A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

(Multiomics OR Omics) AND (Lung OR gastric OR Hepatocellular)

By: Qian Tang · Chen Lian · Xinyan Han · Xuhan Zhang · Zihan Wang · Boyu Wang · Taoyu Zhu · Xinrui Lin · Xiaolei Wang · Yaping Xu · Manyu Xiao · Zijin Wang · Junming Li · Silin Chen · Yunze Wang · Yufei Liu · Songsong Li · Zuolin Shen · Xi Lu · Xueqi Han · Yilu Zhou · Mingyang Xiao · Jiayi Ran · Xiaoran Cao · Xinyi Xu · Hugo Sámano-Sánchez · Alfredo Rodríguez · Lian Wang · Shuifang Chen · Zhanyu Xu · Shirong Zhang · Nuo Yang · Yong Tang · Jian Liu

26 May 2026 at 18:00

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

A Non-Canonical Role of SMAD4 in Regulating 3D Genome Architecture to Inhibit Lung Squamous Cell Carcinoma Development

Omics In Lung

By: Qian Tang · Chen Lian · Xinyan Han · Xuhan Zhang · Zihan Wang · Boyu Wang · Taoyu Zhu · Xinrui Lin · Xiaolei Wang · Yaping Xu · Manyu Xiao · Zijin Wang · Junming Li · Silin Chen · Yunze Wang · Yufei Liu · Songsong Li · Zuolin Shen · Xi Lu · Xueqi Han · Yilu Zhou · Mingyang Xiao · Jiayi Ran · Xiaoran Cao · Xinyi Xu · Hugo Sámano-Sánchez · Alfredo Rodríguez · Lian Wang · Shuifang Chen · Zhanyu Xu · Shirong Zhang · Nuo Yang · Yong Tang · Jian Liu

26 May 2026 at 18:00

Adv Sci (Weinh). 2026 May 26:e75839. doi: 10.1002/advs.75839. Online ahead of print.

ABSTRACT

Lung squamous cell carcinoma (LUSC) lacks clearly defined key drivers and effective targeted therapies, reflecting an incomplete understanding of its molecular pathogenesis. Here, we identify SMAD4 as a critical regulator of three-dimensional (3D) genome organization in LUSC and uncover a mechanistic link between tumor suppressor loss and oncogenic transcriptional activation. By integrating clinical datasets, genetically engineered mouse models, human and murine LUSC cell lines, and multi-omics analyses, we demonstrate that SMAD4 deficiency promotes LUSC progression by unleashing EP300-mediated enhancer-promoter looping at the SOX2 locus. Mechanistically, SMAD4 does not directly bind SOX2 regulatory elements but instead constrains chromatin looping by sequestering EP300 away from loop anchor regions. Loss of SMAD4 leads to enhanced H3K27ac deposition, aberrant SOX2 activation, and increased LUSC tumor cell proliferation. Together, these findings reveal a non-canonical role for a transcription factor (e.g., SMAD4) in regulating dysregulated 3D genome architecture to inhibit tumor development.

PMID:42189071 | DOI:10.1002/advs.75839

Efficient endometrial carcinoma screening via cross-modal synthesis and gradient distillation

cs.AI, q-bio.NC updates on arXiv.org

By: Dongjing Shan · Yamei Luo · Jiqing Xuan · Lu Huang · Jin Li · Mengchu Yang · Zeyu Chen · Fajin Lv · Yong Tang · Chunxiang Zhang

24 February 2026 at 13:00

arXiv:2602.19822v1 Announce Type: cross Abstract: Early detection of myometrial invasion is critical for the staging and life-saving management of endometrial carcinoma (EC), a prevalent global malignancy. Transvaginal ultrasound serves as the primary, accessible screening modality in resource-constrained primary care settings; however, its diagnostic reliability is severely hindered by low tissue contrast, high operator dependence, and a pronounced scarcity of positive pathological samples. Existing artificial intelligence solutions struggle to overcome this severe class imbalance and the subtle imaging features of invasion, particularly under the strict computational limits of primary care clinics. Here we present an automated, highly efficient two-stage deep learning framework that resolves both data and computational bottlenecks in EC screening. To mitigate pathological data scarcity, we develop a structure-guided cross-modal generation network that synthesizes diverse, high-fidelity ultrasound images from unpaired magnetic resonance imaging (MRI) data, strictly preserving clinically essential anatomical junctions. Furthermore, we introduce a lightweight screening network utilizing gradient distillation, which transfers discriminative knowledge from a high-capacity teacher model to dynamically guide sparse attention towards task-critical regions. Evaluated on a large, multicenter cohort of 7,951 participants, our model achieves a sensitivity of 99.5\%, a specificity of 97.2\%, and an area under the curve of 0.987 at a minimal computational cost (0.289 GFLOPs), substantially outperforming the average diagnostic accuracy of expert sonographers. Our approach demonstrates that combining cross-modal synthetic augmentation with knowledge-driven efficient modeling can democratize expert-level, real-time cancer screening for resource-constrained primary care settings.

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