bims-instec 2025-11-23 papers

bims-instec

Biomed News

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

Issue of 2025–11–23
eleven papers selected by
Maria-Virginia Giolito, Université Catholique de Louvain

Autophagy inhibition in intestinal stem cells favors enteroendocrine cell differentiation through Stat92E activity.
LEF1 Suppresses Ferroptosis in Colorectal Cancer Cells by Targeted Promotion of SLC7A11 Transcription.
Single-cell transcriptomic profiling reveals liver fibrosis in colorectal cancer liver metastasis.
Epigenetic conservation infers that colorectal cancer progenitors retain the phenotypic plasticity of normal colon.
FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.
Epithelial-derived basement membranes help orchestrate crypt-villus patterning in vitro.
ACSL6 modulates docosahexaenoic acid-induced cytotoxicity to potentiate chemotherapy response in colorectal and breast cancer.
Drug-tolerant persister cells in cancer: bridging the gaps between bench and bedside.
Single-cell integration analysis reveals molecular signatures of the tumor microenvironment in early-onset colorectal cancer.
Hepatic zonation determines tumorigenic potential of mutant β-catenin.
Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer.

Dis Model Mech. 2025 Nov 20. pii: dmm.052214. [Epub ahead of print]

Autophagy inhibition in intestinal stem cells favors enteroendocrine cell differentiation through Stat92E activity.

Camille Lacarrière-Keïta, Sonya Nassari, Jessica Boutet, Véronique Gaudreault, Steve Jean.

  Because the intestinal epithelium is exposed to various stressors, dysregulation of essential mechanisms that maintain gut homeostasis, such as autophagy, has been linked to inflammatory bowel pathologies. In Drosophila melanogaster, inhibition of autophagy specifically in adult intestinal stem cells (ISCs) affects their proportions differently during aging. Proper intestinal renewal requires a balance between ISC proliferation and differentiation. Here, we show that in adult ISCs, loss of core autophagy genes and regulators of autophagosome-lysosome fusion increases the enteroendocrine cell population and enhances the transcriptional activity of Stat92E. Functional experiments involving cell fate regulators of enteroendocrine or enterocyte differentiation and proliferation suggest that dysfunctional autophagy in adult ISCs enhances Stat92E activity downstream of Hop/JAK kinase. Finally, lineage-tracing analyses confirm that autophagy inhibition promotes enteroendocrine cell differentiation. Thus, our data demonstrate that, under homeostatic conditions, basal autophagy limits enteroendocrine cell differentiation by regulating Stat92E activity, which can be counteracted by the transcription factor Scute.

Keywords:   Drosophila ; Autophagy; Cell fate; Differentiation; Intestinal stem cell; JAK-STAT; Scute; Stat92E

DOI:  https://doi.org/10.1242/dmm.052214
FASEB J. 2025 Nov 30. 39(22): e71231

LEF1 Suppresses Ferroptosis in Colorectal Cancer Cells by Targeted Promotion of SLC7A11 Transcription.

Yanan Chen, Zhennan Ma, Xiuqing Gong.

  Ferroptosis has emerged as a promising therapeutic target for colorectal cancer (CRC) due to its ability to selectively eliminate cancer cells. By inducing ferroptosis, novel treatment strategies aim to overcome traditional challenges such as cancer recurrence and drug resistance. In this study, we screened cells with high LEF1 expression, knocked down LEF1, or simultaneously overexpressed SLC7A11 in these cells, and intervened with ferroptosis inducers and inhibitors to investigate the mechanism of LEF1 in inhibiting ferroptosis and promoting CRC cell growth. Dual-luciferase reporter assays and CHIP-qPCR were utilized to validate the effect of LEF1 on SLC7A11 transcription. Furthermore, a nude mouse subcutaneous xenograft model was established using CRC cells with stable LEF1 knockdown to verify the impact of LEF1 on CRC tumor growth in vivo. Our findings indicate that LEF1 knockdown inhibits CRC cell progression both in vitro and in vivo. Moreover, we discovered that the molecular mechanism underlying the role of LEF1 is the targeted activation of SLC7A11 transcription, which alleviates ferroptosis, ultimately leading to CRC progression. Our results suggest that LEF1 inhibits ferroptosis in CRC cells by promoting SLC7A11 transcription, potentially serving as a therapeutic target for CRC. This study reveals that the promotion of CRC by LEF1 is associated with activating SLC7A11 transcription and inhibiting cellular ferroptosis, providing a new direction for clinical targeted therapy of CRC.

