Researchers have recently uncovered two enzymes that play significant roles in regulating macropinocytosis, a process that allows cancer cells to absorb extra nutrients from the gelatinous substance surrounding cells. This mechanism enables tumors to sustain their growth even when they demand more energy and resources than are available from nearby blood vessels.
Cancer cells behave like rapidly expanding cities that lack proper urban planning. Their swift growth leads to tumors that require more energy and resources than can be obtained from surrounding blood vessels.
Instead of restraining their growth, cancer cells adapt by seeking alternative methods to gather the nutrients they need. A common strategy employed by pancreatic ductal adenocarcinoma (PDAC) involves altering their cell surfaces to capture additional nutrients from the extracellular matrix, a gelatinous network between cells.
This alteration of cell shape is known as macropinocytosis. Inhibiting this process, which supplies energy and essential protein components, has been shown to significantly hinder tumor growth. Although researchers have learned a lot about the crucial role of macropinocytosis in PDAC, there are still many unknowns about how these cancer cells manage their surface changes when nutrients are scarce.
On December 3, 2024, researchers at the NCI-Designated Cancer Center at Sanford Burnham Prebys published a study in Nature Communications detailing their discovery of two enzymes that help regulate macropinocytosis.
The senior author of the study, Cosimo Commisso, PhD, who serves as the interim director and deputy director of the cancer center, along with collaborators, conducted an extensive screening to identify the roles of atypical protein kinase C (aPKC) zeta and iota.
“We suspected that kinases could have a regulatory function, so we performed a screen of the 560 kinases found in humans while observing macropinocytosis in nutrient-starved cells,” explained Commisso.
Glutamine, one of the vital amino acids needed for protein synthesis, was specifically limited in this study because PDAC cells depend on it more than other types of cancer cells do.
The next step for the research team was to determine how aPKC zeta and iota affect the ability of PDAC cells to seek alternative sources of energy and amino acids. Typically, aPKC enzymes are known for helping maintain the distinct shapes and structures of cells across different tissues to facilitate their specialized functions, a phenomenon referred to as cell polarity.
“Cell polarity is crucial for keeping the epithelia around our tissues and organs organized and functional,” noted Guillem Lambies Barjau, PhD, a postdoctoral associate in the Commisso lab and the primary author of the study. “In contrast, cancer cells aim for rapid expansion and disregard the structured nature of cell polarity to achieve uncontrolled growth.”
The researchers discovered that PDAC cells, when deprived of glutamine, repurpose aPKC zeta and iota, along with three other proteins that typically regulate cell polarity, to enhance macropinocytosis and extract more nutrients from their environment.
In subsequent experiments, the team tested whether the repurposing of aPKC zeta and iota in PDAC cells affected the cancer’s growth and survival.
“When we eliminated aPKC zeta or iota in conditions mimicking glutamine-deficient PDAC tumors, we found that the cancer cells could not proliferate without these kinases,” Commisso explained.
The researchers then aimed to confirm their findings in a mouse model of PDAC. They observed that after removing aPKC zeta or iota from mouse PDAC tumors, there was a marked decrease in tumor growth compared to tumors with normal aPKC levels.
“Our findings also showed reduced levels of macropinocytosis in the more nutrient-depleted areas at the cores of tumors lacking aPKCs,” Barjau stated. “Overall, these animal model results support our conclusion that aPKC zeta and iota are essential for controlling macropinocytosis and for the growth of cancers like PDAC.”
This research sheds new light on how PDAC manages limited nutrient supplies to sustain rapid growth, suggesting a potential pathway for developing future cancer therapies by targeting aPKCs.
“Our study illustrates how pancreatic cancer cells exploit cell polarity proteins to regulate macropinocytosis and tumor metabolism, highlighting potential therapeutic vulnerabilities,” said Commisso.
The study also involved contributions from Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, Cheska Marie Galapate, Anagha Deshpande, Aniruddha J. Deshpande, and David A. Scott from Sanford Burnham Prebys, along with David W. Dawson at the David Geffen School of Medicine at UCLA.
This research was supported by the National Institutes of Health (R01CA254806 and R01CA207189) and National Cancer Institute (Cancer Center Support Grant P30CA030199 and R50CA283813).
