Novel drug target suggested by how pancreatic cancer cells ingest nutrients

A longstanding mystery about how pancreatic tumor cells sustain themselves has been unraveled by a new study. This opens up new therapeutic possibilities for a notorious lethal disease with few treatment options.

Pancreatic cancer kills nearly 38,000 patients in the United States each year, which makes it a leading cause of cancer death. The life expectancy for most people diagnosed with it is shorter than a year.

The new study shows how Ras cancer cells exploit the process of macropinocytosis to absorb the protein albumin, when cells then harvest for amino acids essential for growth. Mutated Ras protein has been known to play a central role in the complex events that drive cancer cell growth and survival.

“A big mystery is how certain tumors meet their excessive nutrient demands,” said Cosimo Commisso, PhD, of New York University School of Medicine in New York, New York. “We believe they accomplish this by macropinocytosis.”

The findings suggest that Ras cancer cells are particularly dependent on macropinocytosis for growth and survival. When the researchers used a chemical to block the uptake of albumin via macropinocytosis in mice with pancreatic tumors, the tumors stopped growing and in some cases even shrank. Moreover, pancreatic cancer cells in mice featured more macropinosomes, which are the vesicles that transport nutrients deep into a cell, than normal mouse cells.

The discovery of a “protein eating” mechanism unique to some cancer cells sets the stage for drugs that could block the engulfing process without causing collateral damage to healthy cells and suggests new ways to ferry chemotherapeutic cargo into the heart of cancer cells. This study was published in Nature (2013; doi:10.1038/nature12138).

 “This work offers up a completely different way to target cancer metabolism,” said the study's  principal investigator, Dafna Bar-Sagi, PhD, of New York University Langone Medical Center. She first identified macropinocytosis in Ras-transformed cancer cells. “It's exciting to think that we can cause the demise of some cancer cells simply by blocking this nutrient delivery process.”
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