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Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.

Warisa Khatoon·Kaustar Yadav·Amit Katiyar·Sunil Kumar·Sudheer Arava·Anant Mohan·Rambha Pandey·Chandrashekhara Sh·Aruna Nambirajan·Prabhat Singh Malik·Deepali Jain
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Abstract

INTRODUCTION: Genetic alterations and the tumor microenvironment (TME) influence treatment response in anaplastic lymphoma kinase-rearranged non-small cell lung cancer (ALK+ NSCLC). This study maps site-specific TME adaptations and exploratory risk-associated signatures in lymph node metastases (LNT) to investigate metastatic evolution. METHOD: We applied spatial transcriptomics to profile tumor (PanCK+) and stromal (PanCK-) compartments in a pilot cohort of 16 cases: primary lung tumors (LT, n = 3), LNT (n = 10), and brain metastases (BT, n = 3), with three site-matched non-tumor controls. LNT-derived prognostic signatures were evaluated using The Cancer Genome Atlas-Lung Adenocarcinoma (TCGA LUAD) cohorts. RESULTS: Distinct, site-specific TME features were observed. LNT stroma was enriched in fibroblasts and macrophages, while tumor segments showed increased neutrophils. BT exhibited a macrophage-associated immunosuppressive TME. Tumor cells evolved divergently: LT retained pulmonary identity and showed trend towards translation-associated programs, LNT cells shifted toward senescence and epigenetic remodeling, and BT cells showed activation of Class A/1 (Rhodopsin-like) receptor, GPCR and drug metabolism pathways. In LNT, exploratory risk-associated differences were observed. Low-risk cases (n = 6) showed adaptive immune signatures, whereas high-risk cases (n = 4) showed enrichment for stromal MET signaling and stress-response pathways. Because treatment exposure differed markedly between the risk groups, these observations should be interpreted as hypothesis-generating. TCGA LUAD analysis suggested the broader biological relevance of immune-associated markers, but reflected general LUAD rather than ALK+ specific biology. Discordant associations for GCLC and TIMP1 underscored the importance of spatial context. CONCLUSION: Site-specific microenvironments may influence tumor adaptation across metastatic niches in ALK+ NSCLC. The exploratory risk-associated findings require validation in larger, uniformly treated cohorts.

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HumansLung NeoplasmsAnaplastic Lymphoma KinaseSpatial TranscriptomicsTumor MicroenvironmentCarcinoma, Non-Small-Cell LungFemaleMaleLymphatic MetastasisBrain NeoplasmsMiddle AgedGene RearrangementPrognosisBiomarkers, TumorTranscriptomeAgedALKLung cancerMetastaticPrognostic signaturesSpatial transcriptomicsTumor microenvironmentJournal Article

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Warisa Khatoon, Kaustar Yadav, Amit Katiyar, Sunil Kumar, Sudheer Arava, Anant Mohan, Rambha Pandey, Chandrashekhara Sh, Aruna Nambirajan, Prabhat Singh Malik, Deepali Jain. 2026-09-02. Spatial transcriptomics of primary and metastatic ALK-rearranged NSCLC reveals site-specific adaptations.. https://doi.org/10.1016/j.currproblcancer.2026.101331

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