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

See affiliations

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.

[Link/s to full-text here]

Image data

[Links to image data here]

Running the source code

[Setup and run instructions here]

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: johanna.ivaska@utu.fi and fanny.jaulin@gustaveroussy.fr
^**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