Breast cancer remains the leading cause of cancer-related deaths in women worldwide. Mortality is primarily attributable to incurable metastatic recurrences seeded by residual tumor cells (RTCs) that survive first-line therapy, often in a dormant state. Though RTCs comprise as little as 0.01% of the initial tumor mass, they represent the fittest cells capable of surviving therapy and inhospitable metastatic microenvironments. The mechanisms underlying RTC persistence following therapy remain unclear, limiting clinical strategies targeting minimal residual disease (MRD).

Previous work has demonstrated that a subset of glycans, namely glycosaminoglycans (GAGs), are selectively enriched following therapy and are central regulators of dormant MRD adaptation to therapy (Sreekumar A, et al., Cancer Cell, 2024). Furthermore, this elevated expression of GAG biosynthetic enzymes is also observed in other MRD contexts, including circulating tumor cells and micrometastases, suggesting that GAG biosynthesis may constitute a common, generalizable mechanism of RTC adaptation.

Strikingly, this glycan dependency uncovered in breast cancer paralleled molecular features associated with rare inherited skeletal disorders. This observation led to the discovery that breast cancer RTCs hijack a bone developmental program, termed endochondral ossification, to maintain dormancy (Sreekumar A, et al., Cancer Discovery, 2026). Together, these studies position glycans as central to therapy adaptation in breast cancer and identify new therapeutic vulnerabilities to prevent recurrence.

Our translationally focused research program investigates how glycan biosynthesis promotes breast cancer therapy resistance and metastasis, determines whether these programs are conserved in patient samples post-neoadjuvant therapy, and evaluates the feasibility of targeting glycan remodeling as an approach to prevent disease recurrence. We believe that the exciting and untapped area of glycobiology holds great promise for discoveries with the potential to improve long-term outcomes for breast cancer patients.