R-spondin 1 and SLIT2 cooperate to induce ISCs and enhance survival after chemoradiotherapy.
Major finding: R-spondin 1 and SLIT2 cooperate to induce ISCs and enhance survival after chemoradiotherapy.
Mechanism: SLIT2 and its receptor, ROBO1, are required for intestinal homeostasis and repair after injury.
Impact: Adjuvant R-spondin 1 and SLIT2 treatment may promote tolerance to aggressive chemoradiation.
Intensive chemoradiation regimens used to treat advanced, metastatic cancers can induce significant and often lethal injury in tissues such as the gastrointestinal tract, emphasizing the importance of identifying strategies to repair tissue injury and increase therapeutic tolerance. Zhou and colleagues found that the receptor roundabout 1 (ROBO1) and its ligand SLIT2, which regulate axon guidance, were highly expressed in transient amplifying cells and LGR5+ (leucine-rich repeat containing G protein-coupled receptor 5-positive) intestinal stem cells (ISC) within crypts of the mouse small intestine compared with differentiated cells in villi. Heterozygous deletion of Robo1 or inhibition of the SLIT2–ROBO1 interaction resulted in the formation of aberrantly small villi characterized by reduction in the number of LGR5+ ISCs and proliferating intestinal cells and decreased expression of ISC marker genes, and impaired the formation of intestinal organoids, suggesting that SLIT2–ROBO1 signaling is necessary for intestinal homeostasis. In support of this idea, ectopic expression of Slit2 promoted hypertrophic growth of intestinal villi, accumulation of LGR5+ ISCs, increased expression of ISC markers, and intestinal organoid formation. In addition, SLIT2 cooperated with R-spondin 1 (RSPO1), a secreted protein that activates WNT signaling and has been shown to enhance intestinal repair following chemotherapy- or radiation-mediated tissue damage, to stimulate intestinal organoid growth in vitro and decrease chemotherapy-induced intestinal injury in vivo. Combined SLIT2 and RSPO1 treatment synergistically protected LGR5+ ISCs from chemotherapy-induced depletion, potentiated intestinal regeneration, and prolonged the survival of mice receiving lethal chemotherapy or irradiation. This protective effect required ROBO1 expression and did not enhance intestinal tumor formation or diminish the sensitivity of tumor cells to chemotherapy. These results suggest that adjuvant RSPO1 and SLIT2 may promote intestinal tissue repair following aggressive chemoradiation by inducing adult stem cells.
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