Histone Methyltransferase ASH1L Primes Metastases and Metabolic Reprogramming of Macrophages in the Bone Niche (CUT&RUN)

Bone metastasis is a major cause of cancer death; however, the epigenetic determinants driving this process remain elusive. Here, we uncover that histone methyltransferase ASH1L is genetically amplified in metastatic diseases and is required for cancer invasiveness and bone metastasis. In invading cancer cells, ASH1L rewires methylations at H3K4 and H3K36 and cooperates with transcriptional factor HIF-1α to induce pro-metastatic transcriptome. Leveraging our newly developed metastasis models and single-cell transcriptomic profiling, we demonstrate that ASH1L in invading cancer cells induces monocyte differentiation into lipid-associated macrophage (LA-TAM) and maintains their pro-tumoral and anti-inflammatory phenotype in the metastatic bone niche. Mechanistic studies reveal that IGF-2 is a direct target of ASH1L and mediates LA-TAMs’ differentiation and phenotypic changes by reprogramming oxidative phosphorylation. In patients with metastatic cancers, ASH1L overexpression is associated with enriched LA-TAMs. As a proof of concept, pharmacologic inhibition of the ASH1L-macrophages axis elicits robust anti-metastasis responses in preclinical models.