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Peer-reviewedCC BY-NCScience Advances

Primary tumor–derived lactate primes prostate cancer cells for a dormant fate

  • Luigi Ippolito1
  • Erica Pranzini1
  • Giulia Gangarossa1
  • Marta Iozzo1
  • Giuseppina Comito1
  • Giacomo Venditti1
  • Sara Roccabianca1
  • Elisa Pardella1
  • Matteo Lulli1
  • Alice Santi1
  • Gabriella Nesi2
  • Elisa Giannoni1
1 more authors
  • Paola Chiarugi1
  1. 1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
  2. 2Department of Health Sciences, University of Florence, Viale Pieraccini 6, 50139 Florence, Italy.
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Abstract

The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.

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Cite

BibTeXRIS
BibTeX
@article{ippolito2026primary,
  title = {{Primary tumor–derived lactate primes prostate cancer cells for a dormant fate}},
  author = {Luigi Ippolito and Erica Pranzini and Giulia Gangarossa and Marta Iozzo and Giuseppina Comito and Giacomo Venditti and Sara Roccabianca and Elisa Pardella and Matteo Lulli and Alice Santi and Gabriella Nesi and Elisa Giannoni and Paola Chiarugi},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aeb8595},
  url = {https://www.science.org/doi/10.1126/sciadv.aeb8595},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - Primary tumor–derived lactate primes prostate cancer cells for a dormant fate
AU  - Luigi Ippolito
AU  - Erica Pranzini
AU  - Giulia Gangarossa
AU  - Marta Iozzo
AU  - Giuseppina Comito
AU  - Giacomo Venditti
AU  - Sara Roccabianca
AU  - Elisa Pardella
AU  - Matteo Lulli
AU  - Alice Santi
AU  - Gabriella Nesi
AU  - Elisa Giannoni
AU  - Paola Chiarugi
PY  - 2026
DA  - 2026/10/23
JO  - Science Advances
DO  - 10.1126/sciadv.aeb8595
UR  - https://www.science.org/doi/10.1126/sciadv.aeb8595
AB  - The metastatic outcome depends on the state of disseminated cancer cells (DCCs) leading to overt metastasis or undergoing dormancy. Before distant organ colonization, primary tumor microenvironment may shape the decision between proliferation and dormancy. Here, we identify lactic acid (LA), a highly abundant environmental metabolite at the primary site in prostate cancer (PCa), as a key inducer of dormant state. LA-uploading PCa cells undergo a proliferation delay, associated with stemness, therapy tolerance, and invasiveness through the nuclear receptor subfamily 2 group F member 1 (COUP-TF1/NR2F1) activation. These traits rely on LA-driven accumulation of lipid droplets (LDs), which serve as reservoirs of lipid-derived acetyl moieties essential for histone acetylation. Notably, the epigenetic reader BRD4 is essential for COUP-TF1 expression and for establishing and maintaining dormancy. In metastatic sites, where LA levels are low, dormant features are lost, allowing DCCs to support metastatic growth. Last, targeting LA-mediated LD formation or BRD4 activation prevents dormancy entry, reducing PCa cell adaptability and increasing vulnerability to antiproliferative therapies.
SN  - 2375-2548
ER  -