Dataset Information

SMAD4-NFATc1 protein-protein interaction informed therapeutic vulnerability in SMAD4-deficient pancreatic cancer

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by a median survival rate of approximately six months. While genetic profiling has uncovered common mutations in PDAC, developing targeted therapeutic strategies remains challenging. SMAD4 is frequently mutated or deleted in 30-55% of PDAC patients and correlates with poor survival rates. Such mutations frequently result in loss-of-function, thereby disrupting normal cell cycle regulation and contributing to tumorigenesis. Therefore, translating SMAD4 genotype into actionable targets are highly desired for therapeutic innovation in PDAC. In this study, we performed a SMAD4-focused oncogenic protein-protein interaction (oncoPPI) network mapping and revealed a direct physical interaction between SMAD4 and NFATc1. We found that SMAD4 interacts with NFATc1 in a TGF-independent and NFATc1 phosphorylation-dependent manner. Further, SMAD4 sequesters NFATc1 in cytoplasm and inhibits NFATc1 transcriptional activity. In PDAC cells, SMAD4-loss releases its inhibitory activity on NFATc1, activates NFATc1 transcriptional activity which drives STAT3 mRNA and protein upregulation. Pharmacological profiling identified multiple STAT3 inhibitors selectively inhibit the growth of SMAD4-loss PDAC cells. These results suggested a rewired SMAD4-NFATc1-STAT3 axis and targeting STAT3 as a potential therapeutic strategy in SMAD4-loss PDAC.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: David Gordon

LAB HEAD: Xiulei Mo

PROVIDER: PXD067749 | Pride | 2026-02-02

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20230626_160239_230623_CMB-0008_MoLab_SMAD4.sne	Other
	20230626_160455_230623_CMB-0008_MoLab_SMAD4_Report.tsv	Tabular
	raw_data.zip	Other

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Publications

Identification and characterization of a TGF-β-independent SMAD4-NFATc1-STAT3 regulatory axis.

Ouyang Wukun W Hao Jiaying J Niu Qiankun Q Douglass Eugene F EF Beusch Christian M CM Gordon David E DE Hall Maggie M Moffitt Richard A RA Du Yuhong Y Mo Xiulei X

Journal of molecular cell biology 20260101 6

SMAD4, a central mediator of the TGF-β signaling pathway, plays a critical role in regulating cellular processes such as proliferation, differentiation, and apoptosis. While SMAD4's canonical functions within TGF-β signaling are well-established, its non-canonical, TGF-β-independent roles remain poorly understood, particularly in the context of disease biology. Here, we investigate SMAD4's TGF-β-independent functions by identifying and characterizing its protein-protein interaction network. Usin ...[more]

PMID: 40856537

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Project description:Chemoresistance to gemcitabine limits its clinical implementation for pancreatic ductal adenocarcinoma (PDAC). We previously generated an antibody drug conjugate (ADC) -like agent, EGFR/HER2 dual-targeting ligand-based lidamycin (DTLL), and studied the effect of DTLL combined with gemcitabine and the potential role of SMAD4 in the chemoresistance of PDAC. On the basis of SMAD4 profiles in in vitro and in vivo models, we investigated the antitumor effects of DTLL, gemcitabine and their combination, followed with mechanistic characterization. The results suggested that DTLL combination treatment with gemcitabine significantly repressed tumors with remarkably enhanced efficacy as compared to gemcitabine or DTLL alone given in either SMAD4-deficient/gemcitabine-resistant or SMAD4-sufficient/gemcitabine-sensitive cell line derived xenograft (CDX) and patient derived xenograft (PDX) tumors, respectively. Functional studies indicated that SMAD4 genetic status is responsible for SMAD4 protein level which determines different cellular susceptibility of PDAC. R100T mutation contributes to loss of SMAD4 protein and function with rapid protein degradation, leading to resistance to gemcitabine in PDAC cells. Moreover, DTLL significantly altered the protein half-life time and level of mutant and wild-type SMAD4 by inhibiting protein degradation at different velocities and distinctly changing the interaction of SMAD4 with TRIM33. Mechanism studies implied that DTLL combinational treatment might not only prevent from neoplastic proliferation via blockage of ATK/mTOR signaling and anti-apoptotic proteins (Bcl-2 and MCL1) mediated by impaired NF-B function in SMAD4-sufficient/gemcitabine-sensitive PDAC cells, but also restore the bioactivity of SMAD4 as a tumor suppressor to trigger its downstream NF-B-regulated signaling of cell apoptosis in SMAD4-deficient/gemcitabine-resistant tumors. In conclusion, SMAD4 is the key central mediator of not only the occurrence and development but also susceptibility in PDAC. DTLL sensitized gemcitabine efficacy via distinct action mechanisms based on SMAD4 profiles in SMAD4-sufficient/gemcitabine-sensitive and SMAD4-deficient/-resistant PDAC, respectively. Our findings provide insight into a rational SMAD4-directed precision treatment strategy and reveal a promising DTLL combination therapy to overcome chemoresistance in gemcitabine-resistant PDAC.