bims-instec 2025-05-18 papers

Sci Signal. 2025 May 13. 18(886): eady6765

Chronic stress impairs intestinal stem cell function through the parasympathetic nervous system.

DOI: https://doi.org/10.1126/scisignal.ady6765

Sci Rep. 2025 May 10. 15(1): 16330

Smad4 and TGFβ1 dependent gene expression signatures in conditional intestinal adenoma, organoids and colorectal cancer.

Mirvat Surakhy, Julia Matheson, David J Barnes, Emma J Carter, Jennifer Hughes, Claudia Bühnemann, Sabina Sanegre, Hans Morreau, Paul Metz, Charlotte J Imianowski, Andrew Bassim Hassan.

TGF-β ligands suppress growth yet can paradoxically and potently promote cancer invasion and metastasis depending on downstream pathway mutational context, such as loss of Mothers against decapentaplegic homolog 4 (Smad4). Here, we characterised phenotypes and associated gene expression signatures in conditional murine intestinal adenoma with and without Smad4. Conditional Lgr5-CreERT2 activation in Apcfl/flSmad4fl/fl mice resulted in homozygote floxed alleles (ApcΔ/ΔSmad4Δ/Δ) and adenoma formation. The adenoma phenotype was discordant, with reduced small intestinal adenoma burden yet development of large non-metastatic caecal adenoma with nuclear localisation of phospho-Smad2/3. Derived ApcΔ/ΔSmad4Δ/Δ adenoma organoids resisted TGF-β1 dose dependent growth arrest and cell death (IC50 534 pM) compared to ApcΔ/ΔSmad4+/+ (IC50 24 pM). TGF-β1 (390 pM) altered adenoma bulk mRNA expression most significantly for Id1low and Spp1high in ApcΔ/ΔSmad4Δ/Δ. Single cell RNAseq of caecal adenoma identified expansion of Lgr5low, Pak3high and Id1low progenitor populations in ApcΔ/ΔSmad4Δ/Δ. Of the 76 Smad4 and TGF-β1 dependent genes identified in Apcfl/flSmad4fl/fl adenoma organoids, only 7 human equivalent genes were differentially expressed in SMAD4 mutated colorectal cancer (TCGA cohorts), including ID1low. SMAD4low, ID1low SPP1high and PAK3high all correlated with poorer survival. Murine adenoma identified Smad4 dependent gene expression signatures that require further evaluation as functional biomarker classifiers of SMAD4 mutated cancer subtypes.

Keywords: Adenoma; Apc; Biomarkers; Colorectal cancer; Gene expression; Id1; Intestine; Pak3; Smad4; Spp1; TGF-β1

DOI: https://doi.org/10.1038/s41598-025-00908-4

Cancer Lett. 2025 May 10. pii: S0304-3835(25)00358-1. [Epub ahead of print]626 217791

Activated Schwann cells promote tumor growth in colon cancer.

Kexin He, Hao Wang, Hao Wu, Weihan Li, Ruixue Huo, Luju Jiang, Minhao Yu, Junli Xue.

Schwann cells, traditionally recognized as glial cells of the peripheral nervous system, have emerged as pivotal cellular constituents within the tumor microenvironment. Colon cancer exhibits significant nerve dependence; however, the roles of Schwann cells in colon cancer progression remain insufficiently understood. Here, we identified a significant increase in tumor-associated nonmyelinating Schwann cells within colon tumor samples compared to their normal tissue counterparts. Furthermore, the elevated abundance of these cells was associated with poorer clinical outcomes in colon cancer. Within colon tumor tissues, Schwann cells displayed elevated expression of c-Jun, a key gene involved in their activation and reprogramming. Knocking down c-Jun hampered Schwann cell activation. Single-cell RNA sequencing analysis uncovered that glial cells engage in the most robust cell-cell interactions with malignant cells and fibroblasts. Co-culture experiments demonstrated that tumor cells and cancer-associated fibroblasts specifically promoted c-Jun activation in Schwann cells, whereas co-culture with immune cells did not elicit a similar response. Under In vivo conditions, Schwann cells enhance tumor growth in a c-Jun-dependent manner. Moreover, c-Jun knockout in Schwann cells orchestrated a reprogramming of their secretome, exemplified by a notable reduction in IL-6, a key effector of their tumor-promoting activity. Collectively, our study elucidates the critical role of activated Schwann cells in colon cancer, which may offer a novel therapeutic strategy for treatment.

