Suboptimal extracellular <scp>pH</scp> values alter <scp>DNA</scp> damage response to induced double‐strand breaks

Massonneau, Julien; Ouellet, C; Lucien, Fabrice; Dubois, Claire M.; Tyler, Jessica K.; Boissonneault, Guylain

doi:10.1002/2211-5463.12384

Cited by 12 publications

(7 citation statements)

References 50 publications

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“…Recovery from sublethal DNA damage induced by other stressors is also inhibited at acidic pH o (with associated low pH i ), leading to accumulation of chromosomal aberrations (27). Even subtle decreases in pH o significantly delay repair of double-stranded DNA breaks in noncancer cells (28). Taken together, acidic stress in a preneoplastic setting may increase genetic instability and hence the risk of transition to cancer.…”

Section: Genetic and Epigenetic Changesmentioning

confidence: 99%

The Acidic Tumor Microenvironment as a Driver of Cancer

Boedtkjer

Pedersen

2020

Annu. Rev. Physiol.

681

495

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Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease.

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Section: Genetic and Epigenetic Changesmentioning

confidence: 99%

The Acidic Tumor Microenvironment as a Driver of Cancer

Boedtkjer

Pedersen

2020

Annu. Rev. Physiol.

681

495

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“…Aside from hypoxia, low pH is considered another potential factor in “microenvironment‐induced mutagenesis” . Acidosis indeed impairs DNA repair mechanisms, thereby promoting genetic instability and sensitizing cells to other mutagens such as UV irradiation . Beyond that, elevated proton extrusion can cause dysplasia irrespective of oncogene status .…”

Section: Genetic Alterations During Melanoma Initiation and Progressionmentioning

confidence: 99%

Cutaneous pH landscape as a facilitator of melanoma initiation and progression

Koch

Schwab

2018

Acta Physiologica

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Melanoma incidence is on the rise and currently causes the majority of skin cancer-related deaths. Yet, therapies for metastatic melanoma are still insufficient so that new concepts are essential. Malignant transformation of melanocytes and melanoma progression are intimately linked to the cutaneous pH landscape and its dysregulation in tumour lesions. The pH landscape of normal skin is characterized by a large pH gradient of up to 3 pH units between surface and dermis. The Na /H exchanger NHE1 is one of the major contributors of acidity in superficial skin layers. It is also activated by the most frequent mutation in melanoma, BRAF , thereby causing pH dysregulation during melanoma initiation. Melanoma progression is supported by an extracellular acidification and/or NHE1 activity which promote the escape of single melanoma cells from the primary tumour, migration and metastatic spreading. We propose that viewing melanoma against the background of the acid-base physiology of the skin provides a better understanding of the pathophysiology of this disease and allows the development of novel therapeutic concepts.

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“…Pre-mutational factors, specifically hypoxia and altered intracellular pH, are crucial for creating a conducive microenvironment for transformational changes, leading to the accumulation of genetic alterations. Importantly, a correlation between higher levels of hypoxia, pH, and a higher number of driver mutations has been observed in various types of cancer (45–47). We showed that the high expression of hypoxia gene signatures, such as HIF1A , VEGFA , TMX1 , and TGFBI , among others, in hypermetabolic lesions positively correlates with APOBEC signature genes.…”

Section: Discussionmentioning

confidence: 99%

Insight into spatial intratumoral genomic evolution in glioblastoma

Anand,

Petersen,

Andersen

et al. 2023

Preprint

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Glioblastoma undergoes a complex and dynamic evolution involving genetic and epigenetic changes. Understanding the mechanisms underlying this evolution is vital for the development of efficient therapeutic strategies. Although treatment resistance is associated with intratumoral heterogeneity in glioblastoma, it remains uncertain whether hypometabolic and hypermetabolic lesions observed through positron emission tomography (PET) imaging are influenced by spatial intratumoral genomic evolution. In this study, we precisely isolated autologous hypometabolic and hypermetabolic lesions from glioblastoma using advanced neurosurgical and brain tumor imaging technologies, followed by comprehensive whole-genome exome and transcriptome analyses. Our findings revealed that hypermetabolic lesions evolved from hypometabolic lesions, harbored shrewd focal amplifications and deletions, and exhibited a higher frequency of critical genomic alterations linked to increased aggressiveness, upregulated APOBEC3 and hypoxic genes, and downregulated putative tumor suppressors. This study highlights spatial genomic evolution with diagnostic implications and unveils the obstacles and possibilities that should be considered in the development of novel therapeutic strategies.Statement of significance:Glioblastoma is a multifaceted disease that is difficult to treat, and insights into the metabolic gradient observed in imaging and the underlying role of genomic evolution are lacking. This study is the first to investigate the molecular basis of hypermetabolic tumor lesions in glioblastoma using precise three-dimensional biopsy isolation, whole genome/exome, and mRNA sequencing. These findings have diagnostic significance, provide insights into therapeutic resistance, and shed light on the obstacles encountered by precision therapeutics for glioblastoma.

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Suboptimal extracellular pH values alter DNA damage response to induced double‐strand breaks

Cited by 12 publications

References 50 publications

The Acidic Tumor Microenvironment as a Driver of Cancer

The Acidic Tumor Microenvironment as a Driver of Cancer

Cutaneous pH landscape as a facilitator of melanoma initiation and progression

Insight into spatial intratumoral genomic evolution in glioblastoma

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