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Nitschkowski, D.* ; Vierbuchen, T.* ; Heine, H.* ; Behrends, J.* ; Reiling, N.* ; Reck, M.* ; Rabe, K.F.* ; Kugler, C.* ; Ammerpohl, O.* ; Drömann, D.* ; Muley, T.* ; Kriegsmann, M.* ; Stathopoulos, G.T. ; Arendt, K.A.M. ; Goldmann, T.* ; Marwitz, S.*

SMAD2 linker phosphorylation impacts overall survival, proliferation, TGFβ1-dependent gene expression and pluripotency-related proteins in NSCLC.

Br. J. Cancer, DOI: 10.1038/s41416-025-02970-1 (2025)
Verlagsversion DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
BACKGROUND: We investigated the impact of SMAD2 linker phosphorylation (pSMAD2L) on overall and disease-free survival, signal transduction, as well as cancer-related processes in non-small cell lung cancer (NSCLC). METHODS: We generated A549 cells constitutively lacking pSMAD2L (A549Lsub) to gain mechanistic insights and stimulated NSCLC cell lines with inhibitors against cell cycle-associated kinases or TGFβ1. In addition, we analysed SMAD2 and pSMAD2L in alveolar epithelial cells type 2 from tumour-free lung tissue as well as in benign and malignant T cells by Western blotting. Furthermore, pSMAD2L-positive tumours and immune cells were analysed in an NSCLC patient cohort (n = 316) using multiplex immunofluorescence. RESULTS: In NSCLC cell lines and benign T cells, pSMAD2L was expressed in a mitosis-dependent manner. Loss of pSMAD2L (A549Lsub) had an anti-proliferative effect, slowed migration, and increased alternatively spliced short SMAD2 (SMAD2ΔE3). The gene signature in A549Lsub was associated with developmental and morphogenetic processes and redirected canonical TGFβ1-dependent signalling. By contrast, SMAD2ΔE3 was absent in benign T cells but present in malignant T lymphoblasts. NSCLC patients with low pSMAD2L+ tumour cell density had a poorer prognosis, whereas low pSMAD2L+ immune cell density favoured overall and disease-free survival. CONCLUSIONS: pSMAD2L antagonises anti-proliferative canonical TGFβ-signalling in NSCLC and redirects TGFβ1-dependent gene expression, whereas loss of pSMAD2L enhances SMAD2ΔE3 and affects pluripotency-associated proteins in vitro. In NSCLC patients, pSMAD2L cell density influences disease-free and overall survival in a spatially distinct manner.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter Cell Lung-cancer; Tgf-beta; Metastasis; Resistance; Pathways; Regions; Stage
ISSN (print) / ISBN 0007-0920
e-ISSN 1532-1827
Zeitschrift British Journal of Cancer BJC
Verlag Nature Publishing Group
Verlagsort Campus, 4 Crinan St, London, N1 9xw, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Lung Health and Immunity (LHI)
Förderungen Projekt DEAL
German Center for Lung Research (DZL)