Spatial resolution of transcriptomic plasticity states underpinning lethal morphologies in lung adenocarcinoma

作者：Hannah L. Williams, Nicolas Poulain, Ian Powley, Silvia Martinelli, Robert Bielik, Holly Leslie, Colin Nixon, Claire Wilson, Marco Sereno, Zhangyi He, Leah Officer-Jones, Fiona Ballantyne, Rachel Pennie, Colin S. Wood, David Y. Lewis, Nigel B. Jamieson, John Le Quesne · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.06.11.598228 · 被引用次数：1 · 研究领域：Ferroptosis and cancer prognosis、Gene expression and cancer classification、Bioinformatics and Genomic Networks

Abstract Adenocarcinoma of the lung (LUAD) is a common and highly lethal disease. Clinical grading of disease strongly predicts recurrence and survival after surgery and is determined by morphological assessment of histological growth patterns in resected tumours. The molecular basis of growth pattern is poorly understood at present, as are the mechanisms linking growth pattern to recurrence and death. Interestingly, the two archetypal lethal morphologies, solid and micropapillary patterns, are characterised by their biphasic appearance. Both have an epithelial fraction which is in direct stromal contact, and a fraction which is not. This morphological variance seems likely to represent plasticity, and to be causally linked to mechanisms of virulence. To investigate the gene expression changes related to growth pattern both intra- and intertumoral, we applied spatial transcriptomics (Nanostring GeoMx DSP) to tissue microarray specimens of primary resected human lung adenocarcinoma. Using a variety of region-of-interest (ROI) selection strategies, we sampled 160 pure epithelial ROIs across 7 distinct morphological features of LUAD from 51 patients. Analyses of gene expression reveal fundamental trajectories connecting growth patterns, and crucial modes of plasticity which underly high-risk morphologies. These modes suggest mechanisms for the origins of growth pattern and mechanisms of virulence. Our work highlights dramatic divergence in gene expression programmes between high...