ccRCC Metastatic Latency and Relapse Determinants
Abstract
Renal adenocarcinomas are molecularly and clinically distinct, with clear cell and papillary type accounting for 90% of the cases. Despite increased early detection of primary tumor, approximately 25% of patients are presented with metastatic disease and more than one-third of the patients who undergo nephrectomy with curative intent experience local or distal relapse. Around 78% of metastases occur within 5 years and 11% occur after more than 10 years of initial diagnosis. Therefore, a molecular understanding of how disseminated renal cancer cells survive at secondary sites and initiate metastasis is crucial to improve early detection, predict aggressive disease, enhance treatment options for patients, and ultimately prevent metastatic relapse. The proposed research addresses this knowledge gap. To date, there is no molecular characterization of disseminated latent metastatic cells in renal adenocarcinomas. As it is impractical to obtain L-DTCs from asymptomatic cancer patients, we generated novel ccRCC preclinical models of metastatic latency using mouse as a phenotypic sorter. Employing these models, we will define the gene regulatory components deterministic of metastatic latency and relapse by molecularly dissecting the role of the tumor cell secretome in creating a supportive niche for latent cancer cell survival and by defining the role of enriched Hippo signaling transducer YAP in promoting metastatic latency and relapse. We will also target the identified survival determinants in novel ccRCC preclinical models to demonstrate improved efficacy in limiting metastatic incidence. The KCRP Areas of Emphasis to be addressed by this proposal include new disease model systems to study clinically observed metastatic latency and metastatic relapse, chromatin and gene regulation, and the paradoxical role of microenvironment in limiting and facilitating metastatic relapse. Overall, findings from the proposed research will define the underappreciated role of the YAP signaling response, tumor cell secretome, and infiltrating leukocytes in promoting ccRCC metastasis. Successful completion of the proposed experiments is likely to provide novel therapeutic options to eliminate ccRCC metastatic disease. The proposed studies will benefit both early diagnosed and metastatic ccRCC patients. Our research findings will be the basis for identifying ccRCC patients likely to develop residual or metastatic disease. Preclinical validation of the proposed hypothesis is more than likely to advance the field of kidney cancer research and impact patient care.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110838
Entities
People
- Srinivas Malladi
Organizations
- United States Army
- University of Texas Southwestern Medical Center