TMPO promotes cellular dissemination and metastasis in circulating tumor cells
Metastasis-the process by which cancer cells spread beyond the primary tumor to distant organs-accounts for the vast majority of cancer-related deaths. To elucidate mechanisms underlying dissemination and metastasis in prostate cancer, we have investigated circulating tumor cells (CTCs) obtained from genetically engineered mouse models (GEMMs). The phenotypic and molecular properties of the CTCs, and organoids derived from these CTCs, closely model the tumor and metastatic phenotypes of their parental GEMMs. Moreover, organoids derived from individual CTCs exhibit molecular and morphological heterogeneity that is associated with distinct metabolic states as well as differences in human prostate cancer outcome. Using computational systems analyses, we have identified <i>TMPO</i> , encoding the nuclear membrane protein lamina-associated polypeptide 2 (Lap2), as a key driver of this heterogeneity. <i>TMPO</i> activity is upregulated in advanced human prostate tumors, metastases, and CTCs, and is associated with adverse clinical outcome. Our findings indicate that <i>TMPO</i> promotes dissemination and metastasis <i>in vivo</i> by enhancing survival in conditions of metabolic stress, and reveal a novel mechanistic link between CTC heterogeneity, stress adaptation, and metastatic potential.
Authors
- Aunika Zheng (ORCID: https://orcid.org/0009-0009-1730-2391)
- Matteo Di Bernardo
- David T. Miyamoto (ORCID: https://orcid.org/0000-0003-3692-8823)
- Hermenegildo Garcı́a (ORCID: https://orcid.org/0000-0002-9664-493X)
- Stephanie N. Afari (ORCID: https://orcid.org/0000-0001-6453-1124)
- Florencia Picech (ORCID: https://orcid.org/0000-0002-2783-4270)
- Giuseppe Nicolò Fanelli (ORCID: https://orcid.org/0000-0001-7069-7980)
- Michael M. Shen (ORCID: https://orcid.org/0000-0002-4042-1657)
- Shyamala Maheswaran
- B Robinson
- Aleksandar Obradović (ORCID: https://orcid.org/0000-0002-8009-0186)
- Cory Abate‐Shen (ORCID: https://orcid.org/0000-0002-5021-0570)
- Jaime Y. Kim (ORCID: https://orcid.org/0000-0003-1266-1917)
- Andrea Califano (ORCID: https://orcid.org/0000-0003-4742-3679)
- Renu K. Virk (ORCID: https://orcid.org/0000-0002-2984-4202)
- Caroline Laplaca
- Juan Martín Arriaga (ORCID: https://orcid.org/0000-0001-7523-2955)
- Peter A. Sims (ORCID: https://orcid.org/0000-0002-3921-4837)
- Paraskevi Giannakakou (ORCID: https://orcid.org/0000-0001-7378-262X)
- H. Henry Guo (ORCID: https://orcid.org/0000-0001-5511-1750)
- Alexander Chui (ORCID: https://orcid.org/0009-0002-1782-0235)
- Jung Seung Nam (ORCID: https://orcid.org/0000-0001-8557-131X)
- Min Zou (ORCID: https://orcid.org/0000-0003-0726-1003)
- Jinqiu Lu
- Tian Zheng
- Soonbum Park
- Scott T. Tagawa
- Massimo Loda
- Christine Iok In Chio
- Francisca Nunes de Almeida
- David M. Nanus
- Arianna Giacobbe
- Carlos Pedraz-Valdunciel
- Maya Stella Dixon
- Daniel A. Harber
Institutions
- Howard Hughes Medical Institute (US)
- Harvard University (US)
- Cornell University (US)
- Massachusetts General Hospital (US)
- Center for Cancer Research (US)
- Weill Cornell Medicine (US)
- Columbia University (US)
Publication Details
- Journal
- bioRxiv (Cold Spring Harbor Laboratory)
- Published
- 2025-12-27
- DOI
- https://doi.org/10.64898/2025.12.27.696673
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 0.00