Zabransky Daniel J, Chhabra Yash, Fane Mitchell E, Kartalia Emma, Leatherman James M, Hüser Laura, Zimmerman Jacquelyn W, Delitto Daniel, Han Song, Armstrong Todd D, Charmsaz Soren, Guinn Samantha, Pramod Sneha, Thompson Elizabeth D, Hughes Steven J, O'Connell Jennifer, Egan Josephine M, Jaffee Elizabeth M, Weeraratna Ashani T
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
Cancer Res. 2024 Apr 15;84(8):1221-1236. doi: 10.1158/0008-5472.CAN-24-0086.
Pancreatic cancer is more prevalent in older individuals and often carries a poorer prognosis for them. The relationship between the microenvironment and pancreatic cancer is multifactorial, and age-related changes in nonmalignant cells in the tumor microenvironment may play a key role in promoting cancer aggressiveness. Because fibroblasts have profound impacts on pancreatic cancer progression, we investigated whether age-related changes in pancreatic fibroblasts influence cancer growth and metastasis. Proteomics analysis revealed that aged fibroblasts secrete different factors than young fibroblasts, including increased growth/differentiation factor 15 (GDF-15). Treating young mice with GDF-15 enhanced tumor growth, whereas aged GDF-15 knockout mice showed reduced tumor growth. GDF-15 activated AKT, rendering tumors sensitive to AKT inhibition in an aged but not young microenvironment. These data provide evidence for how aging alters pancreatic fibroblasts and promotes tumor progression, providing potential therapeutic targets and avenues for studying pancreatic cancer while accounting for the effects of aging.
Aged pancreatic fibroblasts secrete GDF-15 and activate AKT signaling to promote pancreatic cancer growth, highlighting the critical role of aging-mediated changes in the pancreatic cancer microenvironment in driving tumor progression. See related commentary by Isaacson et al., p. 1185.
胰腺癌在老年人中更为普遍，且通常预后较差。肿瘤微环境与胰腺癌之间的关系是多因素的，肿瘤微环境中非恶性细胞的年龄相关变化可能在促进癌症侵袭性方面起关键作用。由于成纤维细胞对胰腺癌进展有深远影响，我们研究了胰腺成纤维细胞的年龄相关变化是否会影响癌症生长和转移。蛋白质组学分析显示，衰老的成纤维细胞分泌的因子与年轻的成纤维细胞不同，包括生长/分化因子15（GDF-15）增加。用GDF-15处理年轻小鼠可增强肿瘤生长，而衰老的GDF-15基因敲除小鼠的肿瘤生长则减少。GDF-15激活AKT，使肿瘤在衰老而非年轻的微环境中对AKT抑制敏感。这些数据为衰老如何改变胰腺成纤维细胞并促进肿瘤进展提供了证据，为研究胰腺癌提供了潜在的治疗靶点和途径，同时考虑了衰老的影响。
衰老的胰腺成纤维细胞分泌GDF-15并激活AKT信号以促进胰腺癌生长，突出了衰老介导的胰腺癌微环境变化在推动肿瘤进展中的关键作用。见Isaacson等人的相关评论，第1185页。
