bims-instec Biomed News
on Intestinal stem cells and chemoresistance in colon cancer and intestinal regeneration
Issue of 2025–12–07
sixteen papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain
  1. Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation.
  2. Decay of driver mutations shapes the landscape of intestinal transformation.
  3. FFAR4 drives stem cell fate toward lipid- and iron-storing enterocytes protecting human enteroids from ferroptosis.
  4. Polarized Distribution of Lipid Droplets with Long Acyl Chains and Unsaturation are Hallmarks of Human Intestinal Enteroid Differentiation.
  5. Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
  6. Analysis of experimental colorectal liver metastases identifies distinct proliferation-independent transcriptional programs in micro- versus macrometastases.
  7. Comparative metabolomics reveals specific metabolic signatures in colorectal cancer cell line models.
  8. Fosl1 is a transcriptional effector of BRAF V600E-driven intestinal tumorigenesis.
  9. Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.
  10. Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
  11. Loss of SATB2 in colorectal cancer is associated with inferior survival and adverse clinicopathologic features: a meta-analysis.
  12. Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice.
  13. Bioengineering mini-colons for ex vivo colorectal cancer research.
  14. A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases.
  15. TRPA1 activation prompts lysosome-mediated Nrf2 degradation enhancing the killing of colorectal cancer cells.
  16. A subset of MMR-proficient colon cancers responds to neoadjuvant immunotherapy.
  1. Sci Adv. 2025 Dec 05. 11(49): eady7272
    Drosophila and mouse intestinal stem cells are spatiotemporally specified by Notch suppression and Wnt activation.
    You Wu, Lingxiao Yu, Yuxin Yu, Song Wu, Qili Yuan, Weicheng Duan, Sicheng Cai, Bo Xiong, Rong Lin, Zheng Guo.
      The specification of intestinal stem cells (ISCs) during development is critical for maintaining intestinal homeostasis. However, the mechanisms underlying this process remain elusive. Here, by counting and tracing ISC in Drosophila pupal midgut, we show that ISCs are specified within a narrow 12-hour developmental window, with ~150 ISCs emerging from a pool of ~6000 intestinal epithelial cells. Single-cell sequencing revealed the involvement of Notch and Wnt signaling, with genetic experiments demonstrating that ISC specification requires both Notch suppression and Wnt activation. Furthermore, we showed that Wnt signaling is activated in discrete spatial domains, and Notch-mediated lateral inhibition specifies ISCs in these Wnt-active zones, achieving a ratio of ~1/40. Notably, Notch suppression also promoted the specification of Lgr5+ progenitors in the mouse embryonic intestine. Together, our data show that Wnt activation defines niches permissive for ISC fate, whereas Notch suppression licenses fate commitment, a spatiotemporal coordination conserved from insects to mammals.
    DOI:  https://doi.org/10.1126/sciadv.ady7272
  2. Nature. 2025 Dec 03.
    Decay of driver mutations shapes the landscape of intestinal transformation.
    Filipe C Lourenço, Iannish D Sadien, Kim Wong, Sam Adler, Ashley Sawle, Leonor Schubert Santana, Lee Hazelwood, Giada Giavara, Anna M Nicholson, Matthew D Eldridge, Noori Maka, Gerard Lynch, Stephen T McSorley, Joanne Edwards, Richard Kemp, David J Adams, Douglas J Winton.
      Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins1-4. Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.
    DOI:  https://doi.org/10.1038/s41586-025-09762-w
  3. Stem Cell Res Ther. 2025 Dec 01.
    FFAR4 drives stem cell fate toward lipid- and iron-storing enterocytes protecting human enteroids from ferroptosis.
    Mona Farhadipour, Hui Leng, Theo Thijs, Antoine Dubois, Ellen Deleus, Bart Van der Schueren, Matthias Lannoo, Laurens J Ceulemans, Marc Ferrante, Inge Depoortere.
       BACKGROUND: Intestinal stem cell (ISC) fate is directed by microenvironmental cues, partly regulated through surface receptors, many of which remain incompletely characterized. Here, we investigated the functional role of the lipid-sensing receptor free fatty acid receptor 4 (FFAR4) in regulating ISC fate in normal-weight individuals, and hypothesized that its function may be affected in the lipid-rich environment of patients with obesity.
    METHODS: Human-derived small intestinal organoids (enteroids) were developed from normal-weight multi-organ donors and from patients with obesity who underwent a Roux-en Y gastric bypass.
