Journal Club

Highlighting recently published papers selected by Academy members

Journal Club: Cellular context determines whether factor promotes or tamps down cancer

Healthy cells, such as those in this spherical cluster, know which end is which. This polarity breaks down with aberrant LKB1 activity, tilting cells towards cancer. DNA is shown in blue, polarized protein, Atypical protein kinase C, in green, and E-cadherin in red. Image credit: Viola Hélène Lobert

Healthy cells, such as those in this spherical cluster, know which end is which. This polarity breaks down with aberrant LKB1 activity, tilting cells towards cancer. Polarized protein Atypical protein kinase C is shown here in green, E-cadherin in red, and DNA in blue. Image credit: Viola Hélène Lobert

Some cellular factors have an impressive multitude of roles. One prime example is LKB1 (Liver Kinase B1). It controls both cell metabolism and cell polarity, telling cells which end is which. It also appears to act as both a tumor suppressor as well as, according to some studies, a promoter of cancer cell survival.

In a recent study published in Nature Cell Biology, researchers reveal that LKB1’s potentially critical course of action depends on the cellular context. “This concept that loss of LKB1 promotes carcinogenesis is not that simple,” says Tor Erik Rusten, at the University of Oslo, Sweden, who led the study. He and his colleagues showed instead that LKB1 spurs cancer features in cells with certain alterations that disrupt where LKB1 is localized and how active it is. “There is more to LKB1. It is context dependent and possibly location dependent,” Rusten says.

The researchers found that LKB1 is active on the surface of endosomes—the intracellular vesicles that traffic molecules to and from the cell membrane and internal cellular compartments. When LKB1 activity is altered at this location, for instance in certain mutants, the kinase can disrupt cell polarity and spur cellular events that promote tumor growth. LKB1 is a highly conserved protein, so Rusten and colleagues first turned to flies, and then expanded their findings in human cells.

Their first insight into LKB1’s role in cell polarity and integrity came from examining flies with cell polarity defects, the result of mutations in a factor, called CIII-PI3K, that’s involved in regulating endosomes. The cellular alterations looked a lot like dysplasia—alterations that occur at the very earliest stages of cancer. They found that these defects were mediated by LKB1: knocking out LKB1 in the cells could abolish these cell polarity and growth defects. Moreover, LKB1 had elevated levels of activity in locations where it is normally quiet, such as the cytoplasm.

The researchers recapitulated these findings in cultures of human cells that form polarized spheres. Inactivating the endosomal factor also caused disorganized cell polarity, and aberrant LKB1 activity. “What you get is sort of misfiring of LKB1, making the cells confused so that they polarize in several directions instead of one,” explains Rusten.

The group next identified a factor that interacts with LKB1 on the endosome, WDFY2 (WD repeat and FYVE domain-containing 2). WDFY2 had recently been implicated in several types of cancers, and the new study helped flesh out its function. Taken together, the data make the case that LKB1 helps control cellular polarity from a location on the endosome, and that this action is mediated by WDFY2.

Molecular and cell biologist Reuben Shaw, at The Salk Institute for Biological Studies, in La Jolla, points out that LKB1 is known to activate multiple cellular factors. To keep all that signaling organized, “there must be distinct pools and upstream regulators of LKB1,” says Shaw. “This study clearly defines WDFY2 as one of them. Very cool.”

The researchers also found that LKB1 could drive tumor growth in flies already tilting towards cancer. They found high levels of cell proliferation in fly cells with mutations in Ras, a well-known cancer gene, and the endosomal factor CIII-PI3K. This cell proliferation, they found, was driven by LKB1, again suggesting that LKB1 can act as an oncogene—promoting cancer instead of suppressing it.

The new findings add to the notion that LKB1 can be a “contextual oncogene” says assistant professor Anna-Pavlina Haramis, at Leiden University, the Netherlands. “There may be cross-talk between the effects of LKB1 in metabolism and the effects in epithelial polarity,” she says. “Depending on context LKB1 can either promote or suppress tumor formation.”

Rusten would like to see if his data hold up in other systems, such as live mice. Meanwhile, the data add a new dimension to early-stage research efforts targeting LKB1 to tamp down on tumors, adds Haramis. Researchers will have to watch for unexpected effects on polarity and tumor growth, she says.

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