A gene–environment-induced epigenetic program initiates tumorigenesis

Abstract

Tissue damage increases cancer risk through poorly understood mechanisms 1 . In the pancreas, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to dramatically accelerate the formation of early neoplastic lesions and ultimately pancreatic cancer 2 , 3 . By integrating genomics, single-cell chromatin assays and spatiotemporally-controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an acinar-to-neoplasia ‘chromatin switch’ that contributes to the early dysregulation of genes defining human pancreatic cancer. Among the genes most rapidly activated upon tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine IL-33, which cooperates with mutant Kras in unleashing the epigenetic remodeling program of early neoplasia and neoplastic transformation in the absence of injury. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene regulatory programs that dictate early neoplastic commitment and provides a molecular framework for understanding the interplay between genetics and environmental cues in cancer initiation.

Diverse routes of Club cell evolution in lung adenocarcinoma

“…Tumorigenesis can occur as a disruption of normal regeneration processes, as recently described in pancreatic cancer (Alonso-Curbelo et al, 2021). Club cells are able to regenerate the lung by renewing their own population (Zheng et al, 2017) and transdifferentiating into AT2 and AT1 cells.…”

Epigenomics in the single cell era, an important read out for genome function and cell identity

“…More specifically in a pathological context, metastasis-inducing pathways can modulate histone chaperones, altering the chromatin at promoters of metastasis-inducing transcription factor genes, resulting in the acquisition of more aggressive traits [11]. More recently, an epigenetic gene-environment link was established between mutations in the weak oncogene KRAS and the appearance of malignant pancreatic ductal adenocarcinoma [12]. Mutations on KRAS, together with tissue injury by environmental factors, establish a cancer-associated chromatin accessibility profile before malignant cell transformation occurs.…”

Mutation alters chromatin changes during injury response to drive cancer

“…This contributes to the 'repair' of the metaplasia and limits cellular growth. b, Alonso-Curbelo et al 2 report that, if mouse pancreatic cells that have a Kras mutation are injured, aberrant ADM results in cells gaining a chromatin profile similar to that of a malignant tumour called pancreatic ductal adenocarcinoma (PDAC). BRD4 can access 'open' regions of this chromatin to promote the formation of a premalignant, dysregulated growth termed a neoplasia (specifically, a pancreatic intraepithelial neoplasia).…”

“…Why abnormal repair during meta plasia predisposes cells to form cancer is mainly unknown. Writing in Nature, Alonso-Curbelo et al 2 report a study of pancreatic cancer in mice that reveals how a mutation biases the outcome of metaplasia towards the development of cancer.…”