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.