Progastrin Promotes Colorectal Cancer Stem Cell‐Like Properties via the Receptor PZR
The tumor microenvironment promotes cancer progression in part by supporting cancer stem cells (CSC). In colorectal cancer (CRC), progastrin (PG), an orphan growth factor secreted by tumor cells within the tumor and its microenvironment, maintains CSCs by unidentified mechanisms. Here, the orphan receptor Protein Zero-Related protein (PZR) is identified as an essential component of PG activity and demonstrated its utility as a therapeutic target. PZR is essential for growth of PG-expressing tumors, while genetic inactivation in mice of Mpzl1, which encodes PZR, disrupted chemically-induced colon transformation. Mechanistically, PG binds cellular glycosylated and dimeric PZR and promotes SHP2/SRC/β-catenin-dependent CSC-like signaling. Blocking PZR by monoclonal antibodies inhibited PG-dependent expansion of tumoroids derived from murine intestinal tumors and patient-derived CRC cell lines, while in mice, it reduced adenoma formation triggered by Apc loss in stem cells and disrupted the tumor-initiating capacity of PG-expressing CRC cells. High GAST (which encodes PG) and MPZL1 transcript levels in primary colon cancer patients is predictive of worse prognosis. Collectively, these findings support the inhibition of PZR as a potential targeted treatment of PG-expressing CRC.
Authors
- Michael Hahne (ORCID: https://orcid.org/0000-0002-3953-6430)
- M. Lafitte (ORCID: https://orcid.org/0000-0003-2026-855X)
- Romain M. Larive (ORCID: https://orcid.org/0000-0001-8479-209X)
- Lucile Bansard
- Jacques Colinge (ORCID: https://orcid.org/0000-0003-2466-4824)
- Audrey Sirvent (ORCID: https://orcid.org/0000-0003-4555-6312)
- Maya Jeitany (ORCID: https://orcid.org/0000-0002-2294-7815)
- Valérie Simon (ORCID: https://orcid.org/0000-0002-2624-157X)
- Maud Maillard (ORCID: https://orcid.org/0000-0002-6615-3136)
- Maud Barbery
- Steeve Thirard
- Kevin Espie
- Pierre Martineau (ORCID: https://orcid.org/0000-0002-7993-7183)
- Elise Fourgous (ORCID: https://orcid.org/0000-0002-3626-250X)
- Julie Pannequin (ORCID: https://orcid.org/0000-0002-9956-373X)
- Yvan Boublik
- Serge Roche (ORCID: https://orcid.org/0000-0003-3413-3859)
- Nathalie Coutry (ORCID: https://orcid.org/0000-0001-5830-4013)
- Madeline Neiveyans
- Jihane Vitre
- Julie Nguyen (ORCID: https://orcid.org/0000-0002-8361-0204)
- Conception Paul
- Philippe Jay
Institutions
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université de Montpellier (FR)
- Laboratoire d'Informatique, de Robotique et de Microélectronique de Montpellier (FR)
- Institut de Génétique Moléculaire de Montpellier (FR)
- Géosciences Montpellier (FR)
- Institute for Neurosciences of Montpellier (FR)
- Institut de Recherche en Cancérologie de Montpellier (FR)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-08-03
- DOI
- https://doi.org/10.1002/advs.202502136
- Citations
- 2
- Primary Topic
- Cancer Cells and Metastasis
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Fondation pour la Recherche Médicale