PO.TB10.12 · 肿瘤生物学

肿瘤硬度作为KRAS突变型NSCLC的功能性生物标志物：来自ARTIDIS前瞻性临床队列的见解

Tumor stiffness as a functional biomarker of KRAS-mutant NSCLC: Insights from the ARTIDIS prospective clinical cohort

编号 767 展板 12 时间 4/19 02:00–05:00 区域 Section 31 主讲 Jordi Alcaraz, PhD

分会场 Physicochemical Modulation of Cancer Ecosystems: Mechanical Forces, Hypoxia, and Acidosis

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作者与单位 Authors & Affiliations

Jordi Alcaraz¹, Elba Marin¹, Héctor Sanz-Fraile¹, Marina Querol², Paula Gausa², Keat Neal¹, Marselina Arshakyan¹, Marc Rico-Pastó¹, Marc Boada³, David Sanchez³, Carolina Ortiz Velez⁴, Reinier Oropesa Nunez⁴, Gitika Srivastava⁴, Ahmed Jizawi⁴, Sara Nizzero⁴, Tobias Appenzeller⁴, Philipp Oertle⁴, Marko Loparic⁴, Marija Plodinec⁴, Noemi Reguart⁵

¹Biomedicine, Universitat de Barcelona, Barcelona, Spain,²Thoracic Oncology Unit, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain,³Thoracic Surgery, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain,⁴ARTIDIS AG, Basel, Switzerland,⁵Medical Oncology Department, Hospital Clínic i Provincial de Barcelona, Barcelona, Spain

摘要 Abstract

中文摘要

背景：肿瘤的纳米力学特性是新兴的生物标志物，反映细胞外基质（ECM）重塑、免疫排斥和侵袭性。基于AFM的ARTIDIS平台可在数小时内从新鲜活检组织测量纳米力学特征（NS），提供快速的诊断和预后信息，同时保留组织用于常规分析。既往研究显示，ARTIDIS NS可区分恶性肺组织与未受累肺组织，并预测术后早期复发。然而，NS与KRAS等致癌驱动因素之间的关系仍不明确。由于KRAS影响ECM组成、基质重塑和基质活化，我们在前瞻性队列中评估了KRAS突变型NSCLC的初步纳米力学和微环境特征。方法：从70例接受根治性切除的早期NSCLC患者收集新鲜肿瘤组织及配对的未受累肺组织。在ARTIDIS平台上测量NS。样本经福尔马林固定，用于alpha-SMA、天狼星红、Ki-67、CD31、CD4、CD8、FOXP3、CD68和PD-1的定量免疫组化（IHC）。记录临床特征、驱动突变和结局，随访36个月。对KRAS突变病例进行了重点分析。结果：初步分析显示，ARTIDIS NS区分恶性组织与未受累组织的敏感性为88%、特异性为86%、准确性为87%（n=52对配对样本）。11例患者携带KRAS突变（G12A/D/F/S、G13D、Q16H）。中位年龄68.5岁；63.4%为既往吸烟者。多数肿瘤为早期（IA–IIB），45.5%为低分化。在整个队列中，17例患者复发，其中3例（27.3%）为KRAS突变。ARTIDIS NS预测术后10个月内进展的敏感性为100%、特异性为93%，包括源自未受累组织的预测。KRAS突变型肿瘤的硬度高于KRAS野生型或驱动阴性肿瘤。定量IHC显示，与未受累肺组织相比，KRAS突变样本中增殖癌细胞比例更高，同时Treg浸润和PD-1表达增加，提示免疫耗竭。结论：本研究首次提供证据表明，KRAS突变型NSCLC呈现出独特的、更硬的纳米力学表型。这些发现支持将肿瘤硬度作为KRAS驱动生物学的功能性特征，并强调ARTIDIS NS作为一种快速生物标志物可补充组织病理学和分子分型。一项200例患者的前瞻性验证研究正在进行中，以确认NS在风险分层和个体化治疗规划中的临床效用。

查看英文原文 English abstract

Background: Nanomechanical properties of tumors are emerging biomarkers reflecting extracellular matrix (ECM) remodeling, immune exclusion, and aggressiveness. The AFM-based ARTIDIS platform measures nanomechanical signatures (NS) from fresh biopsies within hours, providing rapid diagnostic and prognostic information while preserving tissue for conventional analyses. Prior work showed that ARTIDIS NS distinguishes malignant from uninvolved lung tissue and predicts early postoperative recurrence. However, the relationship between NS and oncogenic drivers such as KRAS remains unclear. As KRAS influences ECM composition, matrix remodeling, and stromal activation, we evaluated the preliminary nanomechanical and microenvironmental features of KRAS -mutant NSCLC in our prospective cohort. Methods: Fresh tumor and paired uninvolved lung tissue were collected from 70 early-stage NSCLC patients undergoing curative resection. NS were measured on the ARTIDIS platform. Samples were formalin-fixed for quantitative immunohistochemistry (IHC) of alpha-SMA, picrosirius red, Ki-67, CD31, CD4, CD8, FOXP3, CD68, and PD-1. Clinical characteristics, driver mutations, and outcomes were recorded with a 36-month follow-up. A focused analysis was performed in KRAS-mutant cases. Results: Preliminary analyses showed that ARTIDIS NS distinguished malignant from uninvolved tissue with 88% sensitivity, 86% specificity, and 87% accuracy (n=52 paired samples). Eleven patients carried KRAS mutations (G12A/D/F/S, G13D, Q16H). Median age was 68.5 years; 63.4% were former smokers. Most tumors were early-stage (IA-IIB), and 45.5% were poorly differentiated. Across the full cohort, 17 patients recurred, including 3 patients (27.3%) with KRAS mutations. ARTIDIS NS predicted progression within 10 months after surgery with 100% sensitivity and 93% specificity, including predictions derived from uninvolved tissue. KRAS -mutant tumors showed higher stiffness than KRAS -wild-type or driver-negative tumors. Quantitative IHC demonstrated a higher percentage of proliferating cancer cells together with increased Treg infiltration and PD-1 expression in KRAS -mutant samples compared with uninvolved lung tissue, suggesting immune exhaustion. Conclusions: This study provides the first evidence that KRAS -mutant NSCLC displays a distinct, stiffer nanomechanical phenotype. These findings support tumor stiffness as a functional characteristic of KRAS -driven biology and highlight ARTIDIS NS as a rapid biomarker complementing histopathology and molecular profiling. A 200-patient prospective validation study is underway to confirm the clinical utility of NS for risk stratification and personalized treatment planning.

利益披露 Disclosure

J. Alcaraz, None.. E. Marin, None.. H. Sanz-Fraile, None.. M. Querol, None.. P. Gausa, None.. K. Neal, None.. M. Arshakyan, None.. M. Rico-Pastó, None.. M. Boada, None.. D. Sanchez, None.. C. Ortiz Velez, None.. G. Srivastava, None.. A. Jizawi, None.. S. Nizzero, None.. T. Appenzeller, None.. P. Oertle, None.. M. Loparic, None.. M. Plodinec, None.. N. Reguart, None.

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