by Sanford-Burnham Prebys

Representative immunohistochemical staining for p-PKCζ^T560 and total PKCζ from clinical samples on a tissue microarray (TMA) containing 152 surgically resected human PDAC specimens. Individual patient samples stained with p-PKCζ^T560 were pathologically classified according to staining intensity. Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-54788-9

Cancer cells are like booming cities without urban planners. They expand quickly, and in doing so, the resulting tumors consume more energy and other resources than they can acquire from nearby blood vessels.

Rather than limiting their growth to more sustainable rates, cancer cells adapt by finding alternative ways to scavenge what they need. One scrounging strategy prevalent in pancreatic ductal adenocarcinoma (PDAC) involves cancer cells reshaping their cell surfaces to snatch extra nutrients from the jelly-like substance between cells or extracellular matrix.

This cellular contortion is a process called macropinocytosis. Blocking it and cutting off the energy and protein building blocks it provides has been shown to significantly suppress tumor growth.

While scientists have uncovered many details about the functional importance of macropinocytosis in PDAC, many mysteries remain about how PDAC cells control their cell surface gymnastics when confronted with a lack of adequate nutrients.

Researchers at the NCI-Designated Cancer Center at Sanford Burnham Prebys published findings December 3, 2024, in Nature Communications that describe two enzymes newly identified for their roles in regulating macropinocytosis.

Cosimo Commisso, Ph.D., senior author and interim director and deputy director of the institute's cancer center, and collaborators conducted a high-throughput screen to unveil the involvement of atypical protein kinase C (aPKC) zeta and iota.

"We thought that kinases were likely playing a regulatory role so we ran a screen to compare the activity of the 560 kinases present in humans while cells were undergoing macropinocytosis under nutrient-starved conditions," said Commisso.

Glutamine, one of the 20 amino acids used to build proteins throughout the body, was the key nutrient withheld because PDAC relies upon glutamine much more than other cancers.

The next question facing the research team was how aPKC zeta and iota influence PDAC cells' ability to forage for alternative sources of energy and amino acids. Normally, aPKC enzymes are best known for helping maintain the unique shape and structure of cells in different tissues to help facilitate their specialized functions, known as cell polarity.

"Cell polarity is necessary to maintain the epithelia surrounding our tissues and organs in a very structured and functional way," said Guillem Lambies Barjau, Ph.D., a postdoctoral associate in the Commisso lab and the study's first author.

"Cancer, however, wants to expand rapidly, escape the tissue of origin and invade other tissues so it eschews the structure of cell polarity in order to grow in an uncontrolled way."

The scientists found that aPKC zeta and iota—and three other proteins the kinases normally interact and bind with to regulate cell polarity—are repurposed by PDAC cells lacking access to glutamine to increase macropinocytosis and scavenge more alternative resources from their surrounding environment.

In follow-up experiments, the research team tested whether this repurposing of aPKC zeta and iota in PDAC cells contributed to the cancer cells' growth and survival.

"By depleting aPKC zeta or iota in conditions with low levels of glutamine that mimic the nutrient-starved condition of PDAC tumors in the human body, we saw that PDAC cells were unable to proliferate without these kinases," said Commisso.

The researchers then sought to validate these findings from cellular experiments by investigating whether similar results occurred in a mouse model of PDAC. After eliminating aPKC zeta or iota in mouse PDAC tumors, the mice experienced a significant reduction in tumor growth compared to mice with tumors that had normal aPKC levels.

"We also found that there were lower levels of macropinocytosis taking place in the more nutrient-deprived locations at the core of the tumors treated to remove the aPKCs," said Barjau.

"Together, these results in an animal model lend support to our overall finding that aPKC zeta and iota contribute to the control of macropinocytosis and are needed for cancers like PDAC to grow."

In shedding new light on how cancers like PDAC overcome limited supplies to fuel abnormal growth rates, the scientists pointed to the potential for targeting aPKCs to develop future cancer treatments.

"This work highlights how pancreatic cancer cells hijack cell polarity proteins to regulate macropinocytosis and tumor metabolism, and reveals potential therapeutic vulnerabilities," said Commisso.

More information: Guillem Lambies et al, Cell polarity proteins promote macropinocytosis in response to metabolic stress, Nature Communications (2024). DOI: 10.1038/s41467-024-54788-9

Journal information: Nature Communications 

Provided by Sanford-Burnham Prebys