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

Test-Time Deep Thinking to Explore Implicit Rules

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

By: Wentong Chen · Xin Cong · Zhong Zhang · Yaxi Lu · Siyuan Zhao · Yesai Wu · Qinyu Luo · Haotian Chen · Yankai Lin · Zhiyuan Liu · Maosong Sun

26 May 2026 at 12:00

arXiv:2605.24828v1 Announce Type: new Abstract: With the continuous advancement of Large Language Models (LLMs), intelligent agents are becoming increasingly vital. However, these agents often fail in environments governed by implicit rules--hidden constraints that cannot be observed directly and must be inferred through interaction. This causes agents to fall into repetitive trial-and-error loops, ultimately leading to task failure. To address this challenge, we propose Test-Time Exploration (TTExplore), a framework where a thinker component analyzes interaction history to infer these implicit rules and guide an actor. Effective exploration in this setting critically depends on the reasoning ability of the thinker. However, evaluating deep reasoning trajectories is inherently unstable and difficult, which poses a major obstacle to effective training. To overcome this issue, we introduce a novel and stable reinforcement learning pipeline. The core idea is to use accurate task-level scores as indirect rewards to bypass the difficulty of evaluating intermediate reasoning, and to retain only a single thinking node per trajectory to alleviate reward sparsity. Using this pipeline, we train a specialized 7B model, Exp-Thinker. Experiments on five text-based embodied tasks show that TTExplore equipped with Exp-Thinker improves baseline agent performance by an average of $14$-$19$ points, demonstrating the effectiveness of explicitly reasoning about implicit rules.

EchoDistill:Alignment Noisy-to-Clean Self-Distillation for Robust Audio LLMs

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

By: Liang Lin · Chunxi Luo · Kaiwen Luo · Jie Zhang · Jin Wang · Yuanhe Zhang · Cai Yuchen · Qiankun Li · Gongli Xi · Zhenhong Zhou · Kun Wang · Junhao Dong

26 May 2026 at 12:00

arXiv:2605.23954v1 Announce Type: cross Abstract: Audio Large Language Models (ALLMs) are highly vulnerable to real-world noise, which often induces severe semantic drift and hallucinations. Existing robustness methods primarily rely on waveform-level acoustic enhancement, answer-level supervision, or the internal suppression of noise representations. To address these issues, we propose echodistill, an alignment-based noisy-to-clean self-distillation framework. Echodistill leverages a frozen clean-audio teacher to provide semantic references for an inference-time noisy-audio student. Specifically, the student samples candidate responses under noisy conditions to expose its test-time behavior. These trajectories are then optimized via group-relative policy optimization (GRPO), where the token-level consistency with the teacher acts as a reward bonus. By aligning the noisy student's candidate responses with clean semantic evidence, and applying audio-aware reward shaping, our method encourages reasoning trajectories that are both correct and genuinely acoustically grounded. Echodistill significantly improves the semantic reliability and task performance of Audio LLMs under complex noise, without introducing any additional inference costs. Extensive experiments show that: (I) Compared with the strongest baseline, echodistill achieves average improvements of 4.18\%$\uparrow$ in GSR under strong noise. (II) Ablation results on Qwen-Omni further show that echodistill improves over the GRPO-only variant by 3.02\%$\uparrow$ in Acc, 3.89\%$\uparrow$ in Noisy, and 4.53\%$\uparrow$ in GSR on average. Our codes are available at https://anonymous.4open.science/r/echodistill-10DE.

$M^3-Verse$: A "Spot the Difference" Challenge for Large Multimodal Models

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

By: Kewei Wei · Bocheng Hu · Jie Cao · Xiaohan Chen · Zhengxi Lu · Wubing Xia · Weili Xu · Jiaao Wu · Junchen He · Mingyu Jia · Ciyun Zhao · Ye Sun · Yizhi Li · Zhonghan Zhao · Jian Zhang · Gaoang Wang

26 May 2026 at 12:00

arXiv:2512.18735v2 Announce Type: replace-cross Abstract: Modern Large Multimodal Models (LMMs) have demonstrated extraordinary ability in static image and single-state spatial-temporal understanding. However, their capacity to comprehend the dynamic changes of objects within a shared spatial context between two distinct video observations, remains largely unexplored. This ability to reason about transformations within a consistent environment is particularly crucial for advancements in the field of spatial intelligence. In this paper, we introduce $M^3-Verse$, a Multi-Modal, Multi-State, Multi-Dimensional benchmark, to formally evaluate this capability. It is built upon paired videos that provide multi-perspective observations of an indoor scene before and after a state change. The benchmark contains a total of 270 scenes and 2,932 questions, which are categorized into over 50 subtasks that probe 4 core capabilities. We evaluate 16 state-of-the-art LMMs and observe their limitations in tracking state transitions. To address these challenges, we further propose a simple yet effective baseline that achieves significant performance improvements in multi-state perception. $M^3-Verse$ thus provides a challenging new testbed to catalyze the development of next-generation models with a more holistic understanding of our dynamic visual world. You can get the construction pipeline from https://github.com/Wal-K-aWay/M3-Verse_pipeline and full benchmark data from https://www.modelscope.cn/datasets/WalKaWay/M3-Verse.

Reading view