Lipidomic Profiling Reveals Biological Differences between Tumors of Self-Identified African Americans and Non-Hispanic Whites with Cancer

Abstract

In the US, the incidence and mortality of many cancers are disproportionately higher in African Americans (AA). Yet, AA remain poorly represented in molecular studies investigating the roles that biological factors might play in the development, progression, and outcomes of many cancers. Given that sphingolipids, key components of mammalian cellular membranes, have well-established roles in the etiology of cancer progression, malignancy, and responses to therapy, we conducted a robust mass spectrometry analysis of sphingolipids in normal adjacent uninvolved tissues and tumors of self-identified AA and non-Hispanic White (NHW) males with cancers of the lung, colon, liver, and head and neck and of self-identified AA and NHW females with endometrial cancer. In these cancers, AA have worse outcomes than NHW. The goal of our study was to identify biological candidates to be evaluated in future preclinical studies targeting race-specific alterations in the cancers of AA. We have identified that various sphingolipids are altered in race-specific patterns, but more importantly, the ratios of 24- to 16-carbon fatty acyl chain-length ceramides and glucosylceramides are higher in the tumors of AA. As there is evidence that ceramides with 24-carbon fatty acid chain length promote cellular survival and proliferation, whereas 16-carbon chain length promote apoptosis, these results provide important support for future studies tailored to evaluate the potential roles these differences may play in the outcomes of AA with cancer.

GBA Regulates EMT/MET and Chemoresistance in Squamous Cell Carcinoma Cells by Modulating the Cellular Glycosphingolipid Profile

“…We suggest that the contrasting effects of GBA deletion, particularly those in hepatocellular carcinoma, are likely due to differences in the molecular alterations of sphingolipids that take place during transformation in these histologically different tumor-derived cell lines. This is supported by our previous data showing that hepatocellular tumors have significantly decreased GlcCer and LacCer [8], opposite of what we observed in SCC tumors and other tumor histologies where they are increased [8,9]. On the basis of the difference in phenotypic sensitivity of GBA KO hepatocellular carcinoma and SCC cells to GlcCer synthase inhibition, we speculate that malignancy associated with alterations in sphingolipid metabolism are driven by the activity of GlcCer synthase in hepatocellular carcinoma, and by GBA activity in SCC and ovarian cancer-derived cells.…”

“…We previously showed that GlcCer of various acyl chain lengths are significantly increased in the tumors of patients with lung adenocarcinoma, lung squamous cell carcinoma (SCC), head and neck SCC, endometroid endometrial carcinoma, and colorectal adenocarcinoma [8][9][10]. Yet, as we show in this report, GBA copy number amplifications and increased protein and mRNA expression are common features in tumors of these and many other human cancers.…”

“…Therefore, the tumors of patients have significantly higher levels of GlcCer, the substrate of GBA; however, paradoxically, these cancers also have significantly higher GBA expression levels. The exception to this paradoxical observation is hepatocellular carcinoma that has high GBA expression, but we showed that tumors of patients with the disease have significantly lower GlcCer and LacCer [8]. Because of these contrasting cancer-specific effects, it appears that the role of GBA in cancer is not fully understood.…”

“…Mass spectrometry data were normalized per milligram of protein input. Sphingolipids were quantified by liquid chromatography with electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS, 5500 QTRAP, ABI) with the addition of retention time standards as previously described [8,9]. All solvents and water were LC-MS-grade.…”

“…In addition, the precursor for most cellular GSLs, glucosylceramide (GlcCer), is strongly associated with intrinsic and acquired multidrug resistance in cancer cell lines and in the tumors of patients that failed to respond to chemotherapy [7]. Many cancers have altered GSLs, and our group and others have shown that, compared to normal adjacent uninvolved tissues, GlcCer and lactosylceramide are significantly elevated in tumors [8][9][10]. Therefore, because GlcCers are central players in the metabolism of GSLs, it is important to understand how their levels are regulated and what roles they play in transformed cells.…”