Epithelial memory of resolved inflammation limits tissue damage while promoting pancreatic tumorigenesis [scRNA-Seq]

Inflammation is a major risk factor for pancreatic ductal adenocarcinoma (PDAC). When occurring in the context of pancreatitis, mutations of KRAS accelerate tumor development. We discovered that long after its complete resolution, a transient inflammatory event primes pancreatic epithelial cells to subsequent transformation by oncogenic KRAS. Upon recovery from acute inflammation, epithelial cells of the pancreas display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming. Such adaptation enables the prompt reactivation of acinar-to-ductal metaplasia (ADM) upon subsequent inflammatory events, thus efficiently limiting tissue damage via rapid decrease of zymogen production. We propose that since activating mutations of KRAS maintain an irreversible ADM, they may be beneficial and under strong positive selection in the context of recurrent pancreatitis. Pancreata were harvested from C57BL/6J wild-type mice at different time points before and after acute inflammation and digested to obtain single cell suspension. Total RNA from each cell was processed for multiparallel sequencing.

炎症是胰腺导管腺癌（pancreatic ductal adenocarcinoma, PDAC）的主要危险因素。当炎症发生于胰腺炎的病理背景中时，KRAS基因突变可加速肿瘤的发生发展。本研究发现，即便短暂的炎症事件完全消退已久，仍可致敏胰腺上皮细胞，使其后续易于被致癌性KRAS转化。在急性炎症恢复后，胰腺上皮细胞会呈现出持久的适应性应答，该应答伴随持续的转录与表观遗传重编程。这种适应性改变使得在后续的炎症刺激下，腺泡-导管化生(acinar-to-ductal metaplasia, ADM)能够被快速重新激活，进而通过迅速减少酶原生成的方式有效减轻组织损伤。我们据此提出，由于KRAS激活性突变可维持不可逆的腺泡-导管化生，在复发性胰腺炎的背景下，这类突变或具备生存优势，并会受到强烈的正向选择。实验中，我们从急性炎症前后不同时间点的C57BL/6J野生型小鼠体内获取胰腺组织，经消化制备得到单细胞悬液；随后对每个细胞的总RNA进行多重并行测序处理。