, Federico Di Tullio, Carlos Company, Yuliia Dramaretska, Marc Leushacke, Bruno Giotti, Tamsin Rm Lannagan, Daniel Lozano-Ojalvo, Panagiotis Karras, Peter B Vermeulen, Dan Hasson, Robert Sebra, Alexander M Tsankov, Owen J Sansom, Jean-Christophe Marine, Nick Barker, Gaetano Gargiulo, Ernesto Guccione.

Targeting cancer stem cells (CSCs) is crucial for effective cancer treatment, yet resistance mechanisms to LGR5+ CSC depletion in WNT-driven colorectal cancer (CRC) remain elusive. In the present study, we revealed that mutant intestinal stem cells (SCs) depart from their canonical identity, traversing a dynamic phenotypic spectrum. This enhanced plasticity is initiated by oncofetal (OnF) reprogramming, driven by YAP and AP-1, with subsequent AP-1 hyperactivation promoting lineage infidelity. The retinoid X receptor serves as a gatekeeper of OnF reprogramming and its deregulation after adenomatous polyposis coli (APC) loss of function establishes an OnF 'memory' sustained by YAP and AP-1. Notably, the clinical significance of OnF and LGR5+ states in isolation is constrained by their functional redundancy. Although the canonical LGR5+ state is sensitive to the FOLFIRI regimen, an active OnF program correlates with resistance, supporting its role in driving drug-tolerant states. Targeting this program in combination with the current standard of care is pivotal for achieving effective and durable CRC treatment.

DOI: https://doi.org/10.1038/s41588-024-02058-1
J Immunother Cancer. 2025 Feb 10. pii: e010598. [Epub ahead of print]13(2):

Sex and outcomes of patients with microsatellite instability-high and BRAF V600E mutated metastatic colorectal cancer receiving immune checkpoint inhibitors.

Vincenzo Nasca, Joseph Zhao, Javier Ros, Sara Lonardi, Koen Zwart, Romain Cohen, Marwan Fakih, Priya Jayachandran, Jeanine M L Roodhart, Jeroen Derksen, Rossana Intini, Francesca Bergamo, Giacomo Mazzoli, Filippo Ghelardi, Marta Ligero, Jitendra Jonnagaddala, Nicholas Hawkins, Robyn L Ward, Durgesh Wankhede, Hermann Brenner, Michael Hoffmeister, Marco Vitellaro, Lisa Salvatore, Claire Gallois, Pierre Laurent-Puig, Chiara Cremolini, Michael J Overman, Julien Taieb, David Tougeron, Thierry Andre, Jakob Nikolas Kather, Raghav Sundar, Javier Carmona, Elena Elez, Miriam Koopman, Filippo Pietrantonio.

   BACKGROUND: Immune checkpoint inhibitors (ICIs) are the gold standard therapy in patients with deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC). A significant proportion of patients show resistance, making the identification of determinants of response crucial. Growing evidence supports the role of sex in determining susceptibility to anticancer therapies, but data is lacking for patients with MSI-H CRC.
METHODS: In this real-world cohort comprising 624 patients with MSI-H mCRC receiving ICIs, we investigated the impact of sex on patients' outcomes, overall and according to RAS-BRAF mutational status or type of treatment (anti-PD-(L)1 with or without anti-CTLA-4 agents). We then investigated these associations also in two independent cohorts of patients with early-stage or advanced MSI-H CRC unexposed to ICIs. Finally, we explored two public microarray and RNA-seq datasets from patients with non-metastatic or metastatic MSI-H CRC to gain translational insights on the association between sex, BRAF status and immune contextures/ICI efficacy.
RESULTS: Although no differences were observed between females and males either overall or in the BRAF wild-type cohort, male sex was associated with inferior progression-free survival (PFS) and overall survival (OS) in the BRAF mutated cohort (in multivariable models, HR for PFS: 1.79, 95% CI: 1.13 to 2.83, p=0.014, and for OS: 2.33, 95% CI: 1.36 to 3.98, p=0.002). Males receiving anti-PD-(L)1 monotherapy had the worst outcomes, with a 3-year PFS and 3-year OS of 23.9% and 41.8%, respectively, while the addition of anti-CTLA-4 agents rescued such a worse outcome. We also observed that females experienced a higher frequency of any-grade immune-related adverse events. Conversely, sex was not prognostic in the independent cohorts of patients with MSI-H CRCs not treated with ICIs. Exploratory transcriptomic analyses suggest that tumors of males with BRAF mutated MSI-H metastatic CRC are characterized by an enrichment of androgen receptor signature and an immune-depleted microenvironment, with a reduction in memory B cells, activated natural killer cells, and activated myeloid dendritic cells.
CONCLUSIONS: Overall, our findings suggest a complex interplay between sex and BRAF mutational status that may modulate the activity of ICIs in patients with MSI-H mCRC and pave the way to novel tailored strategies.

