Clear Cell renal carcinoma is the most common kidney malignancy in adults. This tumor shows a high within tumor heterogeneity, and worse patient survival is associated with differences in tumor microenvironments.Clear cell renal carcinoma is the most common kidney malignancy in adults. This tumor shows a high within tumor heterogeneity, and worse patient survival is associated with differences in tumor microenvironments. How the cells in the tumor microenvironment contribute to the tumor advance is not yet fully understood. Our long-term goal is to develop useful biomarkers of ccRCC prognosis that represent a target for personalized therapies for this cancer type. Our overall objectives are 1) to elucidate the diversity of tumor cells and tumor microenvironment cells based on single-cell gene expression patterns, and 2) to determine in subjects with short (<20 months) and long (>60 months) survival which cells and differentially expressed genes are associated with ccRCC survival. The central hypothesis is that specific groups (clusters) of non-tumor cell populations in the tumor microenvironment (immune, endothelial, and stromal cells) promote ccRCC proliferation interacting with tumor cells and affecting patient survival. The rationale for this project is that a determination of clusters of tumoral and non-tumoral cells with differentially expressed genes associated with survival is likely to offer a solid scientific framework to develop additional biomarkers and cancer therapy strategies for ccRCC.
Our specific aims will test the following hypotheses:
(Aim 1) different numbers/proportions of non-tumor cell lineages/states (distinct clusters of tumor-infiltrating immune cells, endothelial, stromal and other cells) are related to differences in ccRCC survival;
(Aim 2) tumor and non-tumor cells will express genes related to vascular and hypoxia VHL pathways, but the gene expression of these and other pathways in non-tumor cells will directly affect ccRCC survival. Upon conclusion, we will have identified and characterized gene expression patterns of specific cells in the tumor microenvironment of ccRCC samples and their relation to ccRCC survival. This contribution is significant since it will establish how interactions between tumor and non-tumoral expressed genes affect patient ccRCC survival after adjusting for age, sex, stage, and treatment. Current studies using single-cell RNAseq have not explored the problem in a population setting, limiting the generalizability of their findings. The proposed research is innovative because, unlike in bulk RNA-seq approaches, we will uncover cell-specific and tumor-specific gene expression mechanisms related to groups of tumor and non-tumor cells that are different between short (<20 months) and long-term (>60 months) survivors.
The characterization of individual cell transcriptomes, and mainly of cells altered in the clear cell renal cell carcinoma pathogenesis might have implications for the analysis and treatment of indolent tumors. In the future, we expect to leverage information on tumor aggressiveness from cell heterogeneity of both tumor and non-tumor gene expression alterations into biomarkers of prognosis, and targeted therapies.
|Romano, Megan E; Eliot, Melissa N; Zoeller, R Thomas et al. (2018) Maternal urinary phthalate metabolites during pregnancy and thyroid hormone concentrations in maternal and cord sera: The HOME Study. Int J Hyg Environ Health 221:623-631|
|Everson, Todd M; Punshon, Tracy; Jackson, Brian P et al. (2018) Cadmium-Associated Differential Methylation throughout the Placental Genome: Epigenome-Wide Association Study of Two U.S. Birth Cohorts. Environ Health Perspect 126:017010|
|Emond, Jennifer A; Karagas, Margaret R; Baker, Emily R et al. (2018) Better Diet Quality during Pregnancy Is Associated with a Reduced Likelihood of an Infant Born Small for Gestational Age: An Analysis of the Prospective New Hampshire Birth Cohort Study. J Nutr 148:22-30|
|Nachman, Keeve E; Punshon, Tracy; Rardin, Laurie et al. (2018) Opportunities and Challenges for Dietary Arsenic Intervention. Environ Health Perspect 126:84503|
|Moen, Erika L; Bynum, Julie P; Austin, Andrea M et al. (2018) Assessing Variation in Implantable Cardioverter Defibrillator Therapy Guideline Adherence With Physician and Hospital Patient-sharing Networks. Med Care 56:350-357|
|Braun, Joseph M; Chen, Aimin; Hoofnagle, Andrew et al. (2018) Associations of early life urinary triclosan concentrations with maternal, neonatal, and child thyroid hormone levels. Horm Behav 101:77-84|
|Punshon, Tracy; Jackson, Brian P (2018) Essential micronutrient and toxic trace element concentrations in gluten containing and gluten-free foods. Food Chem 252:258-264|
|El-Jawahri, Areej; Fishman, Sarah R; Vanderklish, Julie et al. (2018) Pilot study of a multimodal intervention to enhance sexual function in survivors of hematopoietic stem cell transplantation. Cancer 124:2438-2446|
|El-Jawahri, Areej; Nelson-Lowe, Margaret; VanDusen, Harry et al. (2018) Patient-Clinician Discordance in Perceptions of Treatment Risks and Benefits in Older Patients with Acute Myeloid Leukemia. Oncologist :|
|Cai, Yunliang; Wu, Shaoju; Zhao, Wei et al. (2018) Concussion classification via deep learning using whole-brain white matter fiber strains. PLoS One 13:e0197992|
Showing the most recent 10 out of 131 publications