Proteomic-based stemness score measures oncogenic dedifferentiation and enables the identification of druggable targets
Cancer progression and therapeutic resistance are closely linked to a stemness phenotype. Here, we introduce a protein-expression-based stemness index (PROTsi) to evaluate oncogenic dedifferentiation in relation to histopathology, molecular features, and clinical outcomes. Utilizing datasets from the Clinical Proteomic Tumor Analysis Consortium across 11 tumor types, we validate PROTsi's effectiveness in accurately quantifying stem-like features. Through integration of PROTsi with multi-omics, including protein post-translational modifications, we identify molecular features associated with stemness and proteins that act as active nodes within transcriptional networks, driving tumor aggressiveness. Proteins highly correlated with stemness were identified as potential drug targets, both shared and tumor specific. These stemness-associated proteins demonstrate predictive value for clinical outcomes, as confirmed by immunohistochemistry in multiple samples. The findings emphasize PROTsi's efficacy as a valuable tool for selecting predictive protein targets, a crucial step in customizing anti-cancer therapy and advancing the clinical development of cures for cancer patients.
Authors
- Emerson de Souza Santos (ORCID: https://orcid.org/0000-0002-3544-6745)
- Yifat Geffen (ORCID: https://orcid.org/0000-0003-3692-4689)
- Felipe da Veiga Leprevost (ORCID: https://orcid.org/0000-0002-8228-5374)
- Jan Lubiński (ORCID: https://orcid.org/0000-0003-2931-3003)
- Paweł Kurzawa (ORCID: https://orcid.org/0000-0002-2223-0291)
- Antonio Colaprico (ORCID: https://orcid.org/0000-0003-1044-4361)
- Erik Storrs (ORCID: https://orcid.org/0000-0002-8041-0864)
- Mehdi Mesri (ORCID: https://orcid.org/0000-0001-7295-9673)
- Renan Simões (ORCID: https://orcid.org/0000-0002-8571-2933)
- Elizabeth G. Demicco (ORCID: https://orcid.org/0000-0003-4144-8824)
- Alexander J. Lazar (ORCID: https://orcid.org/0000-0002-6395-4499)
- Bożena Kamińska (ORCID: https://orcid.org/0000-0002-2642-4616)
- Pietro Pugliese (ORCID: https://orcid.org/0000-0002-0699-7601)
- Waldemar Priebe (ORCID: https://orcid.org/0000-0003-4522-4772)
- Ana I. Robles (ORCID: https://orcid.org/0000-0001-5019-4374)
- Tathiane M. Malta (ORCID: https://orcid.org/0000-0003-1129-5791)
- Houtan Noushmehr (ORCID: https://orcid.org/0000-0003-4051-8114)
- Francesca Petralia (ORCID: https://orcid.org/0000-0001-5096-9854)
- Alexey I. Nesvizhskii (ORCID: https://orcid.org/0000-0002-2806-7819)
- Michele Ceccarelli (ORCID: https://orcid.org/0000-0002-4702-6617)
- Rossana N. Lazcano Segura
- Iga Kołodziejczak-Guglas (ORCID: https://orcid.org/0000-0003-1560-3982)
- Bing Zhang (ORCID: https://orcid.org/0000-0002-1750-1659)
- Pei Wang (ORCID: https://orcid.org/0000-0002-6890-6453)
- Ma Weiping
Institutions
- Broad Institute (US)
- Poznan University of Medical Sciences (PL)
- Mount Sinai Hospital (CA)
- Universidade de Ribeirão Preto (BR)
- The University of Texas MD Anderson Cancer Center (US)
- Henry Ford Health System (US)
- University of Sannio (IT)
- Instytut Biologii Doświadczalnej im. Marcelego Nenckiego (PL)
- Universidade de São Paulo (BR)
- Baylor College of Medicine (US)
- Washington University in St. Louis (US)
- University of Michigan (US)
- International Institute for Molecular Oncology (PL)
- International Institute of Molecular and Cell Biology (PL)
- National Cancer Institute (MY)
- Postgraduate School of Molecular Medicine (PL)
- National Cancer Institute (US)
- Clinics Hospital of Ribeirão Preto (BR)
- Sylvester Comprehensive Cancer Center (US)
- International Hereditary Cancer Center (PL)
- Baylor Genetics (US)
- Icahn School of Medicine at Mount Sinai (US)
Publication Details
- Journal
- Cell Genomics
- Published
- 2025-04-17
- DOI
- https://doi.org/10.1016/j.xgen.2025.100851
- Citations
- 3
- Primary Topic
- Protein Degradation and Inhibitors
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- National Institutes of Health
- National Cancer Institute