Keywords:  Colorectal Cancer; Immune Checkpoint Inhibitor; Microsatellite; Mismatch repair - MMR

DOI:  https://doi.org/10.1136/jitc-2024-010598
J Immunother Cancer. 2025 Feb 13. pii: e010126. [Epub ahead of print]13(2):

Targeting adenosine enhances immunotherapy in MSS colorectal cancer with EGFRvIII mutation.

Fei Sun, Fangzhen Yao, Chunting Zeng, Yang Zhao, Bishan Liang, Shaowei Li, Yawen Wang, Qijing Wu, Yulu Shi, Zhiqi Yao, Jiao Wang, Yu Jiang, Chunhui Gu, Qiong Huang, Wangjun Liao, Na Huang, Chunlin Wang, Xiaoxiang Rong, Jing Wu, Yujing Tan, Jianjun Peng, Yong Li, Min Shi.

   BACKGROUND: Patients with microsatellite stable (MSS) colorectal cancer (CRC) often display resistance to immunotherapy. Epidermal growth factor receptor (EGFR)-targeted therapies have shown potential in enhancing immunotherapy, yet clinical benefits remain unfulfilled, which may relate to inadequate patient stratification.
METHODS: Circulating tumor cells and tumor tissues were collected from multicenter cohorts of patients with CRC receiving cetuximab to analyze EGFR variant type III (EGFRvIII) expression and immune infiltration. Syngeneic mouse models of EGFRvIII CRC were used to investigate the combined efficacy of adenosine inhibition and antiprogrammed cell death protein 1 (anti-PD-1).
RESULTS: EGFRvIII mutations are found in about 10% of MSS CRC and are associated with poor response to cetuximab therapy. EGFRvIII-mutated patients with CRC exhibit an adenosine-mediated immunosuppressive tumor microenvironment (TME) subtype. Combination therapy with adenosine inhibitors remodels the TME, reversing cetuximab resistance and enhancing anti-PD-1 efficacy in EGFRvIII CRC.
CONCLUSIONS: Our findings identified EGFRvIII-positive CRC as a distinct subtype characterized by adenosine-mediated immunosuppressive TME. Targeting adenosine significantly improved the efficacy of anti-PD-1 in MSS CRC.

Keywords:  adenosine; colorectal cancer; immunotherapy

DOI:  https://doi.org/10.1136/jitc-2024-010126
Cancer Cell. 2025 Feb 10. pii: S1535-6108(25)00028-5. [Epub ahead of print]43(2): 175-177

Immunosensitivity cuts across mismatch repair status in colorectal cancer.

Allyson Moraig Peddle, Gertjan Rasschaert, Sabine Tejpar.

In this issue of Cancer Cell, Acha-Sagredo et al. reveal an interferon-high immunophenotype in colorectal cancer that predicts responsiveness to immune checkpoint inhibitors across both mismatch repair-deficient and mismatch repair-proficient subtypes. They identify CD74 as a biomarker and establish the importance of epithelial interferon levels in regulating immune responses.

DOI: https://doi.org/10.1016/j.ccell.2025.01.010
Clin Transl Med. 2025 Feb;15(2): e70219

EpCAM deficiency causes the premature ageing of intestinal stem cells via EGFR/SP1/mTORC1 pathway.

Keying Li, Changlong Xu, Lulu Liu, Yunjuan Wang, Jun Chen, Chunyuan Li, Zitong Peng, Xiaoqian Li, Gang Chang, Zili Lei, Yanhong Yang.

DOI: https://doi.org/10.1002/ctm2.70219
Int J Mol Sci. 2025 Jan 29. pii: 1169. [Epub ahead of print]26(3):

Identification of Lipid Species Signatures in FOLFOXIRI-Resistant Colorectal Cancer Cells.

