Translation reprogramming is an evolutionarily conserved driver of phenotypic plasticity and therapeutic resistance in melanoma

Abstract

The intratumor microenvironment generates phenotypically distinct but interconvertible malignant cell subpopulations that fuel metastatic spread and therapeutic resistance. Whether different microenvironmental cues impose invasive or therapy-resistant phenotypes via a common mechanism is unknown. In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance. However, how MITF is suppressed in vivo and how MITF-low cells in tumors escape senescence are poorly understood. Here we show that microenvironmental cues, including inflammationmediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B. ATF4, a key transcription mediator of the integrated stress response, also activates AXL and suppresses senescence to impose the MITF-low/AXL-high drug-resistant phenotype observed in human tumors. However, unexpectedly, without translation reprogramming an ATF4-high/MITF-low state is insufficient to drive invasion. Importantly, translation reprogramming dramatically enhances tumorigenesis and is linked to a previously unexplained gene expression program associated with anti-PD-1 immunotherapy resistance. Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness, our results suggest that translation reprogramming, an evolutionarily conserved starvation response, has been hijacked by microenvironmental stress signals in melanoma to drive phenotypic plasticity and invasion and determine therapeutic outcome.

Overcoming resistance to BRAF inhibitors

“…The interplay between cancer cell metabolism and response to targeted therapies too warrants further research. A growing number of reports are linking nutrient metabolism (glucose, glutamine) and melanoma cells responsiveness to BRAF inhibition while at the same time it is clear that the MAPK pathway regulates glycolysis and oxidative phosphorylation (16,(135)(136)(137)(138)(139)(140)(141). All these gaps in our understanding of melanoma biology and the potential of managing MAPK inhibitor schedules with drug-holidays or combination with immunotherapies shows that there is room for improvement to better manage advanced melanoma.…”

Translational control of aberrant stress responses as a hallmark of cancer

“…These mRNAs typically contain 5'‐UTR upstream open reading frames (uORFs), as will be discussed below. Stress‐induced translational reprogramming drives cell plasticity, invasion, and progression in melanoma via ATF4 induction as a result of p‐eIF2α‐dependent eIF2B inhibition . Further, genetic signatures associated with eIF2B inhibition correlate with poor responses to adoptive T‐cell and anti‐PD‐1 therapy.…”

“…Further, genetic signatures associated with eIF2B inhibition correlate with poor responses to adoptive T‐cell and anti‐PD‐1 therapy. Therefore, targeting translation reprogramming may overcome resistance to T‐cell‐mediated therapies .…”

Syntaphilin controls a mitochondrial rheostat for proliferation-motility decisions in cancer

“…Both responses are intensely energy-intensive, and it has been speculated that tumors can undergo dynamic cycles of each process, but not both at the same time in a mechanism called cell proliferation-motility dichotomy (9), or phenotype-switching (10). Although this process may dictate metastatic competence and ultimately influence disease outcome, its mechanistic underpinnings (9) have remained elusive (11), with only a handful of regulators of cell cycle transitions (12), transcriptional (13) and translational (14) programs, and membrane dynamics of cell motility (15) potentially implicated in phenotype switching (16).…”