Keywords:   LEF1 ; SLC7A11 ; colorectal cancer; erastin; ferroptosis

DOI:  https://doi.org/10.1096/fj.202502018R
Exp Mol Med. 2025 Nov 14.

Single-cell transcriptomic profiling reveals liver fibrosis in colorectal cancer liver metastasis.

Yiqiao Deng, Chengyao Guo, Xiaomeng Liu, Xin Li, Jianmei Liu, Wenjie Liu, Jinghua Chen, Zhen Huang, Yefan Zhang, Xinyu Bi, Jianjun Zhao, Jianguo Zhou, Zhiyu Li, Hongliang Wu, Baocai Xing, Qichen Chen, Hong Zhao.

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies.

DOI: https://doi.org/10.1038/s12276-025-01573-3
Sci Rep. 2025 Nov 20. 15(1): 40941

Epigenetic conservation infers that colorectal cancer progenitors retain the phenotypic plasticity of normal colon.

Kelly Street, Yifan Zhang, Kimberly Siegmund, Darryl Shibata.

  Plasticity, or the ability to rapidly and reversibly change phenotypes, may help explain how a single progenitor cell eventually generates a tumor with many different cell phenotypes. Normal colon plasticity is characterized by a conserved and broadly permissive epigenome, where expression and phenotype are determined by the microenvironment instead of epigenetic remodeling. To determine whether this stem-like plasticity is retained during progression, gene expression was measured with spatial transcriptomics and compared with gene-level DNA methylation in two colorectal cancers (CRCs). Like normal colon, genes that were differentially expressed between regions, subclones, and phenotypes (superficial, invasive, and metastatic) tended to have lower DNA methylation variability. We propose a quantitative signal of plasticity that correlates gene epigenetic variability with gene expression variability. In this framework, negative correlation implies phenotypic plasticity, as more variably expressed genes tend to have less epigenetic variability. We verify the presence of this signal in multiple external single-cell RNA-Seq datasets, in both normal colon and CRC samples. Therefore, the plasticity of normal colon appears to be retained during progression. A CRC progenitor with a preconfigured plastic phenotype is poised for rapid growth because it expresses, as needed, transcripts required for progression with minimal epigenetic remodeling.

Keywords:  Colorectal cancer; DNA methylation; Phenotypic plasticity; Spatial transcriptomics; Wound healing

DOI:  https://doi.org/10.1038/s41598-025-24703-3
EMBO Rep. 2025 Nov 20.

FOXO1 links KRAS G12D and G12V alleles to glutamine and nitrogen metabolism in colorectal cancer.

Suzan Ber, Ming Yang, Marco Sciacovelli, Shamith Samarajiwa, Khushali Patel, Efterpi Nikitopoulou, Annie Howitt, Simon J Cook, Ashok R Venkitaraman, Christian Frezza, Alessandro Esposito.

  Mutations in KRAS, particularly at codon 12, are frequent in adenocarcinomas of the colon, lungs and pancreas, driving carcinogenesis by altering cell signalling and reprogramming metabolism. However, the specific mechanisms by which different KRAS G12 alleles initiate distinctive patterns of metabolic reprogramming are unclear. Using isogenic panels of colorectal cell lines harbouring the G12A, G12C, G12D and G12V heterozygous mutations and employing transcriptomics, metabolomics, and extensive biochemical validation, we characterise distinctive features of each allele. We demonstrate that cells harbouring the common G12D and G12V oncogenic mutations significantly alter glutamine metabolism and nitrogen recycling through FOXO1-mediated regulation compared to parental lines. Moreover, with a combination of small molecule inhibitors targeting glutamine and glutamate metabolism, we also identify a common vulnerability that eliminates mutant cells selectively. These results highlight a previously unreported mutant-specific effect of KRAS alleles on metabolism and signalling that could be potentially harnessed for cancer therapy.

Keywords:  Colorectal Cancer; FOXO Signalling; Glutamine Metabolism; Glutamine Synthase; KRAS Mutation

DOI:  https://doi.org/10.1038/s44319-025-00641-z
Dev Cell. 2025 Nov 17. pii: S1534-5807(25)00638-0. [Epub ahead of print]60(22): 2997-2999

Epithelial-derived basement membranes help orchestrate crypt-villus patterning in vitro.

Janny Pineiro-Llanes, Mashael F Aldossari, Rodrigo Cristofoletti.

Intestinal organoid culture has widely depended on exogenous laminin-rich matrices to provide a supportive environment for organoid development. In this issue of Developmental Cell, Chrisnandy and Lütolf now report that human and mouse intestinal epithelial cells can secrete their own basement membrane, enabling organoid formation even without exogenous laminin.

