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

Generative Reasoning Re-ranker

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

By: Mingfu Liang · Yufei Li · Jay Xu · Kavosh Asadi · Xi Liu · Shuo Gu · Kaushik Rangadurai · Frank Shyu · Shuaiwen Wang · Song Yang · Zhijing Li · Jiang Liu · Mengying Sun · Fei Tian · Xiaohan Wei · Chonglin Sun · Jacob Tao · Shike Mei · Wenlin Chen · Santanu Kolay · Sandeep Pandey · Hamed Firooz · Luke Simon

24 February 2026 at 13:00

arXiv:2602.07774v4 Announce Type: replace-cross Abstract: Recent studies increasingly explore Large Language Models (LLMs) as a new paradigm for recommendation systems due to their scalability and world knowledge. However, existing work has three key limitations: (1) most efforts focus on retrieval and ranking, while the reranking phase, critical for refining final recommendations, is largely overlooked; (2) LLMs are typically used in zero-shot or supervised fine-tuning settings, leaving their reasoning abilities, especially those enhanced through reinforcement learning (RL) and high-quality reasoning data, underexploited; (3) items are commonly represented by non-semantic IDs, creating major scalability challenges in industrial systems with billions of identifiers. To address these gaps, we propose the Generative Reasoning Reranker (GR2), an end-to-end framework with a three-stage training pipeline tailored for reranking. First, a pretrained LLM is mid-trained on semantic IDs encoded from non-semantic IDs via a tokenizer achieving $\ge$99% uniqueness. Next, a stronger larger-scale LLM generates high-quality reasoning traces through carefully designed prompting and rejection sampling, which are used for supervised fine-tuning to impart foundational reasoning skills. Finally, we apply Decoupled Clip and Dynamic sAmpling Policy Optimization (DAPO), enabling scalable RL supervision with verifiable rewards designed specifically for reranking. Experiments on two real-world datasets demonstrate GR2's effectiveness: it surpasses the state-of-the-art OneRec-Think by 2.4% in Recall@5 and 1.3% in NDCG@5. Ablations confirm that advanced reasoning traces yield substantial gains across metrics. We further find that RL reward design is crucial in reranking: LLMs tend to exploit reward hacking by preserving item order, motivating conditional verifiable rewards to mitigate this behavior and optimize reranking performance.

Reading view