ABSTRACT

Growing evidence demonstrates that macroautophagy/autophagy in the host stroma influences the tumor microenvironment. We have uncovered that autophagy in host stromal fibroblasts is compulsory to initiate and maintain the desmoplastic fibrotic response that fosters mammary tumor progression. Genetic loss of fibroblast autophagy impedes COL1A/type 1 collagen secretion, which is required for the development of a stiff tissue matrix permissive for mammary tumor growth. As a result, stromal fibroblast autophagy deficiency impairs mammary tumor progression in vivo, even when the cancer cells themselves remain autophagy competent. Our results provide unique conceptual insight into how the autophagy pathway can be modulated to abolish the desmoplastic response required for cancer progression.

摘要

越来越多的证据表明，宿主基质中的巨自噬/自噬会影响肿瘤微环境。我们发现宿主基质成纤维细胞中的自噬对于启动和维持促进乳腺肿瘤进展的促结缔组织增生性纤维化反应是强制性的。成纤维细胞自噬的遗传缺失阻碍了 COL1A/1 型胶原蛋白的分泌，这是形成允许乳腺肿瘤生长的坚硬组织基质所必需的。因此，间质成纤维细胞自噬缺陷会损害体内乳腺肿瘤的进展，即使癌细胞本身保持自噬能力。我们的研究结果提供了关于如何调节自噬途径以消除癌症进展所需的促结缔组织增生反应的独特概念见解。