DOI: https://doi.org/10.1016/j.devcel.2025.10.008
Oncogenesis. 2025 Nov 21. 14(1): 45

ACSL6 modulates docosahexaenoic acid-induced cytotoxicity to potentiate chemotherapy response in colorectal and breast cancer.

I-Sung Chen, Chi-Che Hsieh, Chun-Chun Li, You-Lin Wei, Chao-Chun Cheng, Sheng-Wei Feng, Hsin-Lun Lee, Nai-Jung Chiang, Che-Hung Shen, Hui-Ping Hsu.

Docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid, exhibits anticancer properties by modulating cell membrane composition, inducing oxidative stress, and triggering ferroptosis. Acyl-CoA synthetase long chain family member 6 (ACSL6) catalyzes DHA activation, yet its role in tumor growth and tumor sensitivity to DHA treatment remains unclear. We characterized the role of ACSL6 in regulating cell growth and DHA sensitivity in vitro cancer cells and in vivo xenograft tumors. ACSL6 expression was positively associated DHA sensitivity and enhanced chemotherapy efficacy in both colorectal and breast cancer cell lines, as well as with improved responsiveness to standard treatments in patients with these cancers. ACSL6 suppressed cell growth, inhibited AKT/ERK signaling, reduced ATP production, and activated AMPK signaling, supporting its tumor-suppressive role. Importantly, ACSL6 knockdown increased GPX4 expression and colony growth, partially rescuing DHA-induced suppression, whereas ACSL6 overexpression enhanced DHA-mediated GPX4 reduction and colony inhibition, effects reversible by RSL3 or ferrostatin-1. Moreover, ACSL6 enhances DHA-induced lipid peroxidation. These support that ACSL6 enhances DHA-induced ferroptosis, leading to growth suppression. In vivo, DHA supplementation potentiated oxaliplatin-suppressed tumor growth in tumors with upregulated ACSL6 expression, accompanied by GPX4 reduction. Together, these findings highlight ACSL6 as a critical determinant of DHA sensitivity in cancer, underscoring its potential as a predictive biomarker for chemotherapy-DHA combination strategies. By modulating key metabolic and signaling pathways, ACSL6 could influence cellular susceptibility to ferroptosis and may guide therapeutic approaches that enhance chemotherapy through DHA supplementation.

DOI: https://doi.org/10.1038/s41389-025-00588-9
Nat Commun. 2025 Nov 17. 16(1): 10048

Drug-tolerant persister cells in cancer: bridging the gaps between bench and bedside.

Zhile Wang, Mengyao Wang, Bo Dong, Yuqing Wang, Zheyu Ding, Shensi Shen.

Drug-tolerant persister (DTP) cells represent a major obstacle to achieving durable cancer remission, yet their biology and clinical relevance remain poorly understood. This perspective highlights key gaps hindering the translation of DTP research into clinical progress, emphasizing the need to move beyond reductionist models toward integrative, patient-aligned approaches that reflect clinical complexity. Bridging these divides will be crucial to reveal actionable biomarkers and develop therapies capable of eradicating these resilient cell populations.

DOI: https://doi.org/10.1038/s41467-025-66376-6
NPJ Precis Oncol. 2025 Nov 18. 9(1): 360

Single-cell integration analysis reveals molecular signatures of the tumor microenvironment in early-onset colorectal cancer.

Ting Peng, Qimin Zhan.

The incidence of early-onset colorectal cancer (CRC), defined as cases diagnosed in individuals under 50, is rising globally. However, its molecular and immune characteristics remain poorly understood. In this study, we analyze single-cell RNA sequencing data from 168 CRC patients, aged 22 to 91, to investigate differences between early-onset and standard-onset CRC. We find a reduced proportion of tumor-infiltrating myeloid cells, a higher burden of copy number variations, and decreased tumor-immune interactions in early-onset CRC. Additionally, immune signatures unique to early-onset CRC are associated with differential responses to immunotherapy, underscoring the need for tailored therapeutic strategies for this group of patients. These findings provide valuable insights into the molecular and immune landscape of early-onset CRC, emphasizing the importance of developing targeted prevention and treatment strategies.

DOI: https://doi.org/10.1038/s41698-025-01129-8
Nature. 2025 Nov 19.

Hepatic zonation determines tumorigenic potential of mutant β-catenin.

