Cancer Cells Spread When They Stop Recycling Waste

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Cells perpetually produce mountains of waste, such as damaged proteins or haywire organelles, but they have evolved a sustainable recycling plan to prevent trash piles.1 Autophagy is an essential waste disposal process that salvages used parts for resources that the cell can reuse. Scientists are exploring how autophagy affects the growth of tumor cells, but few studies have focused on its role in metastasis.2 

Publishing in Cell Reports, researchers identified a long-overlooked autophagy regulator that stops breast cancers from crossing tissue boundaries.3 By studying variation in this gene, scientists may one day leverage it to predict metastases in cancer patients. 

Although recycling benefits the environment, autophagy has a more nuanced effect on cancer. Previous studies revealed that some autophagy genes either protect against or exacerbate tumors.4 “However, there are a large number of other genes that impact or regulate autophagy that have not been systemically examined,” said Jun-Lin Guan, a cell biologist at the University of Cincinnati and study coauthor. Moreover, researchers primarily examined how autophagy factors control the primary tumor. “There were relatively few investigations looking at metastasis specifically,” Guan noted.

Guan and his team compared 171 genes that influence autophagy to study how they affect metastasis in a mouse model of breast cancer. By using clustered regulatory interspaced palindromic repeats (CRISPR)-CRISPR-associated protein (Cas9) knock-out screens, they systematically deleted each gene to see if its absence allowed tumors to spread unchecked.

Out of 171 autophagy-regulating genes, they identified a few dozen that curbed metastasis. In their absence, tumor cells spread to the lung, an organ to which this cancer type doesn’t typically venture. The gene that codes for p47 protein produced the biggest difference when depleted, suggesting that it plays a key role in curbing breast cancer metastasis. “Previously, it was unknown that it could affect cancer,” Guan remarked.

When the researchers checked an existing breast cancer gene expression database,  they found that individuals with lower p47 expression in their tumor cells were more likely to develop metastases, suggesting that cancers cross tissue borders more easily when their recycling plan fails.5 Guan speculated that scientists might have overlooked p47 in previous studies of metastasis because it wasn’t on their radar as a relevant cancer gene. By carrying out an unbiased approach on 171 known autophagy regulators, he and his team stumbled upon its importance by serendipity.

While studying how p47 influences autophagy, the team zeroed in on lysosomes, organelles that supply the digestive enzymes needed to recycle waste.6 In p47’s absence, Guan and his team observed an abundance of dysfunctional lysosomes, suggesting that the protein is important for the upkeep of these organelles.

Besides regulating autophagy, p47 inhibits an immune signaling cascade that researchers previously linked to metastasis.7 The team found that under normal cellular conditions, p47 shuttled the immune instigator, NFkB essential modulator (NEMO), toward the cell’s recycling plant, thereby preempting an immune response.8 However, in p47’s absence, NEMO set the immune response in motion.

“I was quite excited to see that they carried out such a well-focused genetic screen in the mouse,” said Jean-François Côté, a metastasis researcher at McGill University who was not involved with the work. “99.9 percent of people do it in cell culture,” he added. It’s difficult to gauge which genes control cancer spread between organs using cell culture, but mouse models allow researchers to address those questions.

The researchers used nude mice in their experiments; besides lacking fur, they also lack a completely functional immune system.9 Côté would like to see this study repeated in mice equipped with a full complement of defenses that can influence the tumor. “Metastasis is not solely a process that depends on the cancer cell, but it’s fueled by the whole microenvironment of the primary tumor,” he explained. 

Moving forward, Guan and his team plan to explore whether p47 limits metastasis for other cancer types. Beyond that, they have another 37 genes from their CRISPR-Cas9 screen to scrutinize. Autophagy’s relationship with cancer remains largely uncharted, and these findings may unlock more clues about their intricate connection.

References

1. Kuma A, Mizushima N. Physiological role of autophagy as an intracellular recycling system: With an emphasis on nutrient metabolismSemin Cell Biol. 2010;21(7):683-690. 
2. Santanam U, et al. Atg7 cooperates with Pten loss to drive prostate cancer tumor growthGenes Dev. 2016;30(4):399-407. 
3. Hao M, et al. In vivo CRISPR knockout screen identifies p47 as a suppressor of HER2+ breast cancer metastasis by regulating NEMO trafficking and autophagy fluxCell Reports. 2024;43(2):113780. 
4. Rao S, et al. A dual role for autophagy in a murine model of lung cancerNat Commun. 2014;5(1):3056. 
5. Györffy B, et al. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patientsBreast Cancer Res Treat. 2010;123(3):725-731. 
6. Yim WWY, Mizushima N. Lysosome biology in autophagyCell Discov. 2020;6(1):6. 
7. Malla RR, Kiran P. Tumor microenvironment pathways: Cross regulation in breast cancer metastasisGenes & Diseases. 2022;9(2):310-324.
8. Shibata Y, et al. p47 negatively regulates IKK activation by inducing the lysosomal degradation of polyubiquitinated NEMONat Commun. 2012;3:1061.
9. Pelleitier M, Montplaisir S. The nude mouse: a model of deficient T-cell function. Methods Achiev Exp Pathol. 1975;7:149-166.

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