Preclinical tumor models with native tissue microenvironments provide essential tools to understand how heterogeneous tumor phenotypes relate to drug response. Here, we present syngeneic graft models of aggressive, metastasis-prone histopathology-specific NSCLC tumor types driven by KRAS mutation and loss of LKB1 (KL): adenosquamous carcinoma (ASC) and adenocarcinoma (AC). We show that subcutaneous injection of primary KL-ASC cells results in squamous cell carcinoma (SCC) tumors with high levels of stromal infiltrates, lacking the source heterogeneous histotype. Despite forming subcutaneous tumors, intravenously injected KL-AC cells were unable to form lung tumors. In contrast, intravenous injection of KL-ASC cells leads to their lung re-colonization and lesions recapitulating the mixed AC and SCC histopathology, tumor immune suppressive microenvironment and oncogenic signaling profile of source tumors, demonstrating histopathology-selective phenotypic dominance over genetic drivers. Pan-ERBB inhibition increased survival, while selective ERBB1/EGFR inhibition did not, suggesting a role of ERBB network crosstalk in resistance to ERBB1/EGFR. This immunocompetent NSCLC lung colonization model hence phenocopies key properties of the metastasis-prone ASC histopathology, and serves as a preclinical model to dissect therapy responses and metastasis-associated processes.
Development of an adenosquamous carcinoma histo pathology-selective lung metastasis model
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- Funder(s): Terveyden Tutkimuksen Toimikunta
- Award Id(s): 307111
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- Version of Record 13 December 2022
- Accepted Manuscript 10 November 2022
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I. A. K. Lähdeniemi, J. R. Devlin, A. S. Nagaraj, S. S. Talwelkar, J. Bao, N. Linnavirta, C. Șeref Vujaklija, E. A. Kiss, A. Hemmes, E. W. Verschuren; Development of an adenosquamous carcinoma histo pathology-selective lung metastasis model. Biol Open 2022; bio.059623. doi: https://doi.org/10.1242/bio.059623
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