George M Ramzy, Isabel Meister, Serge Rudaz, Julien Boccard, Patrycja Nowak-Sliwinska.

  Chronic drug treatment can alter the lipidome of cancer cells, potentially leading to significant biological changes, such as drug resistance or increased tumor aggressiveness. This study examines the lipidome profiles of four human colorectal cancer (CRC) cell lines, comparing treatment-naïve cells with the same cells after chronic exposure to a clinically used combination therapy (FOLFOXIRI: folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan). Lipidomic profiling was obtained with untargeted liquid chromatography coupled with high-resolution mass spectrometry (LC-HRMS). For data deconvolution and to interpret the multifactorial dataset generated, Analysis of Variance Multiblock Orthogonal Partial Least Squares (AMOPLS) was used. Our results indicate specific shifts in triglycerides (TGs), sphingolipids, and phospholipids in CRC cells resistant to FOLFOXIRI. The overall shift in TGs, phosphatidylcholine, and cholesteryl ester species was notably linked to FOLFOXIRI resistance (-R) in SW620 cells, whereas an increased abundance of phospholipids, mainly hexosylceramide and sphingomyelin, was present in the signatures of HCT116-R, LS174T-R, and DLD1-R cells. These altered lipid species may serve as potential prognostic markers in CRC following chemotherapy. Furthermore, lipid-targeting therapies aimed at reprogramming the lipid profiles of drug-resistant cells could play a crucial role in restoring drug sensitivity and improving patient survival.

Keywords:  FOLFOXIRI; acquired drug resistance; colorectal carcinoma; drug combination; lipidomic; mass spectrometry; sphingolipids; triglycerides

DOI:  https://doi.org/10.3390/ijms26031169
Clin Transl Med. 2025 Feb;15(2): e70175

Immune profiling of the macroenvironment in colorectal cancer unveils systemic dysfunction and plasticity of immune cells.

Haoxian Ke, Peisi Li, Zhihao Li, Xian Zeng, Chi Zhang, Shuzhen Luo, Xiaofang Chen, Xinlan Zhou, Shichen Dong, Shaopeng Chen, Junfeng Huang, Ming Yuan, Runfeng Yu, Shubiao Ye, Tuo Hu, Zhonghui Tang, Dongbin Liu, Kui Wu, Xianrui Wu, Ping Lan.

   BACKGROUND: Tumour immune macroenvironment is comprised of tumour and surrounding organs responding to tumourigenesis and immunotherapy. The lack of comprehensive analytical methods hinders its application for prediction of survival and treatment response in colorectal cancer (CRC) patients.
METHODS: Cytometry by time-of-flight (CyTOF) and RNA-seq was applied to characterise immune cell heterogeneity in a discovery cohort including tumour, blood and intestinal architecture comprising epithelium, lamina propria, submucosa, muscularis propria of normal bowel and tumour-adjacent bowel tissues. Immunoprofiling was also validated by a validation cohort using single-cell RNA sequencing, spatial transcription, CyTOF and multiplex immunofluorescent staining.
RESULTS: Based on cell phenotype and transcription, we identify distinct immunotypes in the CRC macroenvironment including blood, tumour and different intestinal architecture, showing disturbed immune cell compositions, increasing expression of immunosuppressive markers and cell-cell interactions contributing to immunosuppressive regulation. Furthermore, we evaluate immune macroenvironment influencing factors including tertiary lymphoid structures (TLSs), consensus molecular subtypes (CMSs) and immune checkpoint inhibitors (ICIs). TLS presence fuels anti-tumour immunity by promoting CD8+ T cell infiltration and altering activation or suppression of T cell systematically. TLS presence correlates with patient survival, intrinsic CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in effector memory CD8+ T cells from blood can predict TLS presence in the CRC macroenvironment, serving as potential biomarkers for stratifying CRC patients into immunotherapy.
CONCLUSIONS: Our findings provide insights into the CRC immune macroenvironment, highlighting immune cell suppression and activation in tumourigenesis. Our study illustrates the potential utility of blood for predicting immunotherapy response.
KEY POINTS: Distinct immunotypes are identified in the CRC macroenvironment. TLS and immunotherapy exert influence on the immune macroenvironment. TLS presence correlates with patient survival, CMS and therapeutic efficacy of ICI. PD-1 and CD69 expressed in CD8+ Tem from blood can predict TLS presence in the CRC macroenvironment.

