B3GALT6 promotes dormant breast cancer cell survival and recurrence by enabling heparan sulfate-mediated FGF signaling

• Published in: Cancer cell 2024-01, Vol.42 (1), p.52-69.e7
• Main Authors: Sreekumar, Amulya, Lu, Michelle, Choudhury, Biswa, Pan, Tien-chi, Pant, Dhruv K., Lawrence-Paul, Matthew R., Sterner, Christopher J., Belka, George K., Toriumi, Takashi, Benz, Brian A., Escobar-Aguirre, Matias, Marino, Francesco E., Esko, Jeffrey D., Chodosh, Lewis A.
• Format: Article
• Language: English
• Subjects: 6-O-sulfation; B3GALT6; breast cancer; Breast Neoplasms - genetics; Cell Survival - genetics; dormancy; Female; FGFR2; Galactosyltransferases - genetics; glycans; glycosaminoglycans; Glycosaminoglycans - metabolism; heparan sulfate; Heparitin Sulfate - metabolism; HS6ST1; Humans; Neoplasm Recurrence, Local - genetics; proteoglycans
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2023.11.008

Breast cancer mortality results from incurable recurrences thought to be seeded by dormant, therapy-refractory residual tumor cells (RTCs). Understanding the mechanisms enabling RTC survival is therefore essential for improving patient outcomes. Here, we derive a dormancy-associated RTC signature that mirrors the transcriptional response to neoadjuvant therapy in patients and is enriched for extracellular matrix-related pathways. In vivo CRISPR-Cas9 screening of dormancy-associated candidate genes identifies the galactosyltransferase B3GALT6 as a functional regulator of RTC fitness. B3GALT6 is required for glycosaminoglycan (GAG) linkage to proteins to generate proteoglycans, and its germline loss of function in patients causes skeletal dysplasias. We find that B3GALT6-mediated biosynthesis of heparan sulfate GAGs predicts poor patient outcomes and promotes tumor recurrence by enhancing dormant RTC survival in multiple contexts, and does so via a B3GALT6-heparan sulfate/HS6ST1-heparan 6-O-sulfation/FGF1-FGFR2 signaling axis. These findings implicate B3GALT6 in cancer and nominate FGFR2 inhibition as a promising approach to eradicate dormant RTCs and prevent recurrence. [Display omitted] •Dormant residual tumor cells (RTCs) upregulate heparan sulfate (HS) biosynthesis•CRISPR-Cas9 screen identifies B3galt6 as a regulator of RTC survival and recurrence•B3galt6 is required for glycosaminoglycan-protein linkage to generate proteoglycans•Dormant RTCs upregulate B3galt6/Hs6st1/Fgf1/Fgfr2 signaling to maintain survival Sreekumar et al. identify a previously uncharacterized function for the galactosyltransferase B3galt6 in cancer, specifically enabling dormant residual tumor cell survival following therapy or in a restrictive microenvironment by promoting heparan sulfate-mediated FGF signaling. These findings implicate a poorly studied class of molecules, glycans, in breast cancer dormancy and recurrence.