An androgen-derived transcriptional state reveals signaling and mitochondrial vulnerabilities in cancer
- 1Graduate School of Medical Sciences, Kyushu University
Abstract
Transcriptional states can provide functional information beyond genomic alterations, but whether states derived from nonmalignant physiological perturbations remain informative in cancer is unclear. We separated global RNA-output suppression from relative transcriptional remodeling induced by dihydrotestosterone in mouse adrenal zona fasciculata cells and derived a cross-sex transcriptional signature. Projection of this signature to human orthologs defined an androgen-suppressed transcriptional state (ASTS) across cancer cell lines. Integration with pharmacogenomic and CRISPR dependency datasets showed that higher ASTS was associated with resistance to EGFR-targeted drugs and reduced EGFR dependency, together with increased dependency on mitochondrial pathways, including mitochondrial translation and respiratory electron transport. These associations were not attributable to a single major cancer lineage and remained evident after adjustment for canonical oncogenic drivers and cell-state covariates. ASTS provides a proof of concept that an endocrine-derived transcriptional state can reveal candidate functional vulnerabilities in an unrelated cancer context.
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BibTeX
@misc{miao2026androgenderived,
title = {{An androgen-derived transcriptional state reveals signaling and mitochondrial vulnerabilities in cancer}},
author = {Y. Miao and T. Baba},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.06.757186},
url = {https://www.biorxiv.org/content/10.64898/2026.10.06.757186v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - An androgen-derived transcriptional state reveals signaling and mitochondrial vulnerabilities in cancer
AU - Y. Miao
AU - T. Baba
PY - 2026
DA - 2026/10/06
PB - bioRxiv
DO - 10.64898/2026.10.06.757186
UR - https://www.biorxiv.org/content/10.64898/2026.10.06.757186v1
AB - Transcriptional states can provide functional information beyond genomic alterations, but whether states derived from nonmalignant physiological perturbations remain informative in cancer is unclear. We separated global RNA-output suppression from relative transcriptional remodeling induced by dihydrotestosterone in mouse adrenal zona fasciculata cells and derived a cross-sex transcriptional signature. Projection of this signature to human orthologs defined an androgen-suppressed transcriptional state (ASTS) across cancer cell lines. Integration with pharmacogenomic and CRISPR dependency datasets showed that higher ASTS was associated with resistance to EGFR-targeted drugs and reduced EGFR dependency, together with increased dependency on mitochondrial pathways, including mitochondrial translation and respiratory electron transport. These associations were not attributable to a single major cancer lineage and remained evident after adjustment for canonical oncogenic drivers and cell-state covariates. ASTS provides a proof of concept that an endocrine-derived transcriptional state can reveal candidate functional vulnerabilities in an unrelated cancer context.
ER -