Longitudinal proteomics integrated with multi‑omics reveal molecular drivers of responses to neoadjuvant chemotherapy in rectal cancer

IF 12.2 2区医学 Q1 PHARMACOLOGY & PHARMACY

Pharmacological research Pub Date : 2026-11-01 Epub Date: 2026-10-20 DOI:10.1016/j.phrs.2026.109699

Liudan Mai, Chen Shao, Yong Cao, Fenqi Du, Jingyi Liu, Qi Zhang, Lin Sun, Yanlin Dong, Jie Lou, Yuxuan Hou, Yin Ni, Maopeng Yang, Yanlong Liu, Qiuju Zhang

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Abstract

Neoadjuvant chemotherapy (NAC) is the standard treatment for locally advanced rectal cancer (LARC), yet its molecular determinants of response remain unclear. We conducted longitudinal 4D-DIA proteomic profiling of pre- and post-treatment specimens from 156 patients, including 31 patients with matched pre- and post-treatment specimens, and integrated with bulk RNA sequencing, single-cell transcriptomics, and functional validation. At baseline, responders were enriched in innate and adaptive immune pathways, whereas non-responders showed proliferative and metabolic programs. Pre-treatment RAC2, elevated in responders, was positively associated with immune activation, oxaliplatin sensitivity, and survival, and was validated in GSE139255 and GSE35640 (all P < 0.05). Moreover, RAC2 demonstrated strong predictive performance (training AUC = 0.867; testing AUC = 0.857). During treatment, NAC induced fibrosis-related remodeling across all groups (all P < 0.05), while responders uniquely preserved CD8⁺ T cell infiltration (P = 0.031). Responders and RAC2-high tumors exhibited concordant pathway dynamics during NAC. Single-cell analysis further revealed that pre-treatment tumor RAC2, higher in responders, transmitted signals to CD8⁺ T cells while receiving inputs from fibroblasts (P < 0.05). In vitro and in vivo, RAC2 knockdown reduced baseline tumor growth but promoted under oxaliplatin (all P < 0.05). Overall, this study offers proteomic insights into NAC in LARC, supports therapeutic decision-making, and identifies potential targets.

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纵向蛋白质组学与多组学结合揭示直肠癌新辅助化疗反应的分子驱动因素。

新辅助化疗（NAC）是局部晚期直肠癌（LARC）的标准治疗方法，但其反应的分子决定因素尚不清楚。我们对156例患者的治疗前后标本进行了纵向4D-DIA蛋白质组学分析，其中包括31例治疗前后标本匹配的患者，并结合了大量RNA测序、单细胞转录组学和功能验证。在基线时，应答者在先天和适应性免疫途径中丰富，而无应答者则表现出增殖和代谢程序。在应答者中，治疗前RAC2升高与免疫激活、奥沙利铂敏感性和生存呈正相关，并且在GSE139255和GSE35640中得到验证（均P < 0.05）。此外，RAC2表现出较强的预测性能（训练AUC = 0.867，测试AUC = 0.857）。在治疗期间，NAC诱导所有组的纤维化相关重构（均P < 0.05），而应答者独特地保留了CD8 + t细胞浸润（P = 0.031）。反应者和高rac2肿瘤在NAC期间表现出一致的通路动力学。单细胞分析进一步显示，治疗前的肿瘤RAC2在应答者中较高，在接受成纤维细胞输入的同时将信号传递给CD8 + T细胞（P < 0.05）。体外和体内实验中，敲低RAC2抑制基线肿瘤生长，但奥沙利铂组促进肿瘤生长（均P < 0.05）。总的来说，这项研究为LARC中的NAC提供了蛋白质组学见解，支持治疗决策，并确定了潜在的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Pharmacological research 医学-药学

CiteScore

18.70

自引率

3.20%

发文量

491

审稿时长

8 days

期刊介绍： Pharmacological Research publishes cutting-edge articles in biomedical sciences to cover a broad range of topics that move the pharmacological field forward. Pharmacological research publishes articles on molecular, biochemical, translational, and clinical research (including clinical trials); it is proud of its rapid publication of accepted papers that comprises a dedicated, fast acceptance and publication track for high profile articles.