{"messages":[{"status":"ok","category":"all"}],"collection":[{"title":"Signaling downstream of tumor-stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity","authors":"Pasquier, N.; Isomursu, A.; Hamidi, H.; Mathieu, J. R. R.; Härkönen, J.; Follain, G.; Desterke, C.; Fusilier, Z.; Solis, J.; Belaya, I.; Kankaanpää, P.; Barresi, V.; Cartry, J.; Bedja, S.; Jaulin, F.; Ivaska, J.","author_corresponding":"Johanna Ivaska","author_corresponding_institution":"University of Turku","doi":"10.1101/2024.11.20.624298","date":"2024-11-21","version":"1","type":"new results","license":"cc_by_nc_nd","category":"cancer biology","jatsxml":"https://www.biorxiv.org/content/early/2024/11/21/2024.11.20.624298.source.xml","abstract":"Mucinous colorectal carcinoma (MUC CRC) dissemination into the tumor stroma and metastasis to multiple organs, including the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either a conventional  apical-in or an inverted  apical-out polarity phenotype that influence patient outcome. Identifying the mechanisms controlling MUC CRC polarity is critical to understand disease progression. Here, we analyze patient-derived MUC CRC xenografts, with apical-in or apical-out polarity, ex vivo or within collagen gels to mimic the peritumoral stroma. Single-cell analyses reveal 2{beta}1-integrin as a key collagen-binding receptor in these models. Collagen-2{beta}1-integrin interaction activates Src and ERK/MAPK signaling and upregulates the expression of SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity and carcinoma-stroma interactions by promoting integrin recycling to the plasma membrane and HER2/HER3 expression through a positive feedback mechanism. Accordingly, we observe positive correlation between HER2, HER3 and SorLA in patient samples with the highest HER2 expression in apical-in-presenting tissues. Treatment of tumor spheres with clinically relevant HER2/HER3-targeting antibodies reverts sphere polarity and impedes collagen remodeling and adhesion to mouse peritoneum. This SorLA--integrin--HER2/HER3 signaling axis may represent a basis for MUC CRC-patient stratification and shed light on other carcinomas with similar apical-out phenotypes.","funder":"NA","published":"10.1038/s41467-026-75127-0","server":"bioRxiv"}]}