Bidirectional signalling between the tumour and stroma shapes tumour aggressiveness and metastasis. ATF4 is a major effector of the Integrated Stress Response, a homeostatic mechanism that couples cell growth and survival to bioenergetic demands. Using conditional knockout ATF4 mice, we show that global, or fibroblast-specific loss of host ATF4, results in deficient vascularization and a pronounced growth delay of syngeneic melanoma and pancreatic tumours. Single-cell transcriptomics of tumours grown in Atf4^Δ/Δ mice uncovered a reduction in activation markers in perivascular cancer-associated fibroblasts (CAFs). Atf4^Δ/Δ fibroblasts displayed significant defects in collagen biosynthesis and deposition and a reduced ability to support angiogenesis. Mechanistically, ATF4 regulates the expression of the Col1a1 gene and levels of glycine and proline, the major amino acids of collagen. Analyses of human melanoma and pancreatic tumours revealed a strong correlation between ATF4 and collagen levels. Our findings establish stromal ATF4 as a key driver of CAF functionality, malignant progression and metastasis.

肿瘤和间质之间的双向信号决定了肿瘤的侵袭性和转移。ATF4 是综合应激反应的主要效应物，综合应激反应是一种将细胞生长和存活与生物能量需求相结合的稳态机制。使用条件性敲除 ATF4 小鼠，我们表明宿主 ATF4 的全局或成纤维细胞特异性缺失会导致血管形成不足和同系黑色素瘤和胰腺肿瘤的明显生长延迟。在Atf4 ^Δ/Δ小鼠中生长的肿瘤的单细胞转录组学发现血管周围癌相关成纤维细胞 (CAF) 中激活标志物的减少。Atf4 ^Δ/Δ成纤维细胞在胶原蛋白生物合成和沉积方面表现出明显的缺陷，并且支持血管生成的能力降低。从机制上讲，ATF4 调节Col1a1基因的表达以及甘氨酸和脯氨酸（胶原蛋白的主要氨基酸）的水平。对人类黑色素瘤和胰腺肿瘤的分析表明 ATF4 和胶原蛋白水平之间存在很强的相关性。我们的研究结果表明，基质 ATF4 是 CAF 功能、恶性进展和转移的关键驱动因素。