    RESULTS: In enteroids derived from normal-weight individuals, FFAR4 activation in ISCs promoted differentiation toward lipid-processing absorptive enterocytes while reducing secretory goblet cell formation. Functionally, mucin production was not affected but lipid droplet formation and iron storage were increased and blocked by a MEK1/2 inhibitor. This crosstalk reduced lipid peroxidation and hence the susceptibility to ferroptosis in the presence of environmental stressors. In contrast, FFAR4 activation in enteroids from patients with obesity failed to rewire the composition and function of the enteroid epithelium, suggesting impaired FFAR4 signaling in the obese ISC compartment.
    CONCLUSIONS: Altogether, our findings show that chemosensory receptors on stem cells play a more influential role than previously appreciated in modulating gut epithelial composition and function in response to environmental cues.
    Keywords:  FFAR4; Ferroptosis; Intestinal stem cell differentiation; Lipid metabolism; Obesity
    DOI:  https://doi.org/10.1186/s13287-025-04840-2
  4. Anal Chem. 2025 Dec 04.
    Polarized Distribution of Lipid Droplets with Long Acyl Chains and Unsaturation are Hallmarks of Human Intestinal Enteroid Differentiation.
    Patrik K Johansson, Yueming Liu, Katarina C Klett, Sarah C Heilshorn, Annika Enejder.
      Cell polarization and differentiation require increased energy mobilization and cell membrane synthesis, whereby mitochondria and lipid droplets (LDs) play key roles. However, how these metabolic organelles organize at the subcellular level to efficiently meet energy demands in human intestinal organoids is unclear. To address this, we introduce coherent anti-Stokes Raman scattering (CARS) microscopy multiplexed with confocal fluorescence microscopy to spatially map LDs and mitochondria throughout cell differentiation in human intestinal enteroids. The results show an overall decrease in LDs over time, though less pronounced for cells positive for proliferation or stemness markers. The LD depletion was observed in the apical region, resulting in a polarized distribution to the basal side. A similar mitochondrial polarization pattern was also observed in differentiated enteroids. Spectral CARS further shows that LDs postdifferentiation contain lipids with signatures of longer acyl chains and a higher degree of unsaturation. These observations demonstrate that polarized metabolic and lipid supply infrastructures are formed to support intestinal cell differentiation in organoid cultures.
    DOI:  https://doi.org/10.1021/acs.analchem.5c02648
  5. Cell Metab. 2025 Dec 02. pii: S1550-4131(25)00489-9. [Epub ahead of print]37(12): 2298-2300
    Tumor acidosis: Fusing mitochondrial dynamics and lipid metabolism.
    Sébastien Ibanez, Olivier Feron.
      Cancer cells experience multiple stresses within tumors, stemming from elevated metabolic activity, including nutrient shortage, waste buildup, hypoxia, and acidosis. According to Groessl et al.,1 acidosis is the dominant environmental factor offering metabolic flexibility to support tumor fitness and resilience to the other stresses by promoting mitochondria fusion and enhancing respiration capacity.
    DOI:  https://doi.org/10.1016/j.cmet.2025.11.005
  6. J Transl Med. 2025 Dec 03.
    Analysis of experimental colorectal liver metastases identifies distinct proliferation-independent transcriptional programs in micro- versus macrometastases.
    Niek A Peters, Maria C Heinz, Emre Küçükköse, Bastiaan J Viergever, Matthijs Baars, Mojtaba Amini, Maarten A Huismans, Daan Andel, Andre Verheem, Yvonne Vercoulen, Hugo Snippert, Inne H M Borel Rinkes, Onno Kranenburg.
      
    Keywords:  Caecum implantation; Colorectal cancer; Epithelial-to-mesenchymal transition; Liver metastasis; Micrometastases; Patient-derived organoids; Quiescence; Single-cell RNA sequencing
    DOI:  https://doi.org/10.1186/s12967-025-07218-3
  7. Discov Oncol. 2025 Dec 02.
    Comparative metabolomics reveals specific metabolic signatures in colorectal cancer cell line models.
    Manshan Li, Chuanyang Yu, Zhihua Li, Lianjie Xiong, Jiaru Wang, Xingyu Shang, Hehong Sun, Yanhong Chang, Xinxin Du, Ran Zheng.
      
    Keywords:  Cell line; Colorectal cancer (CRC); Metabolic heterogeneity; Metabolomics; Ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS)
    DOI:  https://doi.org/10.1007/s12672-025-04183-7
  8. iScience. 2025 Nov 21. 28(11): 113875
    Fosl1 is a transcriptional effector of BRAF V600E-driven intestinal tumorigenesis.
