Nuclear biocondensate-forming lncRNA and cellular stress surveillance shape host cancer susceptibility

Host genetics is known to influence cancer susceptibility. However, the specific candidate genes and molecular mechanisms that confer resistance remain poorly understood. Here, we demonstrate the power of haploinsufficiency screen to uncover host genetic regulators of cancer in Drosophila and identify the long noncoding RNA (lncRNA) hsrω , a structural component of nuclear biomolecular condensate known as omega speckles, as a key host cancer susceptibility locus. Loss of hsrω disrupts proteostasis and cell fitness, while its haploinsufficiency accelerates epithelial tumor progression driven by loss of the Lethal giant larvae (Lgl) tumor suppressor. Further validating the breadth of this screening strategy, we independently identified Drosophila STING (innate immunity) and Keap1 (oxidative stress defense) as genetic modifiers of cancer. Moreover, in humans, copy number variations (CNV) in these genes and Sat III (a functional human homolog of hsrω ) correlate with poor cancer prognosis, thereby revealing conserved stress pathways as potential host genetic susceptibility regulators.