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The mechanism of nutrient consumption in pancreatic cancer has been unveiled.

Обнаружен механизм усвоения питательных веществ при раке поджелудочной железы.

They grow rapidly, and the resulting tumors consume more energy and resources than they can acquire from nearby blood vessels.

Instead of limiting their growth to more sustainable rates, cancer cells adapt by finding alternative ways to obtain the substances they need. One such strategy, commonly observed in pancreatic ductal adenocarcinoma (PDAC), involves cancer cells altering the shape of their cell surface to extract additional nutrients from the gel-like substance between cells or from the extracellular matrix. This process is known as macropinocytosis.

Blocking this process and obstructing the pathways for energy and protein building blocks that it provides significantly suppresses tumor growth. While researchers have uncovered many details about the functional importance of macropinocytosis in PDAC, much remains unclear regarding how PDAC cells regulate their surface plasticity in nutrient-deficient conditions.

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

“We thought that kinases were likely to play a regulatory role, so we conducted a screening to compare the activity of 560 kinases present in humans when cells underwent macropinocytosis under nutrient deprivation,” said Cosimo Commisso.

The next question for the research team 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 maintain the unique shape and structure of cells in various tissues, facilitating their specialized functions known as cell polarity.

Cell polarity is essential for maintaining the epithelium that surrounds our tissues and organs in a highly structured and functional form. However, cancer seeks to grow rapidly, leaving its "native" tissues and invading other structures.

The scientists found that aPKC zeta and iota, along with three other proteins with which these kinases typically interact and bind to regulate cell polarity, are repurposed by PDAC cells deprived of access to glutamine to enhance 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 contributed to the growth and survival of cancer cells.

By deactivating aPKC zeta or iota in human cells, the researchers observed that without these kinases, PDAC cells lost their ability to proliferate.

The researchers then sought to validate these findings from cellular experiments and determine whether similar results were observed in a mouse model of PDAC. After removing aPKC zeta or iota in PDAC tumors in mice, there was a significant reduction in tumor growth compared to mice with tumors where aPKC levels were normal.

The scientists also found lower levels of macropinocytosis in nutrient-poor areas within the cores of tumors subjected to aPKC removal. Collectively, these results in the animal model support the overall conclusion that aPKC zeta and iota are crucial for controlling macropinocytosis and are necessary for the growth of such tumors.

By shedding light on how tumors like PDAC overcome limited supplies to fuel abnormal growth rates, the researchers highlight the potential for targeting aPKC in the development of future cancer therapies.

This work illustrates how pancreatic cancer cells hijack proteins of cell polarity to regulate macropinocytosis and tumor metabolism, revealing a potential vulnerability that opens the door for therapeutic development.