    Zakia Alam, Rebecca Nightingale, Analia Lesmana, Cheng Liu, Laura J Jenkins, Mark F Richardson, Lawrence Croft, Ian Y Luk, Camilla M Reehorst, Fiona Chionh, Natalia Vukelic, Faiza Basheer, Eugene Tulchinsky, Joshua Badshah, Troy Dumenil, Latifa Bakiri, Erwin F Wagner, Niall C Tebbutt, Vicki Whitehall, John M Mariadason, Amardeep S Dhillon.
      The serrated neoplasia pathway is an alternate route to colorectal cancer (CRC) development where BRAF V600E is the most common initiating genetic alteration. BRAFV600E-driven tumorigenesis requires gene expression changes mediated by activation of the ERK MAPK signaling pathway. However, the key effectors of this process are elusive. Here, we identify the ERK-regulated transcription factor Fosl1, one such effector. We show that Fosl1 is dispensable for the initiation of BRAFV600E-driven serrated neoplasia in mice but promotes progression of the disease by regulating the expression of genes involved in inflammation, immunity, cell cycle control, fetal-like programming, and gastric metaplasia. Notably, transgenic Fosl1 expression alone was sufficient to induce tumors with a BRAF V600E-like serrated morphology and transcriptional profile. These findings reveal a mechanism through which oncogenic BRAF-driven ERK signaling reprograms transcription to drive serrated neoplasia.
    Keywords:  Biological sciences; Cancer; Molecular mechanism of gene regulation
    DOI:  https://doi.org/10.1016/j.isci.2025.113875
  9. Adv Sci (Weinh). 2025 Dec 01. e14693
    Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.
    Nicole C Huning, Munir H Buhaya, Victor V Nguyen, Afeefah Khazi-Syed, Haider A Ali, Adil Khan, Angela Fan, Robert C Fisher, Zhikai Chi, Indu Raman, Guangchun Chen, Chengsong Zhu, Mengxi Yu, Andrew R Jamieson, Sara Roccabianca, Victor D Varner, Cheryl M Lewis, Emina H Huang, Jacopo Ferruzzi.
      While both incidence and mortality of sporadic average-onset colorectal cancer (AO CRC, above 50 years of age) are in constant decline, sporadic early-onset colorectal cancer (EO CRC, under 50 years of age) is rising rapidly. Yet, the causes behind this rise remain poorly understood. Epidemiological studies indicate that lifestyle and environmental exposures may result in chronic inflammation, which is known to trigger tissue fibrosis. This study tests the hypothesis that fibrotic remodeling and biomechanical stiffening of colorectal tissues represent measurable hallmarks and potential drivers of EO CRC. Using primary human tissues, this work shows that EO CRC is associated with changes in collagen microstructure, increased stiffness, and elevated viscosity of primary tumors. Spatial transcriptional profiling and immunostaining reveal pro-fibrotic signatures in stromal cells, alongside enhanced Yes-associated protein (YAP) mechanotransduction and proliferation in epithelial cells of EO CRC tissues. Mechanistically, increasing matrix stiffness in vitro promotes proliferation of epithelial cells in 2D and 3D colorectal cancer models. Together, these findings establish EO CRC as a disease marked by early and widespread biomechanical remodeling, suggesting that a fibrotic and stiffened tissue microenvironment may orchestrate EO CRC tumor initiation.
    Keywords:  YAP mechanotransduction; average‐onset; biomechanics; colorectal cancer; early‐onset; fibrosis; stiffness
    DOI:  https://doi.org/10.1002/advs.202514693
  10. Nat Aging. 2025 Dec 03.
    Peritumoral colonic epithelial cell-derived GDF15 sustains colorectal cancer via regulation of glycolysis and histone lactylation.
    Bingjie Guan, Mantang Zhou, Weixing Dai, Jing Zhang, Bowen Xie, Yushuai Mi, Xin Zhang, Ping Wei, Youdong Liu, Shanbao Li, Haonan Guan, Xiaoming Zhang, Sanjun Cai, Dawei Li, Dongwang Yan, Senlin Zhao.
