The Solute Carrier MFSD1 Decreases the Activation Status of β1 Integrin and Thus Tumor Metastasis

Marko Roblek; Julia Bicher; Merel van Gogh; Attila György; Rita Seeböck; Bozena Szulc; Markus Damme; Mariusz Olczak; Lubor Borsig; Daria E Siekhaus

doi:10.3389/fonc.2022.777634

The Solute Carrier MFSD1 Decreases the Activation Status of β1 Integrin and Thus Tumor Metastasis

Front Oncol. 2022 Feb 8:12:777634. doi: 10.3389/fonc.2022.777634. eCollection 2022.

Authors

Affiliations

¹ Institute of Science and Technology Austria, Klosterneuburg, Austria.
² Institute of Physiology, University of Zurich, Zurich, Switzerland.
³ Institute of Clinical Pathology, University Hospital St. Polten, St. Polten, Austria.
⁴ Laboratory of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
⁵ Institute of Biochemistry, University of Kiel, Kiel, Germany.

Abstract

Solute carriers are increasingly recognized as participating in a plethora of pathologies, including cancer. We describe here the involvement of the orphan solute carrier Major Facilitator Superfamily Domain-containing protein 1 (MFSD1) in the regulation of tumor cell migration. Loss of MFSD1 enabled higher levels of metastasis in experimental and spontaneous metastasis mouse models. We identified an increased migratory potential in MFSD1^-/- tumor cells which was mediated by increased focal adhesion turnover, reduced stability of mature inactive β1 integrin, and the resulting increased integrin activation index. We show that MFSD1 promoted recycling to the cell surface of endocytosed inactive β1 integrin and thereby protected β1 integrin from proteolytic degradation; this led to dampening of the integrin activation index. Furthermore, downregulation of MFSD1 expression was observed during the early steps of tumorigenesis, and higher MFSD1 expression levels correlate with a better cancer patient prognosis. In sum, we describe a requirement for endolysosomal MFSD1 in efficient β1 integrin recycling to suppress tumor cell dissemination.

Keywords: MFSD1; N-glycan; endolysosomal transport; integrin recycling; solute carriers (SLC); transporter; tumor cell metastasis; tumor cell migration.