Blocking Macropinocytosis Stops Growth of Pancreatic Tumors in Mouse Model

Pancreatic tumors and other cancers with Ras gene mutations utilize a system called macropinocytosis to obtain the nutrients required to fuel their uncontrolled abnormal growth.

Ras signaling stimulates cell growth and division, and overactive Ras signaling can ultimately lead to cancer. Ras is the most common oncogene in human cancer: mutations that permanently activate Ras are found in 20%–25% of all human tumors and up to 90% in certain types of cancer such as pancreatic cancer. However, Ras tumors have certain vulnerability owing to the special nutrient requirements their cells have for growth and survival. The process by which pancreatic cancer cells obtain these nutrients has not been well understood.

In the current study, investigators at the New York University School of Medicine (NY, USA) found that Ras-transformed cells use a process called macropinocytosis to transport extracellular protein into the cell. Macropinocytosis is a highly conserved endocytic process by which extracellular fluid and its contents are internalized into cells through large, heterogeneous vesicles known as macropinosomes. The internalized protein undergoes proteolytic degradation, yielding amino acids including glutamine that can enter central carbon metabolism.

After showing that pancreatic cancer cells growing in mice contained more macropinosomes than did normal mouse cells, the investigators reported in the May 12, 2013, online edition of the journal Nature that drugs capable of blocking formation of macropinosomes inhibited growth of pancreatic cancer cells. This effect was particularly striking in a mouse pancreatic cancer xenograft model where preventing the uptake of albumin via macropinocytosis stopped tumor growth and in some cases reduced tumor size.

“This work offers up a completely different way to target cancer metabolism,” said senior author Dr. Dafna Bar-Sagi, professor of biochemistry and molecular pharmacology, at the New York University School of Medicine. “It is exciting to think that we can cause the demise of some cancer cells simply by blocking this nutrient delivery process.”

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New York University School of Medicine