Keywords:  colorectal cancer; single‐cell omics; spatial transcription; tumour macroenvironment

DOI:  https://doi.org/10.1002/ctm2.70175
Biochem Biophys Res Commun. 2025 Feb 11. pii: S0006-291X(25)00196-2. [Epub ahead of print]752 151482

Comparative analysis of senescence induction by different chemotherapeutic agents in HCT116 colon cancer cells.

Adrien Pioger, Ingrid Loison, Inès Metatla, Nathalie Spruyt, Corinne Abbadie, Vanessa Dehennaut.

  Although chemotherapy-induced senescence (CIS) can slow tumor progression by halting the cell cycle, recent studies suggest that some cancer cells may escape this state, resume proliferation, and acquire a more aggressive phenotype. This phenomenon may contribute to chemotherapy resistance in colorectal cancer, highlighting the need to identify which treatments can effectively induce senescence. We previously demonstrated that low doses of SN38 (the active form of irinotecan) and etoposide induce senescence in HCT116 colon cancer cells, accompanied by reprogramming of the Hexosamine Biosynthesis Pathway (HBP) and O-GlcNAcylation. Here, we investigated whether other chemotherapeutic agents also induce senescence in these cells and whether changes in HBP and O-GlcNAcylation are hallmark features of CIS. Our results show that doxorubicin and cisplatin induce senescence, while 5-FU and oxaliplatin do not. Senescence induced by doxorubicin and cisplatin was associated with decreased expression of GFAT (the rate-limiting enzyme of the HBP), OGT, and OGA (the enzymes driving O-GlcNAcylation cycling), along with reduced O-GlcNAcylation levels, consistent with our previous findings. This suggests that HBP reprogramming and O-GlcNAcylation changes are hallmarks of CIS. Furthermore, they highlight the differential ability of chemotherapeutic agents to induce senescence in colorectal cancer cells, which could have implications for optimizing treatment strategies and exploring therapeutic approaches to counteract CIS.

Keywords:  Chemotherapy-induced senescence; Colorectal cancer; Hexosamine Biosynthesis Pathway; O-GlcNAcylation

DOI:  https://doi.org/10.1016/j.bbrc.2025.151482
Int J Mol Sci. 2025 Jan 30. pii: 1192. [Epub ahead of print]26(3):

Oxidative High Mobility Group Box-1 Accelerates Mitochondrial Transfer from Mesenchymal Stem Cells to Colorectal Cancer Cells Providing Cancer Cell Stemness.

Rika Sasaki, Yi Luo, Shingo Kishi, Ruiko Ogata, Yukiko Nishiguchi, Takamitsu Sasaki, Hitoshi Ohmori, Rina Fujiwara-Tani, Hiroki Kuniyasu.

  Mitochondria are important organelles for cell metabolism and tissue survival. Their cell-to-cell transfer is important for the fate of recipient cells. Recently, bone marrow mesenchymal stem cells (BM-MSCs) have been reported to provide mitochondria to cancer cells and rescue mitochondrial dysfunction in cancer cells. However, the details of the mechanism have not yet been fully elucidated. In this study, we investigated the humoral factors inducing mitochondrial transfer (MT) and the mechanisms. BM-MSCs produced MT in colorectal cancer (CRC) cells damaged by 5-fluorouracil (5-FU), but were suppressed by the anti-high mobility group box-1 (HMGB1) antibody. BM-MSCs treated with oxidized HMGB1 had increased expression of MT-associated genes, whereas reduced HMGB1 did not. Inhibition of nuclear factor-κB, a downstream factor of HMGB1 signaling, significantly decreased MT-associated gene expression. CRC cells showed increased stemness and decreased 5-FU sensitivity in correlation with MT levels. In a mouse subcutaneous tumor model of CRC, 5-FU sensitivity decreased and stemness increased by the MT from host mouse BM-MSCs. These results suggest that oxidized HMGB1 induces MTs from MSCs to CRC cells and promotes cancer cell stemness. Targeting of oxidized HMGB1 may attenuate stemness of CRCs.

