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<p>Mucinous colorectal carcinoma (MUC CRC) metastasis to multiple organs, and to the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either conventional (apical-in) or inverted (apical-out) polarity that influence patient outcomes. Therefore, it is critical to identify how MUC CRC polarity is regulated. Here, we analyze patient-derived MUC CRC xenografts with either apical-in or apical-out polarity. Single-cell analyses reveal α2β1-integrin as a key collagen-binding receptor in these models. Collagen–α2β1-integrin interaction activates Src and upregulates SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity by promoting integrin recycling and HER2/HER3 expression. We observe positive correlation between HER2, HER3 and SorLA in patient samples and higher HER2 expression in apical-in-presenting tissues. Clinically relevant HER2/HER3-targeting antibodies revert tumor sphere polarity, and impede collagen remodeling and adhesion to mouse peritoneum. This SorLA—integrin—HER2/HER3 axis could represent a MUC CRC-patient stratification approach and be relevant for other carcinomas with apical-out phenotypes.</p>

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Signaling downstream of tumor–stroma interaction regulates mucinous colorectal adenocarcinoma apicobasal polarity

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Nicolas Pasquier,
  • Meri Pelkonen,
  • Elise Carraz-Billat,
  • Aleksi Isomursu,
  • Raphaël Merand,
  • Hellyeh Hamidi,
  • Jacques R. R. Mathieu,
  • Jouni Härkönen,
  • Gautier Follain,
  • Christophe Desterke,
  • Zoé Fusilier,
  • Junel Solis,
  • Irina Belaya,
  • Pasi Kankaanpää,
  • Valeria Barresi,
  • Mohamed-Amine Bani,
  • Johanna Protin,
  • Jérôme Cartry,
  • Sabrina Bedja,
  • Olav M. Andersen,
  • Klaus Elenius,
  • Florent Peglion,
  • Fanny Jaulin,
  • Johanna Ivaska

摘要

Mucinous colorectal carcinoma (MUC CRC) metastasis to multiple organs, and to the peritoneum, is associated with poor prognosis. Disseminating MUC CRCs exhibit either conventional (apical-in) or inverted (apical-out) polarity that influence patient outcomes. Therefore, it is critical to identify how MUC CRC polarity is regulated. Here, we analyze patient-derived MUC CRC xenografts with either apical-in or apical-out polarity. Single-cell analyses reveal α2β1-integrin as a key collagen-binding receptor in these models. Collagen–α2β1-integrin interaction activates Src and upregulates SorLA, an endosomal sorting receptor. SorLA supports apical-in polarity by promoting integrin recycling and HER2/HER3 expression. We observe positive correlation between HER2, HER3 and SorLA in patient samples and higher HER2 expression in apical-in-presenting tissues. Clinically relevant HER2/HER3-targeting antibodies revert tumor sphere polarity, and impede collagen remodeling and adhesion to mouse peritoneum. This SorLA—integrin—HER2/HER3 axis could represent a MUC CRC-patient stratification approach and be relevant for other carcinomas with apical-out phenotypes.