Alexander Raven, Kathryn Gilroy, Hu Jin, Joseph A Waldron, Holly Leslie, June Munro, Holly Hall, Rachel A Ridgway, Catriona A Ford, Doga C Gulhan, Nikola Vlahov, Megan L Mills, Andrew Hartley, Eve Anderson, Sheila Bryson, Nathalie Sphyris, Miryam Müller, Stephanie May, Barbara Cadden, Colin Nixon, Scott H Waddell, Rachel Guest, Luke Boulter, Nick Barker, Hans Clevers, Hao Zhu, Johanna Ivaska, Douglas Strathdee, Crispin J Miller, Nigel B Jamieson, Martin Bushell, Peter J Park, Thomas G Bird, Owen J Sansom.

Oncogenic mutations in phenotypically normal tissue are common across adult organs1,2. This suggests that multiple events need to converge to drive tumorigenesis and that many processes such as tissue differentiation may protect against carcinogenesis. WNT-β-catenin signalling maintains zonal differentiation during liver homeostasis3,4. However, the CTNNB1 oncogene-encoding β-catenin-is also frequently mutated in hepatocellular carcinoma, resulting in aberrant WNT signalling that promotes cell growth5,6. Here we investigated the antagonistic interplay between WNT-driven growth and differentiation in zonal hepatocyte populations during liver tumorigenesis. We found that β-catenin mutations co-operate with exogenous MYC expression to drive a proliferative translatome. Differentiation of hepatocytes to an extreme zone 3 fate suppressed this proliferative translatome. Furthermore, a GLUL and Lgr5-positive perivenous subpopulation of zone 3 hepatocytes were refractory to WNT-induced and MYC-induced tumorigenesis. However, when mutant CTNNB1 and MYC alleles were activated sporadically across the liver lobule, a subset of mutant hepatocytes became proliferative and tumorigenic. These early lesions were characterized by reduced WNT pathway activation and elevated MAPK signalling, which suppresses zone 3 differentiation. The proliferative lesions were also dependent on IGFBP2-mTOR-cyclin D1 pathway signalling, in which inhibition of either IGFBP2 or mTOR suppressed proliferation and tumorigenesis. Therefore, we propose that zonal identity dictates hepatocyte susceptibility to WNT-driven tumorigenesis and that escaping WNT-induced differentiation is essential for liver cancer.

DOI: https://doi.org/10.1038/s41586-025-09733-1
bioRxiv. 2025 Oct 03. pii: 2025.10.01.679843. [Epub ahead of print]

Development of antibody-drug conjugates targeting L1CAM to treat metastatic cancer.

Jin Suk Park, Carson Kenum, Lan He, Abdul G Khan, Mary Ann Pohl, Thomas E White, Sreekumar R Kodangattil, Charles M Rudin, Paul J Balderes, Ivo C Lorenz, Joan Massagué, Karuna Ganesh.

Effective treatment for metastatic cancer has remained elusive due to the persistence of drug-resistant metastasis stem cells (MetSCs) that drive relapse. MetSCs are tumor cell subpopulations enriched for their ability to reinitiate and sustain metastatic growth, displaying phenotypic plasticity and resistance to chemotherapy. These cells express the L1 cell adhesion molecule (L1CAM), a transmembrane protein detected in numerous human solid tumor types and at multiple disseminated organ sites. As a selective surface marker of MetSCs, L1CAM is a promising candidate for molecularly targeted drugs aimed at eliminating metastases, yet strategies to date have not achieved clinical success. Here, we develop antibody-drug conjugates to deliver highly toxic PNU-159682 payloads to L1CAM-expressing cells. We report the generation of monoclonal antibodies (mAb) with high binding affinity, specificity and selectivity for the human L1CAM extracellular domain. Optimized L1CAM-targeting mAbs were conjugated to PNU-159682 to generate ADC variants with both cleavable and non-cleavable linkers, with an average drug-antibody-ratio (DAR) of four. ADCs derived from three antibodies targeting various epitopes of the L1CAM extracellular portion potently killed cells exhibiting varying levels of surface L1CAM expression. L1CAM ADCs given as monotherapy resulted in robust tumor control and extended survival in mice harboring subcutaneous L1CAM + xenografts or L1CAM + lung metastases from triple-negative basal breast cancer and lung adenocarcinoma. Safety analyses with mouse cross-reactive antibodies indicate a feasible therapeutic window. Our findings offer strong proof-of-concept to support the preclinical development of these novel L1CAM ADCs as therapeutic agents for advanced solid tumors.

DOI: https://doi.org/10.1101/2025.10.01.679843