Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Rosenstiel Medical Sciences Building Room 4086A, Miami, FL, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Cancer Metastasis Rev. 2023 Jun;42(2):389-407. doi: 10.1007/s10555-023-10116-z. Epub 2023 Jun 15.
Pancreatic cancer is a paradigm for adaptation to extreme stress. That is because genetic drivers are selected during tissue injury with epigenetic imprints encoding wound healing responses. Ironically, epigenetic memories of trauma that facilitate neoplasia can also recreate past stresses to restrain malignant progression through symbiotic tumor:stroma crosstalk. This is best exemplified by positive feedback between neoplastic chromatin outputs and fibroinflammatory stromal cues that encase malignant glands within a nutrient-deprived desmoplastic stroma. Because epigenetic imprints are chemically encoded by nutrient-derived metabolites bonded to chromatin, primary tumor metabolism adapts to preserve malignant epigenetic fidelity during starvation. Despite these adaptations, stromal stresses inevitably awaken primordial drives to seek more hospitable climates. The invasive migrations that ensue facilitate entry into the metastatic cascade. Metastatic routes present nutrient-replete reservoirs that accelerate malignant progression through adaptive metaboloepigenetics. This is best exemplified by positive feedback between biosynthetic enzymes and nutrient transporters that saturate malignant chromatin with pro-metastatic metabolite byproducts. Here we present a contemporary view of pancreatic cancer epigenetics: selection of neoplastic chromatin under fibroinflammatory pressures, preservation of malignant chromatin during starvation stresses, and saturation of metastatic chromatin by nutritional excesses that fuel lethal metastasis.
胰腺癌是适应极端压力的典范。这是因为遗传驱动因素在组织损伤过程中被选择，而表观遗传印记则编码了伤口愈合反应。具有讽刺意味的是，促进肿瘤发生的创伤表观遗传记忆也可以通过共生肿瘤-基质相互作用重新创造过去的压力，从而抑制恶性进展。这在肿瘤染色质产物与纤维炎性基质线索之间的正反馈中得到了最好的体现，这些线索将恶性腺体包裹在营养缺乏的纤维母细胞基质中。由于表观遗传印记是由与染色质结合的营养衍生代谢物化学编码的，因此原发性肿瘤代谢会适应饥饿以保持恶性表观遗传保真度。尽管有这些适应，基质压力不可避免地会唤醒原始驱动力，以寻找更适宜的环境。随之而来的侵袭性迁移有助于进入转移级联。转移途径提供了富含营养的储库，通过适应性代谢表观遗传学加速恶性进展。这在生物合成酶和营养转运蛋白之间的正反馈中得到了最好的体现，这些酶和蛋白使恶性染色质充满促进转移的代谢物副产物。在这里，我们提出了一种胰腺癌表观遗传学的现代观点：在纤维炎性压力下选择肿瘤染色质，在饥饿压力下保存恶性染色质，以及通过营养过剩使转移染色质饱和，从而促进致命转移。
