Tumor cell-intrinsic epigenetic dysregulation shapes cancer-associated fibroblasts heterogeneity to metabolically support pancreatic cancer The interactions between tumor cells and cancer-associated fibroblasts (CAFs) were complicated and they influenced each other to regulate the tumor growth. However, the mechanism of lipid metabolism regulating tumor cells and CAFs was unclear. Here, the authors identified a lipid-laden CAF subset marked by ABCA8a in Setd2-deficient pancreatic tumors. and revealed that deficiency of tumor-intrinsic SETD2, a histone H3K36 trimethyl-transferase functioned as a tumor suppressor, induced epigenetic reprogramming and unleashed BMP signaling to foster the differentiation of lipid-laden CAFs. Lipid-laden CAFs then enhanced tumor progression by providing lipids for mitochondrial oxidative phosphorylation via ABCA8a transporter. ABCA8a facilitates lipid transfer from lipid-laden CAFs to tumor cells for fueling OXPHOS. In summary, they revealed the dynamic nature of epigenetic dysregulation added complexity to pancreatic tumor biology, making it crucial for exploring comprehensive therapeutic strategies.DOI: 10.1016/j.ccell.2024.03.005
Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage
cross-talk, promoting immunosuppression and immunotherapy resistance ![]()
Tommaso Scolaro. et al.
Nucleotide
metabolism played an important role in immunotherapy for cancer. However, the
possible contribution of the pyrimidine salvage pathway enzyme cytidine
deaminase (CDA) to immunotherapy resistance had never been studied. Here, they
identified CDA among the top upregulated metabolic genes in several
immunotherapy-resistant tumors. Targeting CDA skews TAMs toward a T cell
stimulatory phenotype and improved anti-PD-1 therapy efficacy. CDA regulated
uracil nucleotide production by cancer cells. Expression profile of the UDP
cognated receptor P2Y6. CDA–UDP–P2Y6 axis shaped macrophage phenotype. CDA- and
UDP-dependent anti-PD-1 resistance was executed by macrophages via the P2Y6
receptor. Clinically, in individuals with PDAC high CDA levels in cancer cells
correlated with increased TAMs, lower cytotoxic T cells and possibly anti-PD-1
resistance. In summary, they provided compelling evidence that inhibiting this
axis in PDAC, and other cancer types, had the potential to enhance
immunotherapy.
DOI: 10.1038/s43018-024-00771-8
Editor & Reviewer: Shiyang Song