Keywords: Cancer neuroscience; Colon adenocarcinoma; Colorectal cancer; Tumor-associated schwann cells

DOI: https://doi.org/10.1016/j.canlet.2025.217791

Front Genet. 2025 ;16 1545017

In vitro 3D modeling of colorectal cancer: the pivotal role of the extracellular matrix, stroma and immune modulation.

Veroniaina Hanitrarimalala, Zdenka Prgomet, My Hedhammar, Helena Tassidis, Anette Gjörloff Wingren.

Colorectal cancer (CRC) is a leading global cancer with high mortality, especially in metastatic cases, with limited therapeutic options. The tumor microenvironment (TME), a network comprising various immune cells, stromal cells and extracellular (ECM) components plays a crucial role in influencing tumor progression and therapy outcome. The genetic heterogeneity of CRC and the complex TME complicates the development of effective, personalized treatment strategies. The prognosis has slowly improved during the past decades, but metastatic CRC (mCRC) is common among patients and is still associated with low survival. The therapeutic options for CRC differ from those for mCRC and include surgery (mostly for CRC), chemotherapy, growth factor receptor signaling pathway targeting, as well as immunotherapy. Malignant CRC cells are established in the TME, which varies depending on the primary or metastatic site. Herein, we review the role and interactions of several ECM components in 3D models of CRC and mCRC tumor cells, with an emphasis on how the TME affects tumor growth and treatment. This comprehensive summary provides support for the development of 3D models that mimic the interactions within the TME, which will be essential for the development of novel anticancer therapies.

Keywords: 3D model; colorectal cancer; extracellular matrix; immune cells; in vitro; therapy; tumor microenvironment

DOI: https://doi.org/10.3389/fgene.2025.1545017

Nat Commun. 2025 May 11. 16(1): 4369

Basal-shift transformation leads to EGFR therapy-resistance in human lung adenocarcinoma.

Although EGFR tyrosine kinase inhibitors (EGFR-TKIs) are effective for EGFR-mutant lung adenocarcinoma (LUAD), resistance inevitably develops through diverse mechanisms, including secondary genetic mutations, amplifications and as-yet undefined processes. To comprehensively unravel the mechanisms of EGFR-TKI resistance, we establish a biobank of patient-derived EGFR-mutant lung cancer organoids, encompassing cases previously treated with EGFR-TKIs. Through comprehensive molecular profiling including single-cell analysis, here we identify a subgroup of EGFR-TKI-resistant LUAD organoids that lacks known resistance-related genetic lesions and instead exhibits a basal-shift phenotype characterized by the hybrid expression of LUAD- and squamous cell carcinoma-related genes. Prospective gene engineering demonstrates that NKX2-1 knockout induces the basal-shift transformation along with EGFR-target therapy resistance. Basal-shift LUADs frequently harbor CDKN2A/B loss and are sensitive to CDK4/6 inhibitors. Our EGFR-mutant lung cancer organoid library not only offers a valuable resource for lung cancer research but also provides insights into molecular underpinnings of EGFR-TKI resistance, facilitating the development of therapeutic strategies.

DOI: https://doi.org/10.1038/s41467-025-59623-3

Nat Rev Cancer. 2025 May 12.

NOTUM-mediated stem cell competition in CRC.

Praver Gupta, Tamal Das.

DOI: https://doi.org/10.1038/s41568-025-00827-6