Kang, J. I. | bioRxiv Science

bioRxiv2025

Colorectal cancer relies on an immunosuppressive cellular topography and genomic adaptations for establishing brain metastases

Colorectal cancer (CRC) brain metastases have a poor prognosis and limited treatment options, including resistance to radiation therapy. Little is known about the molecular and cellular mechanisms that enable CRC tumor cells to adapt to the brain and establish a supportive tumor microenvironment. To address this gap we used spatial transcriptomics to analyze 51 CRC brain metastases. A subset had matched primary colon tumors and longitudinally paired metastatic resections before and after radiation treatment. We identified the critical spatial cellular features of the tumor epithelium and the surrounding tumor microenvironment that support metastatic growth in the brain. CRC brain metastases developed a stromal microenvironment with abundant fibroblasts and tumor-associated macrophages. A fibroblast-macrophage cellular neighborhood promoted angiogenesis, extracellular matrix remodeling, and immune suppression. Tumor cells showed local adaptations. In endothelial-rich regions, they were proliferative whereas in macrophage-rich regions, they were more differentiated and immune evasive. Compared with paired primary tumors, CRC brain metastases showed increased chromosomal instability, with activation of RNA-processing, stress response, and junctional remodeling pathways. After radiation treatment, resistant clones had increased epithelial-mesenchymal transition, while the immunosuppressive stroma remained intact. We identified tumor-derived MIF, GDF15, PRSS3 and SEMA3C ligands and macrophage-derived SPP1 that have the potential to affect multiple cell types in the metastatic niche. These ligand-receptor interactions drive angiogenesis, stromal activation and immune suppression. In a macrophage-tumor-fibroblast co-culture model, knockout of SPP1 in macrophages led to reduced expression of lipid-metabolism related genes and disrupted tumor-promoting interactions. Together, these results indicate that CRC growth in the brain is sustained by a specific cellular organization with immunosuppressive multicellular interactions.

cancer biology↗

bioRxiv2022

Fasting Induces a Highly Resilient Deep Quiescent State in Muscle Stem Cells via Ketone Body Signaling

Short-term fasting is beneficial for the regeneration of multiple tissue types. However, the effects of fasting on muscle regeneration are largely unknown. Here we report that fasting slows muscle repair both immediately after the conclusion of fasting as well as after multiple days of refeeding. We show that ketosis, either endogenously produced during fasting or a ketogenic diet, or exogenously administered, promotes a deep quiescent state in muscle stem cells (MuSCs). Although deep quiescent MuSCs are less poised to activate, slowing muscle regeneration, they have markedly improved survival when facing sources of cellular stress. Further, we show that ketone bodies, specifically {beta}-hydroxybutyrate, directly promote MuSC deep quiescence via a non-metabolic mechanism. We show that {beta}-hydroxybutyrate functions as an HDAC inhibitor within MuSCs leading to acetylation and activation of an HDAC1 target protein p53. Finally, we demonstrate that p53 activation contributes to the deep quiescence and enhanced resilience observed during fasting.

cell biology↗