• Expression of ERGM40 in mouse prostate organoids promotes their survival and growth in the absence of Egf. • ERGM40 alters the extracellular signaling network of mouse prostate organoids. • Canonical Wnt pathway is substantially reduced in ERG + prostate organoids due to decreased autocrine signaling of Wnt4. • Gsk3b promotes Nkx3.1 proteolysis and, in turn, accumulation of double strand breaks in ERG + prostate organoids. • Paracrine signaling of ERG + prostate organoids modulates Arginase 1 expression in M1-polarized macrophages.