Keywords:  NF–κB; cancer stemness; chemoresistance; colorectal cancer; mitochondrial transfer; oxidized HMGB1

DOI:  https://doi.org/10.3390/ijms26031192
Nature. 2025 Feb 12.

Topological segregation of stress sensors along the gut crypt-villus axis.

Kouki K Touhara, Nathan D Rossen, Fei Deng, Joel Castro, Andrea M Harrington, Tifany Chu, Sonia Garcia-Caraballo, Mariana Brizuela, Tracey O'Donnell, Jinhao Xu, Onur Cil, Stuart M Brierley, Yulong Li, David Julius.

The crypt-villus structure of the small intestine serves as an essential protective barrier. The integrity of this barrier is monitored by the complex sensory system of the gut, in which serotonergic enterochromaffin (EC) cells play an important part1,2. These rare sensory epithelial cells surveil the mucosal environment for luminal stimuli and transmit signals both within and outside the gut3-6. However, whether EC cells in crypts and villi detect different stimuli or produce distinct physiological responses is unknown. Here we address these questions by developing a reporter mouse model to quantitatively measure the release and propagation of serotonin from EC cells in live intestines. Crypt EC cells exhibit a tonic low-level mode that activates epithelial serotonin 5-HT4 receptors to modulate basal ion secretion and a stimulus-induced high-level mode that activates 5-HT3 receptors on sensory nerve fibres. Both these modes can be initiated by the irritant receptor TRPA1, which is confined to crypt EC cells. The activation of TRPA1 by luminal irritants is enhanced when the protective mucus layer is compromised. Villus EC cells also signal damage through a distinct mechanism, whereby oxidative stress activates TRPM2 channels, which leads to the release of both serotonin and ATP and consequent excitation of sensory nerve fibres. This topological segregation of EC cell functionality along the mucosal architecture constitutes a mechanism for the surveillance, maintenance and protection of gut integrity under diverse physiological conditions.

DOI: https://doi.org/10.1038/s41586-024-08581-9
Clin Cancer Res. 2025 Feb 10.

Results of the phase I/II study and preliminary B cell gene signature of combined inhibition of glutamine metabolism and EGFR in colorectal cancer.

Kristen K Ciombor, Seong-Woo Bae, Jennifer G Whisenant, Gregory D Ayers, Quanhu Sheng, Todd E Peterson, Gary T Smith, Kangyu Lin, Saikat Chowdhury, Preeti Kanikarla Marie, Alexey Sorokin, Allison S Cohen, Laura W Goff, Dana B Cardin, John Paul Shen, Scott Kopetz, Cathy Eng, Yu Shyr, Jordan Berlin, H Charles Manning.

PURPOSE: EGFR-targeting monoclonal antibodies are essential for managing RAS WT metastatic colorectal cancer (mCRC), but their limited efficacy necessitates exploring immunological and metabolic factors influencing response. This study evaluated glutamine metabolism targeting with EGFR inhibition to identify response biomarkers in patients with prior anti-EGFR treatment progression.
EXPERIMENTAL DESIGN: We conducted a phase I/II trial in KRAS WT mCRC patients, combining panitumumab and CB-839, hypothesizing that dual inhibition of glutamine metabolism and MAPK signaling would enhance outcomes. As study correlatives, we investigated the B cell activation signature 'Bscore' and glutamine PET as potential treatment response biomarkers.
RESULTS: The combination of panitumumab and CB-839 was tolerable with manageable side effects, including Grade 4 hypomagnesemia in four patients, a known panitumumab-related event. Two patients achieved partial response (PR), and five had stable disease (SD), with a 41% disease control rate (DCR). Median progression-free survival (PFS) and overall survival (OS) were 1.84 and 8.87 months, respectively. A positive correlation between 'Bscore' and lesion size reduction suggested its association with clinical benefit (PR and SD). Lower 'Bscore' correlated with greater tumor avidity for glutamine by PET, indicating B cell activation sensitivity to glutamine depletion.
CONCLUSIONS: The combination of CB-839 and panitumumab showed safety and promising preliminary responses, but the study closed early due to CB-839 development termination. The B cell activation signature 'Bscore' emerged as a potential biomarker for EGFR and glutaminase inhibition in mCRC, warranting further studies. These findings suggest opportunities to improve immune response and therapies in glutaminolysis-dependent tumors.

DOI: https://doi.org/10.1158/1078-0432.CCR-24-3133