Altogether, our data indicate that pRb and RBL2 expression in PDAC cells has a negative effect on CSC characteristics via WNT ligand-mediated non-cell autonomous effects emphasising the importance of RB tumour suppressors as regulators of autocrine and paracrine signalling that shapes the stem cell-like characteristics of cancer cells and cross-talks with the surrounding cells through the tumour microenvironment. Here, RBL2 is linked to cancer.