Makela, T. P. | bioRxiv Science

bioRxiv2023

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

Peutz-Jeghers syndrome (PJS) is associated with early-onset and recurring gastrointestinal hamartomatous polyposis caused by hereditary inactivating mutations in the tumor suppressor gene LKB1 (STK11). Due to lack of efficient prophylactic therapies PJS patients require regular surgical interventions and have an increased risk of cancer. LKB1-deficient fibroblasts have been identified as drivers of polyposis, but a safely druggable target remains to be identified. Here we investigate tumorigenic mechanisms in PJS polyps using single-cell RNA sequencing of predisposed and tumor tissue and identified a ST2-expressing crypt top fibroblast (CTF) cluster enriched in polyps. The relevance of CTFs was supported by the fast polyposis following deletion of Lkb1 in CTFs. The transcriptional signature characterizing the ST2+ fibroblasts (ST2-CTFs) was enriched in inflammation-associated fibroblasts, and PJS polyposis was exacerbated by inflammation. Cell-cell communication analysis identified the ST2-CTF signature gene interleukin 11 (IL-11) as an upstream regulator of the ST2-CTFs, and consistently, reprogramming toward ST2 fibroblasts in vitro was dependent on IL-11. Importantly, a neutralizing IL-11 antibody efficiently reduced the tumor burden in a PJS mouse model. In summary, our results reveal ST2+ tumorigenic fibroblasts as drivers of PJS polyposis and identify IL-11 as the key mediator and a potential therapeutic target in PJS.

cancer biology↗

bioRxiv2020

Ciliary signaling-patterned smooth muscle drives tubular elongation

During development, many tubular organs undergo extensive longitudinal growth to reach their defined length, essential for their function, but how they lengthen is poorly understood. Here, we found that primary cilia are critical for the elongation of the small intestine and esophagus during murine embryonic development. More specifically, HH ligands produced by the epithelium signaled via cilia in the surrounding mesenchyme to pattern the smooth muscle. Like attenuated ciliary HH signaling, partial ablation of the smooth muscle reduced elongation, revealing an essential role for smooth muscle in longitudinal growth. Disruption of cilia, HH signaling or the smooth muscle reduced residual stress within the gut wall, indicating that smooth muscle contributes to the mechanical properties of the developing gut. Reducing residual stress decreased nuclear YAP, an effector of the mechanotransductive Hippo pathway. Removing YAP in the mesenchyme did not affect smooth muscle formation, but attenuated proliferation and elongation, demonstrating that YAP interprets smooth muscle-generated force to promote proliferation. Together, our results reveal that ciliary signaling directs the formation of the smooth muscle layer which, in turn, generates mechanical forces that activate YAP-mediated proliferation. As this interplay of biochemical and mechanical signals drives elongation of both the esophagus and small intestine, we propose that this mechanism may underlie tubular organ elongation generally. HighlightsO_LIPrimary cilia are essential for the elongation of the small intestine and esophagus during embryonic development C_LIO_LICiliary signaling patterns the smooth muscle in the developing intestine and esophagus C_LIO_LIThe smooth muscle contributes to tissue mechanics C_LIO_LISmooth muscle-generated strain activates YAP to drive longitudinal growth of the tubular organs C_LI

developmental biology↗