      One of the most abundant cellular components of the normal adjacent tissue surrounding colorectal cancer is colonic epithelial cells (CECs); however, little is known about their interactions with tumor cells. Here we found that peritumoral CECs collaborate with cancer cells to orchestrate a pro-carcinogenic niche. In clinical cohort analyses, we show that growth differentiation factor 15 (GDF15) levels increase in normal adjacent tissue, in particular in CECs, at advanced disease and are inversely correlated with survival. Using mouse models, organoids and in vitro approaches, we link GDF15 upregulation to senescence in peritumoral CECs and identify a CEC-derived GDF15-driven metabolic feedback loop fueling tumor survival. We show that GDF15 secretion upregulates the glycolytic enzyme ENO1 in cancer cells, which triggers extracellular lactate release and subsequent lactylation of H4K8 in CECs, augmenting GDF15 transcription. Our findings establish a mode of intercellular crosstalk mediating collaboration between colorectal cancer cells and peritumoral CECs, providing a potential avenue for targeted intervention in colorectal cancer.
    DOI:  https://doi.org/10.1038/s43587-025-01023-9
  11. Am J Clin Pathol. 2025 Nov 29. pii: aqaf124. [Epub ahead of print]
    Loss of SATB2 in colorectal cancer is associated with inferior survival and adverse clinicopathologic features: a meta-analysis.
    Barry Maguire, Jochen H M Prehn, John P Burke.
       OBJECTIVES: Special AT-rich sequence binding protein 2 (SATB2) is a sensitive immunohistochemical marker of colorectal origin. Loss of SATB2 staining in colorectal cancer (CRC) has been associated with adverse outcomes, poor response to chemotherapy, and clinicopathologic features. This study summarizes the survival outcomes and clinicopathologic associations of SATB2 expression and CRC.
    METHODS: A literature search for studies of survival outcomes and clinicopathologic associations of SATB2 in CRC was undertaken. Meta-analysis with random-effects models was used to combine data.
    RESULTS: We analyzed 17 published studies comprising 7733 patients. SATB2 loss was seen in 19% of cases (risk ratio [RR], 0.19 [95% CI, 0.14-0.27]). SATB2 loss was associated with worse overall survival (RR, 0.76 [95% CI, 0.70-0.84]; P < .001) and worse disease-free survival (RR, 0.78 (95% CI, 0.72-0.86]; P < .001). SATB2 loss was associated with more advanced overall stage, nodal involvement, distant metastases, and right-sided tumor location. Loss was also associated with high-risk histologic features, including poor differentiation; lymphatic, venous, and perineural invasion; mucinous and signet ring histology; and tumor budding. SATB2 loss was also seen more commonly in microsatellite unstable and BRAF-mutated cases but was not associated with KRAS mutation.
    CONCLUSIONS: Loss of SATB2 staining in CRC is associated with inferior survival outcomes and adverse clinicopathologic features.
    Keywords:  SATB2 protein; cancer staging; colorectal cancer; prognosis
    DOI:  https://doi.org/10.1093/ajcp/aqaf124
  12. Nat Commun. 2025 Dec 05.
    Lack of intestinal Mucin-1 impairs intestinal epithelial barrier and promotes metabolic dysfunction-associated steatotic liver disease in male mice.
    Zecheng Li, Runchuan Gu, Donghai Liu, Yijia Zhang, Yijin Qin, Xinyu Li, Yuan Qiao, Ziyao Li, Jing Guo, Jun Wang, Hua Meng, Liang Peng.
      Accumulating evidence suggests that a compromised intestinal epithelial barrier (IEB) contributes to the progression of metabolic dysfunction-associated steatotic liver disease (MASLD); however, the exact mechanisms remain unclear. Here we reveal that intestinal mucin 1 (MUC1) levels and glycosylation are decreased in both humans and male mice with MASLD. Enterocyte-specific Muc1 knockout aggravates high-fat diet (HFD)-induced IEB impairment and MASLD progression in male mice. Mechanistically, HFD feeding reduces the glycosylation of intestinal epithelial MUC1, triggering its clathrin-mediated endocytosis and NEDD4-mediated lysosomal degradation, which subsequently induces β-Catenin degradation and ultimately impaires the IEB. Notably, enterocyte-specific overexpression of cytoplasmic-tail-deleted MUC1 protects against IEB impairment and mitigates MASLD progression. These findings indicate that reduced intestinal epithelial MUC1 levels facilitate the progression of MASLD. Preserving the glycosylation and levels of intestinal MUC1 to maintain IEB integrity is a potential therapeutic strategy to explore for MASLD.
    DOI:  https://doi.org/10.1038/s41467-025-67034-7
  13. Nat Protoc. 2025 Dec 03.
    Bioengineering mini-colons for ex vivo colorectal cancer research.
