Project Summary/Abstract Malignant tumors characterized by rhabdoid features often display highly aggressive biology, frequently resulting in fatal outcomes, even when these features are localized to small areas within the tumors. Despite their relatively low occurrence, rhabdoid features have been observed across various tumor types and are linked with early metastasis. Notably, clear cell renal cell carcinoma (ccRCC) with rhabdoid features represents a recently identified histopathologic variant of renal cell carcinoma (RCC). The current management and clinical trajectory of these tumors exhibit significant variability with limited success. Researchers face challenges in accurately diagnosing rhabdoid features from biopsy specimens and lacking definitive data to comprehend these features thoroughly. To uncover the molecular mechanisms and understand the role of SERPINE family genes underlying rhabdoid tumorigenesis, Dr. Li will leverage recent advances and availabilities of the multi-omics data set and his integrative computational and experimental approach consisting of multi-omics, spatial, histopathology, and in situ analysis. During the K99 mentored phase of the award, Dr. Li proposes identifying the molecular signatures and mechanisms underlying rhabdoid tumorigenesis in ccRCC (Aim 1). During the R00 independent phase of the award, expanding on his earlier SERPINE-related findings in ccRCC, Dr. Li will apply multi-omics technologies and functional studies to understand the role of SERPINE family genes in rhabdoid tumorigenesis of ccRCC (Aim 2). Furthermore, Dr. Li aims to ascertain the aggressiveness and heterogeneity signatures of advanced tumors with rhabdoid features at the broader pan-cancer level, given their presence in varied cancer types (Aim 3). The results of this proposal have the potential to give fundamental new insight into the associated aggressiveness signature and mechanisms underlying the rhabdoid phenotypes, which will assist the clinical procedures for diagnosis and treatment. Notably, a better understanding of the role of SERPINE family genes in rhabdoid tumorigenesis can potentially lead to the development of effective treatment strategies for advanced tumors with rhabdoid features. This proposal also describes a detailed training plan to advance Dr. Li’s career as an independent investigator, combining computational and analytical approaches on varied data types with histopathology and experimental biology to uncover the mechanisms underlying tumorigenesis and progression better, identify therapeutic vulnerability and predict the treatment response. Throughout the K99 phase, Dr. Li will receive strong support from an interdisciplinary team of experts to expand his knowledge and refine his skill set for the transition into an independent investigator.

Project Narrative Malignant tumors containing rhabdoid features tend to be highly aggressive, with frequent fatal outcomes, even when the rhabdoid components are only focal and limited to small areas within the tumors. The treatment and clinical course are highly variable with little success, and it remains uncertain which factors influence treatment response and prognosis. This proposal aims to understand the aggressive signatures and the molecular mechanisms underlying rhabdoid tumorigenesis and determine the role of SERPINE family genes as potential therapeutic targets in treating advanced tumors with rhabdoid features.