Fibroblast-derived IL-11 is a driver and therapeutic target in Peutz-Jeghers syndrome polyposis

Inactivating germline mutations in the tumor suppressor kinase LKB1 (STK11) predispose to Peutz-Jeghers Syndrome (PJS) with increased cancer risk and early-onset development of gastrointestinal polyps requiring regular surveillance. Studies using PJS mouse models have indicated fibroblasts as drivers of polyp formation. Here, we use single-cell RNA sequencing to investigate the fibroblast heterogeneity and tumorigenic mechanisms in a PJS mouse model. We identify five distinct gastric fibroblast subsets, including a polyp-enriched ST2 (Il1rl1)-expressing crypt top fibroblast (CTF) cluster, and show that the polyps arise from Foxl1-expressing CTFs. The transcriptional signature of the ST2-CTFs overlapped with the effects seen by LKB1 loss in vitro and in vivo. The ST2-CTFs also shared similarities with inflammation-associated fibroblasts, and inflammation exacerbated polyposis. Interestingly, the tumorigenic ST2-CTFs showed a distinct signaling pattern, including high expression of interleukin 11 (IL-11). Notably, IL-11 was required for the LKB1 loss-induced transcriptional changes in fibroblasts, and treatment with an IL-11 neutralizing antibody substantially reduced the tumor burden in the PJS mouse model, suggesting therapeutic value. In summary, our study uncovers a critical mechanism underlying PJS polyposis and suggests that PJS patients could benefit from anti-IL-11 therapy. ### Competing Interest Statement S.A.C is a co-inventor of the published patents related to IL-11 therapies: WO/2017/103108, WO/2018/109170, WO/2018/109174. S.A.C. and W.-W.L are co-inventors of the published patent WO/2019/073057. S.A.C. is a co-founder and shareholder of Enleofen Bio PTE LTD, a company that develops anti-IL11 therapeutics, whose preclinical IL-11 platform was acquired by Boehringer Ingelheim in 2019 for further development.