    L Francisco Lorenzo-Martín, Tania Hübscher, Jakob Langer, Mikhail Nikolaev, Matthias P Lutolf.
      Tumor initiation remains one of the least understood events in cancer biology, largely due to the challenge of dissecting the intricacy of the tumorigenic process in laboratory settings. The insufficient biological complexity of conventional in vitro systems makes animal models the primary experimental approach to study tumorigenesis. Despite providing valuable insights, these in vivo models function as experimental black boxes with limited spatiotemporal resolution of cellular dynamics during oncogenesis. In addition, their use raises ethical concerns, further underscoring the need for alternative ex vivo systems. Here we provide a detailed protocol to integrate state-of-the-art microfabrication, tissue engineering and optogenetic approaches to generate topobiologically complex miniature colons ('mini-colons') capable of undergoing tumorigenesis in vitro. We describe the key methodology for the generation of blue light-inducible oncogenic cells, the establishment of hydrogel-based mini-colon scaffolds within microfluidic devices, the development of mini-colons and the induction of spatiotemporally controlled tumorigenesis. This protocol enables the formation and long-term culture of complex cancerous tissues that capture in vivo-like tumoral biology while offering real-time and single-cell resolution analyses. It can be implemented in 4-6 weeks by researchers with prior experience in 3D cell culture techniques. We anticipate that these methodological guidelines will have a broad impact on the cancer research community by opening new avenues for tumorigenesis studies.
    DOI:  https://doi.org/10.1038/s41596-025-01292-z
  14. J Exp Clin Cancer Res. 2025 Dec 02.
    A novel role of secreted methionine adenosyltransferase α2 in colorectal liver metastases.
    Monica Justo, Youngyi Lim, Heping Yang, Andrea Floris, Swati Chandla, Manisha Dagar, Alexandra Gangi, Edwin Posadas, Mouad Edderkaoui, Stephen Pandol, Neil Bhowmick, Maria Lauda Tomasi, Shelly C Lu.
       BACKGROUND: Colorectal liver metastasis (CRLM) occurs frequently in patients with colorectal cancer (CRC). Methionine adenosyltransferase (MAT) catalyzes the formation of S-adenosylmethionine, the principal methyl donor. MAT1A (encodes MATα1) is expressed mainly in normal adult liver, whereas MAT2A (encodes MATα2) is expressed in all extrahepatic tissues. MAT1A is a major defense against CRLM as loss of Mat1a sensitizes the liver to CRLM. In contrast, MAT2A is overexpressed in CRC and promotes oncogenicity. Here, we sought to determine if CRCs secrete MATα2 and if this influences CRLM.
    METHODS: Our study included human hepatocytes, human CRC cells, extracellular vesicle (EV) isolation, chromatin immunoprecipitation (ChIP), ChIP-seq, promoter activity assays, proliferation, migration, and invasion assays, western blotting, immunohistochemistry and immunofluorescence. We confirmed some of the findings using human hepatocyte spheroids, CRLM and normal liver tissue array, and plasma samples.
    RESULTS: CRCs secrete MATα2 in free but truncated form (MATα2-t) and intact within EVs (EV-MATα2). EV-MATα2 can be internalized by human hepatocytes and CRCs, found within the nucleus, which then binds to MAT1A and MAT2A promoters on ChIP to lower and increase MAT1A and MAT2A promoter activities, respectively. In human CRLM samples, hepatocytes in nontumor regions express lower MATα1 but higher MATα2 as compared to normal liver. Treating RKO cells with EVs released from RKO cells overexpressing MAT2A promoted cell proliferation, migration, and invasion. MATα2-t was detected at a higher level in media from colon, pancreatic, and prostate cancer cell lines than corresponding normal epithelial cells as well as in the plasma of CRC patients as compared to healthy controls. RKO cells treated with MATα2-t activated focal adhesion kinase (FAK), an important kinase for cancer cell evasion of apoptosis. Conversely, treatment with MATα2 neutralizing antibody inhibited FAK and induced apoptosis.
    CONCLUSIONS: CRC cells secrete both MATα2 within EVs and free MATα2-t. EV-MATα2 can be internalized and act as a transcription factor to lower hepatocytes' MAT1A, the major defense against CRLM, while promoting CRC oncogenicity. Freely released MATα2-t acts as a ligand in an autocrine fashion to activate FAK, which is essential for CRC survival. Taken together, secreted MATα2 plays an essential role in promoting CRLM.
