Signaling downstream of tumor-stroma interaction regulates mucinous colorectal carcinoma apicobasal polarity

Nicolas Pasquier^1,2, Aleksi Isomorsu^1,**, Jacques RR Mathieu², Hellyeh Hamidi¹, Jouni Härkönen¹, Gautier Follain¹, Christophe Desterke³, Zoé Fusilier^4,5, Junel Solis⁶, Irina Belaya⁶, Pasi Kankaanpää⁶, Valeria Barresi⁷, Fanny Jaulin^*2 & Johanna Ivaska^*1,8-11

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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 determine 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1-integrin as a key collagen-binding receptor in these models. Collagen–2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 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.

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Organizational affiliations

¹Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
²INSERM-U1279, Gustave Roussy, Université Paris-Saclay, Villejuif F-94805, France
³INSERM UMR-S1310, Université Paris-Saclay, Hôpital Paul Brousse, Villejuif F-94805, France
⁴INSERM-U932, Immunity and Cancer, Institut Curie, Paris-Cité University, Paris, France
⁵INSERM-U932, Immunity and Cancer, Institut Curie, PSL University, Paris, France
⁶Turku BioImaging, Åbo Akademi University and University of Turku, Turku, Finland
⁷Department of Diagnostics and Public Health, University of Verona, Verona 37134, Italy
⁸Department of Life Technologies, University of Turku, Turku, Finland
⁹InFLAMES Research Flagship Center, University of Turku, Turku, Finland
¹⁰Foundation for the Finnish Cancer Institute, Helsinki, Finland
¹¹Western Finnish Cancer Center, University of Turku, Turku FI-20520, Finland

^*Correspondence: [email protected] and [email protected]
^**Current address: Cell Polarity, Migration and Cancer Unit, Institut Pasteur, CNRS UMR3691, Université Paris Cité, Équipe Labellisée Ligue Contre le Cancer, F-75015, Paris, France