Department of Thoracic Surgery, Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Department of Thoracic Surgery, Shanghai Pulmonary Hospital, Shanghai 200433, China.
Department of Thoracic Surgery, Thoracic Oncology Institute, Peking University People's Hospital, Beijing 100044, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China.
Cell Rep Med. 2024 Apr 16;5(4):101488. doi: 10.1016/j.xcrm.2024.101488. Epub 2024 Apr 1.
Most recurrences of lung cancer (LC) occur within 3 years after surgery, but the underlying mechanism remains unclear. Here, we collect LC tissues with shorter (<3 years, recurrence group) and longer (>3 years, non-recurrence group) recurrence-free survival. By using 16S sequencing, we find that intratumor microbiome diversity is lower in the recurrence group and butyrate-producing bacteria are enriched in the recurrence group. The intratumor microbiome signature and circulating microbiome DNA can accurately predict LC recurrence. We prove that intratumor injection of butyrate-producing bacteria Roseburia can promote subcutaneous tumor growth. Mechanistically, bacteria-derived butyrate promotes LC metastasis by increasing expression of H19 in tumor cells through inhibiting HDAC2 and increasing H3K27 acetylation at the H19 promoter and inducing M2 macrophage polarization. Depletion of macrophages partially abolishes the metastasis-promoting effect of butyrate. Our results provide evidence for the cross-talk between the intratumor microbiome and LC metastasis and suggest the potential prognostic and therapeutic value of the intratumor microbiome.
大多数肺癌（LC）的复发发生在手术后 3 年内，但潜在机制尚不清楚。在这里，我们收集了 LC 组织，这些组织的无复发生存期较短（<3 年，复发组）和较长（>3 年，非复发组）。通过 16S 测序，我们发现复发组肿瘤内微生物组多样性较低，而产丁酸细菌在复发组中富集。肿瘤内微生物组特征和循环微生物组 DNA 可准确预测 LC 复发。我们证明，向肿瘤内注射产丁酸细菌 Roseburia 可以促进皮下肿瘤生长。在机制上，细菌衍生的丁酸通过抑制 HDAC2 并增加 H19 启动子处的 H3K27 乙酰化，增加肿瘤细胞中 H19 的表达，从而促进 LC 转移，并诱导 M2 巨噬细胞极化。巨噬细胞耗竭部分消除了丁酸的促转移作用。我们的研究结果为肿瘤内微生物组与 LC 转移之间的相互作用提供了证据，并提示了肿瘤内微生物组的潜在预后和治疗价值。