    Keywords:  Colorectal cancer; Colorectal liver metastasis; Exosomes; Extracellular vesicles; FAK; Hepatocytes; MAT1A; MAT2A
    DOI:  https://doi.org/10.1186/s13046-025-03599-x
  15. Redox Biol. 2025 Nov 25. pii: S2213-2317(25)00455-0. [Epub ahead of print]88 103942
    TRPA1 activation prompts lysosome-mediated Nrf2 degradation enhancing the killing of colorectal cancer cells.
    Najmeh Eskandari, Davide Delisi, Maedeh Vakili Saatloo, Gizem Keceli, Nathalia Pinheiro, Scott Eblen, Nazareno Paolocci, Saverio Gentile.
      Redox homeostasis is crucial for cancer cell survival and resistance to therapy. The transcription factor NRF2, a master regulator of antioxidant and metabolic genes, is often upregulated in tumors to mitigate oxidative stress. Although NRF2 stability is canonically governed by KEAP1-CUL3-proteasome degradation, emerging evidence implicates lysosomal and autophagic pathways in non-canonical NRF2 turnover. The mechanisms by which these alternative pathways are engaged during chronic oxidative signaling remain unclear. We investigated whether sustained activation of the redox-sensitive ion channel TRPA1 by cannabidiol (CBD) disrupts redox homeostasis and promotes NRF2 degradation in colorectal cancer models. Using five independent CRC cell lines (RKO, HCT116, HT29, SW480, and MC38), we assessed reactive oxygen species (ROS), mitochondrial function, autophagy, and NRF2 protein dynamics through biochemical assays, lysosomal fractionation, and imaging. Xenograft models were used for in vivo validation. Chronic TRPA1 activation induced a biphasic ROS response, characterized by an early increase linked to mitochondrial Ca2+ influx and a delayed ROS surge associated with mitochondrial dysfunction. This oxidative trajectory initially stabilized but subsequently led to its degradation after 24 h via a KEAP1-independent, autophagy-lysosome pathway. Proteasome inhibition failed to rescue NRF2, whereas bafilomycin A1 restored its levels and blocked co-localization with lysosomal markers (e.g., LAMP2A). Importantly, CBD-induced TRPA1 activation sensitized CRC cells to oxaliplatin, triggering apoptotic-not senescent-cell death. These effects were dose-dependent and consistent across all tested cell lines. Our findings reveal a non-canonical bioelectric-lysosomal axis that links TRPA1 activity to NRF2 destabilization in colorectal cancer. This work expands the understanding of NRF2 proteostasis under sustained oxidative stress and highlights TRPA1 as a tractable redox-modulating target for overcoming chemoresistance.
    DOI:  https://doi.org/10.1016/j.redox.2025.103942
  16. Mol Oncol. 2025 Nov 30.
    A subset of MMR-proficient colon cancers responds to neoadjuvant immunotherapy.
    Eleonora Piumatti, Giovanni Germano, Pietro Paolo Vitiello, Alberto Bardelli.
      Mismatch repair-proficient (pMMR) colorectal cancers (CRC) have long been considered nonresponsive to immune checkpoint blockade (ICB), in contrast to their mismatch repair-deficient (dMMR) counterparts. Recent evidence indicates that neoadjuvant immunotherapy can be used to treat pMMR CRC before surgery, potentially reducing postoperative relapse. Tan et al. report results from the NICHE-2 trial, which achieved a 26% response rate in early-stage pMMR colon cancer (CC) patients. Molecular studies show that despite low tumor mutational burden (TMB), responders exhibit higher chromosomal instability (CIN), TP53 mutations, and enrichment of proliferative and cell-cycle signatures, associated with higher density of Ki-67+ tumor and CD8+ T cells. In contrast, nonresponders display metabolic and stromal reprogramming, enhanced TGF-β signaling, and immune exclusion. Circulating tumor DNA (ctDNA) clearance correlated with pathological response and long-term disease-free survival postsurgery. While the biological and molecular determinants underlying the response rates observed in the NICHE-2 trial remain to be fully elucidated, the work by Tan et al. suggests that biomarker-guided neoadjuvant immunotherapy could represent a valuable strategy to achieve pathological responses in early-stage pMMR CC, despite its clinical relevance requiring further evaluation.
    Keywords:  Colon cancer; MMR‐proficient; chromosomal instability; circulating tumor DNA; neoadjuvant immunotherapy; tumor microenvironment
    DOI:  https://doi.org/10.1002/1878-0261.70178
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