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Genomic Profiling of Prostate Cancers From Men With African and European Ancestry

Researchers have identified genes that are more frequently altered in prostate tumors from men of African ancestry compared to other racial groups (Clin Canc Res 2020; doi: 10.1158/1078-0432.CCR-19-4112). None of the individual tumor genetic differences that were identified are likely to explain significant differences in health outcomes or to prevent Black Americans from benefiting from a new generation of precision prostate cancer therapies, the authors said, as long as the therapies are applied equitably. The research team set out to better understand differences in the mutations driving prostate cancer tumors in Black Americans compared to European Americans, and whether any such differences could influence disease outcomes or the effectiveness of PARP inhibitors or other targeted therapies. The researchers collected and analyzed DNA sequencing data from previously published studies and from a commercial molecular diagnostics company. They examined mutational patterns in prostate cancers from more than 600 Black men. The team found that the frequency of mutations in DNA repair genes and other genes that are targets of current therapeutics are similar between the two groups, suggesting that at least these classes of current precision prostate cancer therapies should be beneficial in people of both African and European ancestry. While the researchers found no significant differences in frequencies of mutations in genes important for current prostate cancer therapies, they did identify other genes, such as ZFXH3, MYC, and ETV3, that were more frequently mutated in prostate cancers from Black men. Developing a comprehensive understanding of how tumor genomics and other biological factors interact with social and environmental inequities to drive poorer clinical outcomes for Black prostate cancer patients should be an important priority for the efforts to improve precision medicine for these patients, the researchers say.



Mechanical Strain Induces Phenotypic Changes in Breast Cancer Cells and Promotes Immunosuppression in the Tumor Microenvironment

Expansion stress can have an alarming impact on breast cancer cells by creating conditions that could lead to dangerous acceleration of the disease, an interdisciplinary team of researchers has found (Lab Invest 2020; As breast tumors grow, biomechanical forces in the tumor microenvironment, or TME, cause elevated compression at the tumor interior, tension at the periphery, and altered interstitial fluid flow-promoting aggressive growth, invasion, and metastasis. Biomechanical forces also may modulate the immune response through cancer cell-immune cell crosstalk. The researchers created a novel, tissue-engineered, three-dimensional breast cancer mimetic system. This system recapitulates the in vivo growth of breast cancer cells in the presence of tumor-associated fibroblasts, endothelial cells, and immune cells within a physiologically relevant extracellular matrix. The researchers found that biomechanical forces significantly altered the proteome of breast cancer cells and enhanced exosome production. Tumor cell-secreted exosomes, one of the intercellular mediators of signaling in the TME, are now recognized as key regulators of tumor progression. In the study, the exosomes directly promoted aggressive tumor cell growth, induced immune suppression, and altered immune cell polarization in the TME. The researchers engineered an oscillatory compression device for real-time application of biomechanical force on orthotopic mammary tumors in vivo, which allowed them to observe exosome-mediated immunosuppression and aggressive tumor growth in mice. Preliminary analyses of exosome migration, immune cell uptake, and polarization superimposed onto a novel computational algorithm indicated the significance of exosome concentration gradient and time in predicting the kinetics of protumorigenic events, linking biomechanical force, exosome release by tumor cells, exosome uptake, and polarization of immune cells in the TME.



Proteogenomics of Non-Smoking Lung Cancer in East Asia Delineates Molecular Signatures of Pathogenesis and Progression

Lung cancer in non-smokers is a diverse and distinct disease from that in smokers, and it is likely to respond differently to targeted treatments, a major new study shows (Cell 2020; Scientists studied a population in Taiwan with high rates of lung cancer among non-smokers and found a range of genetic changes which varied depending on a patient's age or sex. Many non-smokers with lung cancer had signs of DNA damage from environmental carcinogens, with young women in particular having particular genetic changes which are known to drive cancer to evolve aggressively. Scientists analyzed tumor samples from 103 lung cancer patients from Taiwan-the majority of whom were non-smokers. The researchers conducted a detailed analysis of genetic changes, gene activation, protein activity, and cellular "switches" in lung cancer to develop the most comprehensive overview of the biology of disease in non-smokers to date. Looking at the genetics and the related proteins produced by cancer cells in the tumor samples, scientists found that some early-stage lung tumors in non-smokers were biologically similar to more advanced disease in smokers. Tumors in women often had a fault in the gene EGFR, whereas in men the most common faults were in the KRAS and APC genes. These differences could affect the response to targeted drugs in men and women. Picking out people with "late-like" early-stage lung tumors could help guide treatment decisions, and patients could be monitored more closely for signs of their disease progressing. The study found a pattern of genetic changes involving the APOBEC gene family in three-quarters of tumors of female patients under the age of 60 and in all women without faults in the EGFR gene. Patients without EGFR faults tend to do better on immunotherapy, and so testing for APOBEC could help pick out women more likely to respond to this form of treatment. The team also picked out groups of patients-particularly among older women-whose cancers had mutation patterns linked to cancer-causing substances in their environment such as pollutants. Finally, the team identified 65 proteins that were overactive in lung tumors that matched with existing candidate drugs. They found that one protein that cuts away at the surrounding tissue, MMP11, was linked to poorer survival-and could be explored as a marker for early detection.



Comprehensive Palmitoyl-Proteomic Analysis Identifies Distinct Protein Signatures for Large and Small Cancer-Derived Extracellular Vesicles

A new study sheds light on how a blood test involving extracellular vesicles might be used to diagnose cancer in the future, avoiding the need for invasive surgical biopsies. (J Extracell Vesicles 2020; Extracellular vesicles have gained significant attention in the last decade because they contain proteins and other biologically important molecules whose information can be transferred from cell to cell. They are known to help cancer metastasize to distant sites in the body, but exactly how this happens is not clear. To learn more about this process, the research team looked into a process called palmitoylation, in which enzymes transfer lipid molecules onto proteins. Palmitoylation can affect where proteins are located within cells, their activities, and their contribution to cancer progression. The investigators examined two types of extracellular vesicles, small and large, in samples of human prostate cancer cells. Using centrifuges, they separated the extracellular vesicles from the other cell materials and analyzed the levels of palmitoylation and the types of proteins present. The team found extracellular vesicles derived from the cancer cells contained palmitoylated proteins that are associated with the spread of cancer. Further, when the team chemically suppressed the palmitoylation process, the level of some of these proteins went down in the extracellular vesicles.