An age-old response, one deep inside the molecular networks of individual cancer cells, is so well worn that it may account for why cancer spreads and resists certain kinds of treatment. The response is the urge to migrate when resources are scarce. It is shared by cancer cells and the cells of many organisms, including fungi and bacteria. Yet in cancer cells, it has an extra twist or two. It can be activated not only by famine-like conditions, but also by other stresses, such as inflammatory signals.

Essentially, cancer cells may interpret various kinds of stress as starvation and respond by activating a starvation response, part of which involves the conservation and recycling of resources, and part of which involves mobility. This response, under the scrutiny of scientists based at the Ludwig Center for Cancer Research, has yielded new details that flesh out the “why” of metastasis, and not just the “how.” These details also suggest new approaches to the development of cancer therapies.

The new findings appeared January 17 in the journal Genes & Development, in an article entitled, “Translation Reprogramming Is an Evolutionarily Conserved Driver of Phenotypic Plasticity and Therapeutic Resistance in Melanoma.” The article describes how the punishing conditions within a tumor can mold a subset of tumor cells into an invasive state. The article suggests why some melanoma patients respond relatively poorly to both a key targeted therapy and an immunotherapy known as programmed cell death protein 1 (PD-1) blockade.

“In melanoma, low expression of the lineage survival oncogene microphthalmia-associated transcription factor (MITF) correlates with invasion, senescence, and drug resistance,” wrote the article’s authors. “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 inflammation-mediated resistance to adoptive T-cell immunotherapy, transcriptionally repress MITF via ATF4 in response to inhibition of translation initiation factor eIF2B.”

The Ludwig scientists, led by Colin Goding, Ph.D., set out to learn whether such “MITF-low” cancer cells move for the same reasons other mobile creatures move. “Fungi and bacteria become invasive if they starve,” noted Dr. Goding. “Wildebeest on the Serengeti migrate every year to find new pasture. So, we asked, do cancer cells move because they're starving, or think they're starving? The results we got suggested, yes, absolutely.”

The researchers show that when deprived of a key nutrient, melanoma cells switch on an innate stress-response mechanism that stops the production of proteins that drive cell division, but step up the production of those that help them recycle and import nutrients. At the same time, this mechanism also sparks up a program to go mobile and seek food.

“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,” the Genes & Development article indicated. “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.”

The researchers showed that when deprived of a key nutrient, melanoma cells switch on an innate stress-response mechanism that stops the production of proteins that drive cell division, but step up the production of those that help them recycle and import nutrients. At the same time, this mechanism also sparks up a program to go mobile and seek food.

Melanoma cells go about doing this, the researchers demonstrated, by changing which of their active genes are used to make proteins. They switch off a key controller of most protein synthesis named eIF2B. Switching off eIF2B enables cells to conserve resources under starvation conditions. Switching off this controller, however, also turns on a gene named ATF4 that orchestrates the cell's responses to stress. Both these changes combine to suppress MITF. But the reprogramming of the protein-making machinery, Dr. Goding's team found, is absolutely required to prompt cells to become invasive.

They found this mechanism is a potent driver of cancer's spread. When the researchers starved melanoma cells—or chemically suppressed eIF2B to make them think they were starving even when nutrients were abundant—they formed far more tumors than did their well-fed peers.

“Since we show that inhibition of eIF2B also drives neural crest migration and yeast invasiveness,” the authors concluded, “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.”

Notably, the study shows that inflammatory signals, which are known to fuel tumor progression and metastasis, appear to activate the same stress-response mechanism in melanoma cells. They seem to have hijacked the starvation mechanism that serves as a universal “get out of here” signal to adapt to and escape from challenging environments.

“It seems that once cells evolved a good idea, to move in response to starvation, they kept it and retooled it to be useful in stressful environments in general, not just in response to low food supply,” explained Dr. Goding.

The current study has discoveries of relevance to the clinic as well. The researchers show that the starvation mechanism they identify induces a program of gene activity—PD-1 blockade—known to be linked to resistance to immunotherapy. They also found that the starvation response induces changes in gene activity that render MITF-low cells resistant to a class of targeted therapies known as BRAF inhibitors.

The researchers are now studying the details of how the starvation response mechanism is engaged in melanoma and other cancer cells and will be examining how these circuits might be exploited for therapy.

“You can imagine small-molecule drugs that restore elevated demand for nutrients in cells that can survive only by restricting their demand,” stated Dr. Goding. “That way we could either kill them directly, or restore their sensitivity to immunotherapy and other treatments.”

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