Cancer cells are like thriving cities without city planners. They expand rapidly, and in doing so, the resulting tumors use up more energy and other resources than they can get from nearby blood vessels.
Instead of limiting their growth to more sustainable rates, cancer cells adapt by finding alternative ways to scavenge what they need. A prevalent encroachment strategy in pancreatic ductal adenocarcinoma (PDAC) involves cancer cells remodeling their cell surfaces to grab extra nutrients from the jelly-like substance between cells or the extracellular matrix.
This cell deformation 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 fitness when faced with a lack of adequate nutrients.
Researchers at the NCI-Designated Cancer Center at Sanford Burnham Prebys published findings on Dec. 3, 2024, in Nature communications that describe two enzymes recently identified for their role in the regulation of macropinocytosis.
Cosimo Commisso, PhD, senior author and interim director and associate director of the institute’s cancer center, and colleagues conducted a high-throughput assay to reveal the involvement of atypical protein kinase C (aPKC) zeta and iota.
We thought that kinases likely played a regulatory role, so we performed an assay to compare the activity of the 560 kinases present in humans while cells were undergoing macropinocytosis under nutrient-starved conditions.”
Cosimo Commisso, PhD, senior author
Glutamine, one of the 20 amino acids used to make proteins throughout the body, was the key nutrient being hidden because PDAC relies on glutamine far more than other cancers.
The next question the research team addressed was how aPKC zeta and iota affect the ability of PDAC cells to forage for alternative sources of energy and amino acids. Normally, aPKC enzymes are best known for maintaining the unique shape and structure of cells in different tissues to facilitate their specialized functions, known as cell polarity.
“Cell polarity is essential to keep the epithelia that surround our tissues and organs in a highly structured and functional manner,” said Guillem Lambies Barjau, PhD, a postdoctoral fellow in the Commisso lab and first author of the study. “Cancer, however, wants to spread rapidly, escape from the tissue of origin and invade other tissues, so it avoids the structure of cell polarity to grow in an uncontrolled manner.”
The scientists found that aPKC zeta and iota -? and three other proteins with the kinases that normally interact and bind to them to regulate cell polarity -? are reused by glutamine-deprived PDAC cells to increase macropinocytosis and scavenge more alternative resources from their environment.
In follow-up experiments, the research team examined whether this repurposing of aPKC zeta and iota in PDAC cells contributed to cancer cell growth and survival.
“By depleting aPKC zeta or iota in low-glutamine conditions that mimic the nutrient-starved state 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 knocking out aPKC zeta or iota in mouse PDAC tumors, the mice showed a significant reduction in tumor growth compared to mice with tumors that had normal levels of aPKC.
“We also found that there were lower levels of macropinocytosis occurring at the most nutrient-deprived sites in the core of tumors treated to remove aPKCs,” Barjau said. “Together, these results in an animal model support our overall finding that aPKC zeta and iota contribute to the control of macropinocytosis and are required for cancers such as PDAC to develop.”
By shedding new light on how cancers like PDAC overcome limited supplies to fuel abnormal growth rates, the scientists pointed to the potential of targeting aPKCs to develop future cancer therapies.
“This work highlights how pancreatic cancer cells hijack cell polarity proteins to regulate macropinocytosis and tumor metabolism and reveals potential therapeutic vulnerabilities,” said Commisso.
Additional authors on the study include: Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska Marie Galapate, Anagha Deshpande, Aniruddha J. Deshpande and David A. Scott, of Sanford Burnham Prebys. and David W. Dawson at the David Geffen School of Medicine at the University of California, Los Angeles.
The study was supported by the National Institutes of Health (R01CA254806 and R01CA207189) and the National Cancer Institute (Cancer Center Support Grant P30CA030199 and R50CA283813).
Source:
Journal Reference:
Lambies, G., et al. (2024). Cell polarity proteins promote macropinocytosis in response to metabolic stress. Nature communications. doi.org/10.1038/s41467-024-54788-9.
