Integrative spatial omics reveals distinct tumor-promoting multicellular niches and immunosuppressive mechanisms in African American and European American patients with TNBC.

Racial disparities in triple-negative breast cancer (TNBC) outcomes have been reported. However, the biological mechanisms underlying these disparities remain unclear. We integrated imaging mass cytometry and spatial transcriptomics, to characterize the tumor microenvironment (TME) of African American (AA) and European American (EA) patients with TNBC. The TME in AA patients was characterized by interactions between endothelial cells, macrophages, and mesenchymal-like cells, which were associated with poor patient survival. In contrast, the EA TNBC-associated niche is enriched in T-cells and neutrophils suggestive of an exhaustion and suppression of otherwise active T cell responses. Ligand-receptor and pathway analyses of race-associated niches found AA TNBC to be immune cold and hence immunotherapy resistant tumors, and EA TNBC as inflamed tumors that evolved a distinctive immunosuppressive mechanism. Our study revealed the presence of racially distinct tumor-promoting and immunosuppressive microenvironments in AA and EA patients with TNBC, which may explain the poor clinical outcomes.

Role of adenosine deaminase in prostate cancer progression.

Prostate cancer (PCa) is the second most common cancer and constitutes about 14.7% of total cancer cases. PCa is highly prevalent and more aggressive in African-American (AA) men than in European-American (EA) men. PCa tends to be highly heterogeneous, and its complex biology is not fully understood. We use metabolomics to better understand the mechanisms behind PCa progression and disparities in its clinical outcome. Adenosine deaminase (ADA) is a key enzyme in the purine metabolic pathway; it was found to be upregulated in PCa and is associated with higher-grade PCa and poor disease-free survival. The inosine-to-adenosine ratio, which is a surrogate for ADA activity was high in PCa patient urine and higher in AA PCa compared to EA PCa. To understand the significance of high ADA in PCa, we established ADA overexpression models and performed various in vitro and in vivo studies. Our studies have revealed that an acute increase in ADA expression during later stages of tumor development enhances in vivo growth in multiple pre-clinical models. Further analysis revealed that mTOR signaling activation could be associated with this tumor growth. Chronic ADA overexpression shows alterations in the cells' adhesion machinery and a decrease in cells' ability to adhere to the extracellular matrix in vitro. Losing cell-matrix interaction is critical for metastatic dissemination which suggests that ADA could potentially be involved in promoting metastasis. This is supported by the association of higher ADA expression with higher-grade tumors and poor patient survival. Overall, our findings suggest that increased ADA expression may promote PCa progression, specifically tumor growth and metastatic dissemination.

Uridine Diphosphate Glucuronosyl Transferase 2B28 (UGT2B28) Promotes Tumor Progression and Is Elevated in African American Prostate Cancer Patients.

Prostate cancer (PCa) is the second most diagnosed cancer in the United States and is associated with metabolic reprogramming and significant disparities in clinical outcomes among African American (AA) men. While the cause is likely multi-factorial, the precise reasons for this are unknown. Here, we identified a higher expression of the metabolic enzyme UGT2B28 in localized PCa and metastatic disease compared to benign adjacent tissue, in AA PCa compared to benign adjacent tissue, and in AA PCa compared to European American (EA) PCa. UGT2B28 was found to be regulated by both full-length androgen receptor (AR) and its splice variant, AR-v7. Genetic knockdown of UGT2B28 across multiple PCa cell lines (LNCaP, LAPC-4, and VCaP), both in androgen-replete and androgen-depleted states resulted in impaired 3D organoid formation and a significant delay in tumor take and growth rate of xenograft tumors, all of which were rescued by re-expression of UGT2B28. Taken together, our findings demonstrate a key role for the UGT2B28 gene in promoting prostate tumor growth.

Correction: UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

UDP-glucose 6-dehydrogenase regulates hyaluronic acid production and promotes breast cancer progression.

An improved understanding of the biochemical alterations that accompany tumor progression and metastasis is necessary to inform the next generation of diagnostic tools and targeted therapies. Metabolic reprogramming is known to occur during the epithelial-mesenchymal transition (EMT), a process that promotes metastasis. Here, we identify metabolic enzymes involved in extracellular matrix remodeling that are upregulated during EMT and are highly expressed in patients with aggressive mesenchymal-like breast cancer. Activation of EMT significantly increases production of hyaluronic acid, which is enabled by the reprogramming of glucose metabolism. Using genetic and pharmacological approaches, we show that depletion of the hyaluronic acid precursor UDP-glucuronic acid is sufficient to inhibit several mesenchymal-like properties including cellular invasion and colony formation in vitro, as well as tumor growth and metastasis in vivo. We found that depletion of UDP-glucuronic acid altered the expression of PPAR-gamma target genes and increased PPAR-gamma DNA-binding activity. Taken together, our findings indicate that the disruption of EMT-induced metabolic reprogramming affects hyaluronic acid production, as well as associated extracellular matrix remodeling and represents pharmacologically actionable target for the inhibition of aggressive mesenchymal-like breast cancer progression.

Methionine-Homocysteine Pathway in African-American Prostate Cancer.

African American (AA) men have a 60% higher incidence and two times greater risk of dying of prostate cancer (PCa) than European American men, yet there is limited insight into the molecular mechanisms driving this difference. To our knowledge, metabolic alterations, a cancer-associated hallmark, have not been reported in AA PCa, despite their importance in tumor biology. Therefore, we measured 190 metabolites across ancestry-verified AA PCa/benign adjacent tissue pairs (n = 33 each) and identified alterations in the methionine-homocysteine pathway utilizing two-sided statistical tests for all comparisons. Consistent with this finding, methionine and homocysteine were elevated in plasma from AA PCa patients using case-control (AA PCa vs AA control, methionine: P = .0007 and homocysteine: P < .0001), biopsy cohorts (AA biopsy positive vs AA biopsy negative, methionine: P = .0002 and homocysteine: P < .0001), and race assignments based on either self-report (AA PCa vs European American PCa, methionine: P = .001, homocysteine: P < .0001) or West African ancestry (upper tertile vs middle tertile, homocysteine: P < .0001; upper tertile vs low tertile, homocysteine: P = .002). These findings demonstrate reprogrammed metabolism in AA PCa patients and provide a potential biological basis for PCa disparities.