Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming

Abstract

Considerable progress has been made in identifying microenvironmental signals that effect the reversible phenotypic transitions underpinning the early steps in the metastatic cascade. However, although the general principles underlying metastatic dissemination have been broadly outlined, a common theme that unifies many of the triggers of invasive behavior in tumors has yet to emerge. Here we discuss how many diverse signals that induce invasion converge on the reprogramming of protein translation via phosphorylation of eIF2a, a hallmark of the starvation response. These include starvation as a consequence of nutrient or oxygen limitation, or pseudo-starvation imposed by cell-extrinsic microenvironmental signals or by cell-intrinsic events, including oncogene activation. Since in response to resource limitation single-cell organisms undergo phenotypic transitions remarkably similar to those observed within tumors, we propose that a starvation/pseudo-starvation model to explain cancer progression provides an integrated and evolutionarily conserved conceptual framework to understand the progression of this complex disease. Glutamine, the most abundant amino acid in the blood (Brosnan, 2003), can be depleted in tumors (Kamphorst et al., 2015;Pan et al., 2016;Roberts et al., 1956), most likely as a result of it being used to fuel anabolic metabolism (Altman et al., 2016; DeBerardinis et al.

Evolutionary Response to Resource Deprivation: Parallelism and Nonmonotonicity

“…First, if the evolution of cooperation is key to the emergence of population substructure 29 , our findings suggest cooperation is harder to evolve in extremely resource-limited environments, possibly due to a combination of low mutation rates and limited pool of beneficial mutations. This echoes the findings that resource-deficient environments promote detachment of biofilm formers 33 or metastasis of cancer cells 34 .…”

Melanoma plasticity and phenotypic diversity: therapeutic barriers and opportunities

“…The second mechanism, which is gaining recognition, relies on an intrinsic plasticity in the cancer genome that allows cells to engage adaptive responses to a changing intra-tumor microenvironment that leads to a fundamental change in the biological properties of the cell (Brabletz et al 2005;Gupta et al 2009aGupta et al , 2011Hoek and Goding 2010;Chaffer et al 2011;Ocana et al 2012;Tsai et al 2012;Huang et al 2013;Quail and Joyce 2013;Chaffer et al 2016;Nieto et al 2016;García-Jiménez and Goding 2019). In contrast to irreversible genetic variation, phenotypic plasticity, in which the epigenetic landscape of a cell has the potential to be remodeled, endows each cell with the potential to adapt its gene expression repertoire in response to perceived changes in the microenvironment in a reversible fashion.…”

“…Transcription factor activity is regulated by specific signals that may affect their mRNA expression and translation, their subcellular localization and interaction with cofactors, mRNA and protein stability, and target specificity (Calkhoven and Ab 1996;Westermarck 2010;Filtz et al 2014;Lu et al 2016). Notably, many of the epigenetic regulators that act as transcription cofactors use metabolic intermediates as cofactors (van der Knaap and Verrijzer 2016), and the coordination of metabolism and gene expression is a critical determinant of tumor behavior (Lehuédé et al 2016;García-Jiménez and Goding 2019).…”

“…As a consequence, phospho-eIF2α reduces nutrient demand by down-regulating the translation of most transcripts while increasing translation of proteins that increase nutrient import and autophagy to restore nutrient supply. It was proposed that this translation switch was an evolutionarily conserved response to starvation that drives invasion in yeast as well as in other single cell organisms as a means to seek new nutrient supplies when experiencing resource limitation (Falletta et al 2017;García-Jiménez and Goding 2019). Significantly, inducing the translation switch in nutrient rich conditions, using an inhibitor of the eIF2α phosphatase, salubrinal, led to cells becoming invasive but maintaining proliferation (Falletta et al 2017).…”

A population of stress-like cancer cells in melanoma promotes tumorigenesis and confers drug resistance

“…Increased oxidative stress is associated with invasiveness (Taddei et al, 2012) and higher levels of Wnt5A are associated with a slow cycling, nearly senescent type of cell that has invasive characteristics (Webster et al, 2015) . Recent work has highlighted that translational reprogramming induces a "pseudo-starvation" state, which may be mediated by the ER stress response, as a central element of invasion (Falletta et al, 2017;García-Jiménez and Goding, 2019) . Whether the stress population we identified in our studies has increased metastatic capacity remains to be determined.…”