Authors: Edoardo Del Poggetto, I-Lin Ho, Chiara Balestrieri, Er-Yen Yen, Shaojun Zhang, Francesca Citron, Rutvi Shah, Denise Corti, Giuseppe R. Diaferia, Chieh-Yuan Li, Sara Loponte, Federica Carbone, Yoku Hayakawa, Giovanni Valenti, Shan Jiang, Luigi Sapio, Hong Jiang, Prasenjit Dey, Sisi Gao, Angela K. Deem, Stefan Rose-John, Wantong Yao, Haoqiang Ying, Andrew D. Rhim, Giannicola Genovese, Timothy P. Heffernan, Anirban Maitra, Timothy C. Wang, Linghua Wang, Giulio F. Draetta, Alessandro Carugo, Gioacchino Natoli, Andrea Viale
Summary: Introduction: The association between tumors and inflammation is a long-established clinical observation. Although many studies have demonstrated that the inflammatory microenvironment can promote tumor growth through the activation of survival and proliferation programs in cancer cells, the reason why inflammation, an evolutionarily conserved response to damage aimed at reestablishing tissue integrity upon injury, might be integral to tumorigenesis remains unknown.
Rationale: Pancreatic ductal adenocarcinoma, a tumor characterized by poor prognosis, represents a distinctive example of cooperation between inflammation and activated oncogenes. Frequently developed in a context of chronic pancreatitis, pancreatic cancer is associated with an inflammatory microenvironment. As supported by a substantial body of evidence across a multitude of experimental models, when occurring in the context of pancreatitis, mutations of KRAS, the universal oncogenic driver of pancreatic cancer, lead to accelerated tumor development and induce the appearance of neoplastic precursor lesions, such as acinar-to-ductal metaplasia and pancreatic intraepithelial neoplasia, which can evolve into invasive tumors. Interestingly, preneoplastic pancreatic alterations, specifically acinar-to-ductal metaplasia, have been previously identified during acute and chronic pancreatitis in the absence of oncogene activation, suggesting an alternative role other than oncogenic transformation. To better understand the relationship between inflammatory processes and pancreatic tumorigenesis, we used different mouse models to investigate the long-term effects of transient inflammatory events in response to acute pancreatic damage and how resolved inflammation cooperates with activated oncogenes to drive tumor progression in normal epithelial cells.
Results: By investigating the effects of inflammation on normal pancreatic epithelial cells in different mouse models, we discovered that long after the complete resolution, a transient inflammatory event primes pancreatic epithelial cells to cooperate with oncogenic Kras to induce pancreatic tumors. Indeed, upon recovery from a single acute inflammation, epithelial pancreatic cells display an enduring adaptive response associated with sustained transcriptional and epigenetic reprogramming that leads to the activation of multiple gene expression programs, including embryonic programs activated during cancer progression. While promoting tumor development, such adaptation to tissue damage facilitates the prompt acquisition of acinar-to-ductal metaplasia upon subsequent inflammatory events. This rapid dedifferentiation program of acinar cells, that lasts for the length of the stimulus and from which the tissue promptly and apparently completely recovers, represents a physiological mechanism for limiting tissue damage through the rapid decrease of zymogen production that would otherwise fuel further damage and inflammation. As a result, pancreatic tissues exposed to initial inflammation undergo a markedly attenuated response and limited tissue damage to subsequent inflammatory episodes. Because metaplastic lesions are mediated by the activation of mitogen-activated protein kinase (MAPK) signaling, we demonstrate that activating mutations of Kras, maintaining an irreversible acinar-to-ductal metaplasia through MAPK constitutive signaling, are protective against tissue damage induced by pancreatic inflammation.
Conclusion: We have uncovered a new physiologic role of somatic mutations in preserving tissue homeostasis during repeated damages. We propose that KRAS mutations, independent from the eventual contribution to tumorigenesis, may be beneficial and under strong positive selection in the context of recurrent pancreatitis, perhaps representing a nearly universal event in the development of pancreatic cancer.
Source: Science, 2021; 373 (6561)