The mechanism of nutrient intake in pancreatic cancer is revealed

Cancer cells are like booming cities without city planners. They proliferate rapidly, and in doing so, the tumors that form consume more energy and other resources than they can get from nearby blood vessels.

Instead of limiting their growth to a more sustainable rate, cancer cells adapt by finding alternative ways to extract the substances they need. One such strategy, common in pancreatic ductal adenocarcinoma (PDAC), is for cancer cells to change the shape of their cell surface to obtain additional nutrients from the jelly-like substance between cells or from the extracellular matrix. This process is called macropinocytosis.

Blocking this process and closing off the pathways of energy and protein building blocks it provides significantly suppresses tumor growth. Although scientists have uncovered many details of the functional importance of macropinocytosis in PDAC, much remains unclear about how PDAC cells control their plastic activity on the cell surface under nutrient-deficient conditions.

Researchers at the NCI-Designated Cancer Center at Sanford Burnham Prebys have published a study in Nature Communications describing two newly identified enzymes that play a role in regulating macropinocytosis. Cosimo Commisso, PhD, senior author and deputy director of the institute’s cancer center, and colleagues conducted a high-throughput screening and identified the involvement of the atypical protein kinases C (aPKC) zeta and iota.

“We thought that kinases likely play a regulatory role, so we performed a screen to compare the activity of 560 kinases present in humans when cells underwent macropinocytosis under nutrient-deficient conditions,” Cosimo told Commisso.

The next question the research team faced was how aPKC zeta and iota affect the ability of pancreatic cancer cells to seek alternative sources of energy and amino acids. Normally, aPKC enzymes are best known for helping to maintain the unique shape and structure of cells in various tissues by helping them perform specialized functions known as cell polarity.

Cell polarity is necessary to keep the epithelium surrounding our tissues and organs very structured and functional. However, cancer tends to proliferate rapidly, leaving “native” tissues and invading other structures.

The scientists found that aPKC zeta and iota, and three other proteins with which these kinases normally interact and bind to regulate cell polarity, are repurposed by PDAC cells deprived of access to glutamine to increase macropinocytosis and extract more alternative resources from the environment.

In subsequent experiments, the research team tested whether this repurposing of aPKC zeta and iota in pancreatic cancer cells promoted cancer cell growth and survival.

By deactivating aPKC zeta or iota in humans, the scientists saw that without these kinases, PDAC cells lost their ability to proliferate.

The researchers then sought to confirm these findings from cellular experiments and see if similar results were observed in a mouse model of PDAC. After eliminating aPKC zeta or iota in PDAC tumors, the mice showed a significant reduction in tumor growth compared to mice with tumors in which aPKC levels were normal.

The scientists also found lower levels of macropinocytosis at more nutrient-poor sites in the core of aPKC-deleted tumors. Together, these results in an animal model support the general conclusion that aPKC zeta and iota contribute to the control of macropinocytosis and are essential for the growth of these cancers.

Проливая свет на то, как раковые опухоли, подобные PDAC, преодолевают ограниченные запасы, чтобы подпитывать аномальные темпы роста, ученые указывают на потенциал воздействия на aPKC для разработки будущих методов лечения рака.

This work shows how pancreatic cancer cells hijack cell polarity proteins to regulate macropinocytosis and tumor metabolism, and reveals a potential vulnerability that opens the door to the development of therapeutics.

Severance Gangnam Hospital Republic of Korea,SeoulLeave a request

Schneider Children's Medical Center Israel,Petah TikvaLeave a request

Published: 14.12.2024

Updated: 14.12.2024

Medical author, Medical editor:

Stepan Yuk

Medical expert:

PhD. Olexandr Voznyak