Selected Grantee Publications
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- 4 results found
- nci
- nigms
- Women's Health
Integrative Multi-omics Analysis Uncovers Tumor-Immune-Gut Axis Influencing Immunotherapy Outcomes in Ovarian Cancer
Rosario et al., Nature Communications. 2024.
https://pubmed.ncbi.nlm.nih.gov/39638782
Recurrent ovarian cancer (OC) is the deadliest gynecological malignancy, with a 5-year survival rate of 50% and a median progression-free survival (PFS) of 1.9 to 2.1 months. A trial cohort of 40 patients was treated with a combination of the anti-PD-1 pembrolizumab, the anti–vascular endothelial growth factor bevacizumab, and cyclophosphamide. The investigators conducted a multi-omics analysis—including transcriptomic analysis, digital spatial profiling, 16s-rRNA sequencing, and metabolomics—to understand the underlying mechanisms for the enhanced PFS to a median of 10.2 months and overall response rate of 47.5%. Multi-omics analysis highlighted the formation of tertiary lymphoid structures known to improve responses to immunotherapy, differential microbial patterns, and alterations in the metabolites in three key metabolism pathways that enhanced immune response in patients to produce a durable clinical response. These findings highlight the importance of the tumor microenvironment and the gut microbiome, along with its metabolites, in elevating the efficacy of the cocktail therapy in recurrent OC patients, thereby enhancing their survival and quality of life. Supported by ORIP (S10OD024973) and NCI.
p38MAPKα Stromal Reprogramming Sensitizes Metastatic Breast Cancer to Immunotherapy
Faget et al., Cancer Discovery. 2023.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10238649/
This study emphasizes the importance of the metastatic tumor microenvironment in metastatic breast cancer growth and the identification of effective antimetastatic therapies. Using a stromal labeling approach and single-cell RNA sequencing, the authors showed that a combination of p38MAPK inhibition (p38i) and anti-OX40 synergistically reduced metastatic tumor growth and increased overall survival. Further engagement of cytotoxic T cells cured all metastatic disease in mice and produced durable immunologic memory. The Cancer Genome Atlas data analysis revealed that patients with p38i metastatic stromal signature and a high tumor mutational burden (TMB) had increased overall survival. These findings suggest that patients with high TMB would benefit the most from the p38i plus anti-OX40 approach. Supported by ORIP (S10OD028483), NIA, NCI, and NIGMS.
Infection of the Maternal–Fetal Interface and Vertical Transmission Following Low-Dose Inoculation of Pregnant Rhesus Macaques (Macaca mulatta) with an African-Lineage Zika Virus
Koenig et al., PLOS ONE. 2023.
https://doi.org/10.1371/journal.pone.0284964
Researchers examined transmission of Zika virus to nonhuman primate fetuses during pregnancy. Even with a low dosage of inoculation of the dams, the investigators found that the Zika virus infected fetuses, despite the presence of a “placental fortress,” which normally protects fetuses during gestation. This transmission illustrates the high level of infectivity threat that Zika poses, which may increase if mosquitoes expand their global habitats. Understanding how Zika breaches the placental barrier will help researchers develop strategies to prevent fetal infection during pregnancy and thereby prevent adverse outcomes, such as brain malformation defects. Supported by ORIP (P51OD011106, S10OD023526), NIAID, NCI, and NIGMS.
Stromal P53 Regulates Breast Cancer Development, the Immune Landscape, and Survival in an Oncogene-Specific Manner
Wu et al., Molecular Cancer Research. 2022.
https://www.doi.org/10.1158/1541-7786.MCR-21-0960
Loss of stromal p53 function drives tumor progression in breast cancer, but the exact mechanisms have been relatively unexplored. Using mouse models, researchers demonstrated that loss of cancer-associated fibroblast (CAF) p53 enhances carcinoma formation driven by oncogenic KRAS G12D, but not ERBB2, in mammary epithelia. These results corresponded with increased tumor cell proliferation and DNA damage, as well as decreased apoptosis, in the KRAS G12D model. Furthermore, a gene cluster associated with CAF p53 deficiency was found to associate negatively with survival in microarray and heat map analyses. These data indicate that stromal p53 loss promotes mammary tumorigenesis in an oncogene-specific manner, influences the tumor immune landscape, and ultimately affects patient survival. Supported by ORIP (K01OD026527) and NCI.