Spatially Resolved Proteomic and Transcriptomic Proﬁling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter-and Intratumoral Heterogeneity

Sep 28, 2026

Pulmonary adenocarcinomas with ALK rearrangement are a rare cancer subtype requiring detailed molecular work to clarify heterogeneity and guide therapy. This pilot study used spatial transcriptomics (NanoString GeoMx) and proteomic profiling on seven treatment-naïve ALK-rearranged pADCs, sampling multiple annotated regions from each FFPE tumor slide. Proteomics and transcriptomics showed only modest gene-level correlation (average Pearson r = 0.43). Intertumoral heterogeneity exceeded intratumoral heterogeneity, and adjacent normal tissue displayed distinct molecular traits with immune infiltration, mucin, stroma content, and extracellular-matrix variability.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

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Abstract

Introduction

Lung cancer background and histological subtypes

Molecular subtypes and ALK-driven adenocarcinoma

Article Spatially Resolved Proteomic and Transcriptomic Proﬁling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter-and Intratumoral Heterogeneity Be¡ta Szeitz 1, Tibor Glasz 2, Zolt¡n Herold 1, G¡bor Tâth 3, Mirjam Balbisi 3,4, J¡nos Fillinger 5, Szabolcs Horv¡th 5, R²ka Moh¡csi 1, Ho Jeong Kwon 6, Judit Moldvay 7, Lilla Turi¡k 3,4 and Attila Marcell Sz¡sz 1,8,9, * Citation: Szeitz, B.; Glasz, T.; Herold, Z.; Tóth, G.; Balbisi, M.; Fillinger, J.; Horváth, S.; Mohácsi, R.; Kwon, H.J.; Moldvay, J.; et al. Spatially Resolved Proteomic and Transcriptomic Proﬁling of Anaplastic Lymphoma Kinase-Rearranged Pulmonary Adenocarcinomas Reveals Key Players in Inter-and Intratumoral Heterogeneity. Int. J. Mol. Sci. 2023, 24, 11369. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms241411369 Academic Editor: Barbara Ruaro Received: 9 June 2023 Revised: 28 June 2023 Accepted: 4 July 2023 Published: 12 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . 1 Division of Oncology, Department of Internal Medicine and Oncology, Semmelweis University, 1083 Budapest, Hungary; [szeitz.beata@phd.semmelweis.hu](szeitz.beata@phd.semmelweis.hu) (B.S.) 2 Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1091 Budapest, Hungary 3 MS Proteomics Research Group, Institute of Organic Chemistry, Research Centre for Natural Sciences, 1117 Budapest, Hungary 4 Doctoral School of Pharmaceutical Sciences, Semmelweis University, 1085 Budapest, Hungary 5 Department of Pathology, National Kor¡nyi Institute of Pulmonology, 1121 Budapest, Hungary 6 Department of Biotechnology, Division of Life Sciences, Yonsei University, Seoul 03722, Republic of Korea 7 1st Department of Pulmonology, National Kor¡nyi Institute of Pulmonology, 1121 Budapest, Hungary 8 Department of Tumor Biology, National Kor¡nyi Institute of Pulmonology, 1121 Budapest, Hungary 9 Department of Bioinformatics, Semmelweis University, 1094 Budapest, Hungary * Correspondence: [szasz.attila_marcell@med.semmelweis-univ.hu](szasz.attila_marcell@med.semmelweis-univ.hu); Tel.: +36-1-459-1500 Abstract: Pulmonary adenocarcinomas (pADCs) with an ALK rearrangement are a rare cancer subtype, necessitating comprehensive molecular investigations to unravel their heterogeneity and improve therapeutic strategies. In this pilot study, we employed spatial transcriptomic (NanoString GeoMx) and proteomic proﬁling to investigate seven treatment-naïve pADCs with an ALK rearrangement. On each FFPE tumor slide, 12 smaller and 2–6 larger histopathologically annotated regions were selected for transcriptomic and proteomic analysis, respectively. The correlation between proteomics and transcriptomics was modest (average Pearson's r = 0.43 at the gene level) . Intertumoral heterogeneity was more pronounced than intratumoral heterogeneity, and normal adjacent tissue exhibited distinct molecular characteristics. We identiﬁed potential markers and dysregulated pathways associated with tumors, with a varying extent of immune inﬁltration, as well as with mucin and stroma content. Notably, some markers appeared to be speciﬁc to the ALK-driven subset of pADCs. Our data showed that within tumors, elements of the extracellular matrix, including FN1, exhibited substantial variability. Additionally, we mapped the co-localization patterns of tumor microenvironment elements. This study represents the ﬁrst spatially resolved proﬁling of ALK-driven pADCs at both the gene and protein expression levels. Our ﬁndings may contribute to a better understanding of this cancer type prior to treatment

FAQs

What methods were used to profile ALK-rearranged pulmonary adenocarcinomas spatially?

The study combined spatial transcriptomic profiling using NanoString GeoMx with proteomic profiling. Regions were selected from FFPE tumor slides for transcriptomic and proteomic analysis.

How strong was the correspondence between proteomics and transcriptomics?

The correlation was modest, with an average Pearson r of 0.43 at the gene level.

Which type of heterogeneity was more pronounced, between tumors or within the same tumor?

Intertumoral heterogeneity was more pronounced than intratumoral heterogeneity, and normal adjacent tissue showed distinct molecular characteristics.

Sep 28, 2026

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