Yasuto Takeuchi

Recurrence and metastasis remain major causes of cancer mortality, sustained by therapy–resistant micrometastatic cells. Bone is a frequent site of breast–cancer relapse, yet the cues that reawaken disseminated cells remain poorly defined. We identify a previously unrecognized, highly plastic CXCL16⁺ macrophage population that integrates tumor–associated macrophage programs found in distant metastatic sites such as lung and brain with non–tumor disease–associated traits in bone marrow. These CXCL16⁺ macrophages establish a transient niche that restrains disseminated cancer–cell proliferation. Single–cell transcriptomics delineate functional remodeling of myeloid niches within the bone metastatic microenvironment: a CXCL16⁺ macrophage niche that transiently constrains metastatic growth, and G–CSF⁺ macrophage and neutrophil niches that reignite tumor outgrowth. In primary tumors, cancer–associated fibroblasts (CAFs) aberrantly secrete G–CSF in response to cancer–cell signals, expanding G–CSF–receptor–positive subset of cancer cells with high metastatic potential. In advanced human bone metastases, CXCL16⁺ macrophages localize to CAF–rich stroma but are excluded from cancer–cell clusters, indicating immune evasion. Together, these findings uncover CAF–bone–marrow cross–talk as a therapeutic target linking stromal inflammation, immune remodeling, and metastatic progression.

One-carbon (1C) metabolism is frequently upregulated in cancer to support anabolic growth and nucleotide biosynthesis. However, the contribution of mitochondrial 1C metabolism to cancer stemness and metastatic progression remains incompletely understood. Here, we identify methylenetetrahydrofolate dehydrogenase 1-like (MTHFD1L), a mitochondrial 1C metabolic enzyme, as a critical regulator of breast cancer stemness, tumor initiation, and lung metastasis. Genetic depletion of MTHFD1L in triple-negative breast cancer (TNBC) cell lines and patient-derived breast cancer models markedly impaired proliferation, sphere formation, tumorigenicity, and lung colonization. Metabolomic profiling revealed extensive metabolic rewiring following MTHFD1L loss, characterized by accumulation of the purine biosynthetic intermediates SAICAR and AICAR together with perturbations in glycolytic and pentose phosphate pathways. Importantly, suppression of lung metastasis was accompanied by reduced expression of the stemness-associated transcription factor SOX2 and decreased proliferative activity in metastatic lesions. Collectively, our findings establish MTHFD1L as a key metabolic dependency linking mitochondrial 1C metabolism to stem-like properties and metastatic progression in breast cancer, and highlight MTHFD1L as a promising therapeutic target in metastatic TNBC.