The acidic pH of the tumor microenvironment plays a critical role in driving cancer development toward a more aggressive phenotype, but the underlying mechanisms are unclear. To this end, phenotypic and genotypic changes induced by adaptation of cancer cells to chronic acidosis have been studied. However, the generality of acid adaptation patterns across cell models and their correlation to the molecular phenotypes and aggressiveness of human cancers are essentially unknown. Here, we define an acid adaptation expression response shared across three cancer cell models, dominated by metabolic rewiring, extracellular matrix remodeling, and altered cell cycle regulation and DNA damage response. We find that many genes which are upregulated by acid adaptation are significantly correlated to patient survival, and more generally, that there are clear correlations between acid adaptation expression response and gene expression change between normal and tumor tissues, for a large subset of cancer patients. Our data support the notion that tumor microenvironment acidity is one of the key factors driving the selection of aggressive cancer cells in human patient tumors, yet it also induces a growth-limiting genotype that likely limits cancer cell growth until the cells are released from acidosis, for instance during invasion.
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers globally with a mortality rate exceeding 95% and very limited therapeutic options. A hallmark of PDAC is its acidic tumor microenvironment, further characterised by excessive fibrosis and depletion of oxygen and nutrients due to poor vascularity. The combination of PDAC driver mutations and adaptation to this hostile environment drives extensive metabolic reprogramming of the cancer cells toward non-canonical metabolic pathways and increases reliance on scavenging mechanisms such as autophagy and macropinocytosis. In addition, the cancer cells benefit from metabolic cross-talk with nonmalignant cells within the tumor microenvironment, including stellate cells, fibroblasts, endothelial and immune cells. Increasing evidence shows that this metabolic rewiring is closely related to chemo-and radioresistance and immunosuppression, causing extensive treatment failure. Indeed, stratification of human PDAC tumors into subtypes based on their metabolic profiles was shown to predict disease outcome. Accordingly, an increasing number of clinical trials target pro-tumorigenic metabolic pathways, either as stand-alone treatment or in conjunction with chemotherapy. In this review, we highlight key findings and potential future directions of pancreatic cancer metabolism research, specifically focusing on novel therapeutic opportunities.
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy with minimal treatment options and a global rise in prevalence. PDAC is characterized by frequent driver mutations including KRAS and TP53 (p53), and a dense, acidic tumor microenvironment (TME). The relation between genotype and TME in PDAC development is unknown. Strikingly, when wild type (WT) Panc02 PDAC cells were adapted to growth in an acidic TME and returned to normal pH to mimic invasive cells escaping acidic regions, they displayed a strong increase of aggressive traits such as increased growth in 3-dimensional (3D) culture, adhesion-independent colony formation and invasive outgrowth. This pattern of acidosis-induced aggressiveness was observed in 3D spheroid culture as well as upon organotypic growth in matrigel, collagen-I and combination thereof, mimicking early and later stages of PDAC development.Acid-adaptation-induced gain of cancerous traits was further increased by p53 knockout (KO), but only in specific extracellular matrix (ECM) compositions. Akt-and Transforming growth factor-β (TGFβ) signaling, as well as expression of the Na + /H + exchanger NHE1,
The harsh environments in poorly perfused tumor regions have been proposed to select for traits that may drive cancer aggressiveness. Here, we tested the hypothesis that tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks, including drug resistance, in pancreatic cancer. We gradually adapted mouse organoids from normal pancreatic duct (mN) and early PDAC (mP, with KRAS G12V mutation and +/- p53 knockout ), from pH 7.4 (physiological level) to 6.7, representing acidic tumor niches. Acid adaptation rewired organoid transcriptional activity, increased viability and, strikingly, increased Gemcitabine- and Erlotinib resistance. Importantly, this response only occurred in organoids expressing wild-type p53 and was most pronounced when acid-adapted cells were returned to physiological pH (mimicking increased perfusion or invasion). While the acid adaptation transcriptional change was overall not highly similar to that induced by drug adaptation of the organoids, acid adaptation induced expression of cytidine deaminase (Cda) and ribonucleotide reductase regulatory subunit M2 (Rrm2), both associated with Gemcitabine resistance, and inhibition of these proteins partially restored Gemcitabine sensitivity. Thus, adaptation to the acidic tumor microenvironment increases drug resistance even after cells leave this niche, and this is in part dependent on acid-adaptation-induced transcriptional upregulation of Cda and Rrm2.
DDX3 RNA helicase is intensively studied as a therapeutic target due to participation in the replication of some viruses and involvement in cancer progression. Here we used transcriptome analysis to estimate the primary response of hepatocytes to different levels of RNAi-mediated knockdown of DDX3 RNA helicase both in vitro and in vivo. We found that a strong reduction of DDX3 protein (>85%) led to similar changes in vitro and in vivo—deregulation of the cell cycle and Wnt and cadherin pathways. Also, we observed the appearance of dead hepatocytes in the healthy liver and a decrease of cell viability in vitro after prolonged treatment. However, more modest downregulation of the DDX3 protein (60–65%) showed discordant results in vitro and in vivo—similar changes in vitro as in the case of strong knockdown and a different phenotype in vivo. These results demonstrate that the level of DDX3 protein can dramatically influence the cell phenotype in vivo and the decrease of DDX3, for more than 85% leads to cell death in normal tissues, which should be taken into account during the drug development of DDX3 inhibitors.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.