KDM1A-associated tumor–myeloid communication and extracellular vesicle-mediated microglia-like responses in lung cancer brain metastasis
Abstract
IntroductionLung cancer brain metastasis is shaped by reciprocal interactions between tumor cells and the brain microenvironment, yet whether KDM1A/LSD1 influences this communication through tumor-derived extracellular vesicles (EVs) remains unclear.MethodsHere, we combined within-patient single-cell transcriptomic analysis with genetic and pharmacological LSD1 perturbation, EV-based functional assays, and an intracranial xenograft model to define an LSD1-associated tumor-myeloid communication phenotype.ResultsSingle-cell analysis identified a reproducible KDM1A co-expression-associated tumor-cell state characterized by coordinated communication- and microenvironment-remodeling programs and recurrent APP-CD74- and MDK-related signaling patterns. Among the prioritized candidates, MDK showed the most consistent experimental response to LSD1 knockout, with concordant reductions in donor-cell mRNA, cellular protein and EV-associated protein. Functionally, EVs derived from LSD1-deficient tumor cells shifted HMC3 microglia-like cells toward a mixed inflammatory and immunoregulatory state and altered their secretory output. Conditioned medium from these EV-exposed HMC3 cells subsequently suppressed H1299 proliferation and enhanced apoptosis, indicating a secondary tumor-myeloid-tumor paracrine effect. Pharmacological LSD1 inhibition produced a partially overlapping functional phenotype. In mice with established intracranial tumors, LSD1-KO-EV treatment was associated with lower endpoint ex vivo brain bioluminescence, with representative H&E sections showing a qualitatively concordant pattern.DiscussionThese findings support EV-mediated tumor-myeloid communication as one consequence of LSD1 perturbation and nominate MDK-associated EV remodeling for direct mechanistic testing.
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BibTeX
@article{li2026kdm1aassociated,
title = {{KDM1A-associated tumor–myeloid communication and extracellular vesicle-mediated microglia-like responses in lung cancer brain metastasis}},
author = {Zi-Hao Li and Juan-Juan Peng and Bao-Xin-Zi Liu and Qing-Feng Li and Mian-Hua Wu and Lei Wang and Zhong-Rui Li},
journal = {Frontiers in Pharmacology},
year = {2026},
month = nov,
doi = {10.3389/fphar.2026.1912724},
url = {https://www.frontiersin.org/articles/10.3389/fphar.2026.1912724},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - KDM1A-associated tumor–myeloid communication and extracellular vesicle-mediated microglia-like responses in lung cancer brain metastasis
AU - Zi-Hao Li
AU - Juan-Juan Peng
AU - Bao-Xin-Zi Liu
AU - Qing-Feng Li
AU - Mian-Hua Wu
AU - Lei Wang
AU - Zhong-Rui Li
PY - 2026
DA - 2026/11/13
JO - Frontiers in Pharmacology
DO - 10.3389/fphar.2026.1912724
UR - https://www.frontiersin.org/articles/10.3389/fphar.2026.1912724
AB - IntroductionLung cancer brain metastasis is shaped by reciprocal interactions between tumor cells and the brain microenvironment, yet whether KDM1A/LSD1 influences this communication through tumor-derived extracellular vesicles (EVs) remains unclear.MethodsHere, we combined within-patient single-cell transcriptomic analysis with genetic and pharmacological LSD1 perturbation, EV-based functional assays, and an intracranial xenograft model to define an LSD1-associated tumor-myeloid communication phenotype.ResultsSingle-cell analysis identified a reproducible KDM1A co-expression-associated tumor-cell state characterized by coordinated communication- and microenvironment-remodeling programs and recurrent APP-CD74- and MDK-related signaling patterns. Among the prioritized candidates, MDK showed the most consistent experimental response to LSD1 knockout, with concordant reductions in donor-cell mRNA, cellular protein and EV-associated protein. Functionally, EVs derived from LSD1-deficient tumor cells shifted HMC3 microglia-like cells toward a mixed inflammatory and immunoregulatory state and altered their secretory output. Conditioned medium from these EV-exposed HMC3 cells subsequently suppressed H1299 proliferation and enhanced apoptosis, indicating a secondary tumor-myeloid-tumor paracrine effect. Pharmacological LSD1 inhibition produced a partially overlapping functional phenotype. In mice with established intracranial tumors, LSD1-KO-EV treatment was associated with lower endpoint ex vivo brain bioluminescence, with representative H&E sections showing a qualitatively concordant pattern.DiscussionThese findings support EV-mediated tumor-myeloid communication as one consequence of LSD1 perturbation and nominate MDK-associated EV remodeling for direct mechanistic testing.
SN - 1663-9812
ER -