August 15, 2022 -- University of Michigan (U-M) researchers have identified in a mouse study a hormone -- neuregulin 4 (NRG4) -- that serves as a checkpoint for the progression of nonalcoholic steatohepatitis (NASH) and appears to have potential as a treatment for hepatocellular carcinoma (HCC), the most common type of primary liver cancer.
Their study, published August 15 in the journal Cell Metabolism, looked at how molecular and cellular changes are affected by nonalcoholic fatty liver disease and how these changes lead to the progression of the disease into NASH, which increases the risk of liver cancer.
In a previous study, researchers used single-cell RNA sequencing to build a liver cell atlas and a blueprint of intercellular signaling in healthy and NASH mouse livers. In their latest study, they identified specific molecular changes in the NASH state that disrupt the balance and interactions of these cell types.
The researchers showed that mice lacking NRG4, which is secreted primarily by fat cells, develop more severe NASH and more liver tumors than mice with normal levels of the hormone. In addition, when researchers boosted NRG levels in mice -- either by genetically elevating the expression of NRG4 in fat tissues or by treating mice with a recombinant NRG4 fusion -- the increased levels of the hormone suppressed NASH liver cancer progression.
"In a therapeutic setting, recombinant NRG4-Fc fusion protein exhibited remarkable potency in suppressing HCC and prolonged survival in the treated mice. These findings pave the way for therapeutic intervention of liver cancer by targeting the NRG4 hormonal checkpoint," according to the study's authors.
In their study, researchers noticed changes in two types of immune cells -- macrophages and T cells -- that appear to contribute to the development of HCC. T cells in mouse livers with NASH showed hallmarks of functional impairments while macrophages acquired molecular features typically associated with cancers.
"These changes we saw in macrophages and T cells resemble the tumor microenvironment, but they are happening even before any cancer becomes apparent," Jiandie Lin, PhD, research professor at the U-M Life Sciences Institute. "It gives us a hint that maybe these changes in the liver microenvironment could provide fertile ground for liver cancer cells to appear and grow. It almost looks like the liver, once it develops NASH, is already preparing for cancer cells to thrive."
While more research is needed before NRG4 can be pursued as a therapeutic for HCC, the U-M researchers plan to investigate approaches for improving the hormone's effectiveness and to better understand the nature underlying its regulation of macrophages and T cells in the liver.
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