Research Projects

Renal cell carcinoma (RCC) is the 14th most common cancer worldwide, with over 4,34,000 new cases and 1,55,000 deaths in 2022. Same year, in India RCC accounted for 17,480 cases and 10,464 deaths, resulting in a death-to-case ratio of 60%, nearly double the global average [1]. Clear cell RCC (ccRCC) makes up ~80% of RCC cases [2], typically diagnosed around age 60, with a male-to-female ratio of 2:1. While 70% of ccRCC patients are initially diagnosed with low-grade tumors through incidental abdominal imaging, prognosis deteriorates as tumors progress to high-grade [3]. In this study Grades 1 and 2 will be consider as low-grade tumors due to their less aggressive characteristics, while Grades 3 and 4 will represent high-grade more aggressive tumors [4]. Loss of chromosome 3p and bi-allelic inactivation of VHL are present in over 90% of ccRCC cases, representing a key truncal mutation in tumor initiation [5]. 3p loss results copy number loss of key tumor suppressor genes including VHL, PBRM1, BAP1 and SETD2 [6], in this VHL loss stabilizes HIF2 activity, a key feature of ccRCC [7, 8] (Tech Doc Fig 1-2). My postdoc lab has developed Belzutifan, an FDA-approved HIF2 inhibitor [9, 10], and I contributed to trials demonstrating siRNA as a potential approach to counter Belzutifan resistance [11]. I also found that mutations in TP53 and SMARCA4 increase tumor aggressiveness [12]. Additionally, I contributed in investigating the role of tumor microenvironment in rapalog resistance [13], and tumorigenesis mechanisms in translocation RCC (tRCC) [14]. My preliminary data from genetically engineered mouse models (GEMMs) deficient in Vhl, Bap1, and Pbrm1 [15], along with ccRCC patient samples, suggest that BAP1-deficient tumors quickly progress to high-grade, while PBRM1-deficient tumors transition more slowly, indicating two distinct ccRCC subtypes [16, 17]. BAP1 acts as a deubiquitinase [18], removing repressive histone marks, whereas BAF180 from PBRM1 gene is part of the PBAF complex that modulates chromatin accessibility [19] (Tech Doc Fig 3). However precise mechanisms driving tumor progression remain unclear. I hypothesize that dissecting the mechanisms of tumor grade progression in ccRCC through bulk and single-cell multi-omics analysis will provide crucial insights to inform the development of targeted, personalized therapies to inhibit ccRCC progression. This study will employ bulk genomic assays to identify key mutations, structural variants, and pathways associated with tumor grade [20]. Single-cell RNA and ATAC sequencing will characterize tumor heterogeneity, cell interactions, and chromatin accessibility changes, particularly due to BAP1 and PBRM1 loss [21]. Finally, integrated multi-omics analysis will map tumor progression pathways and identify novel therapeutic targets [22](Tech Doc Fig 4). Patient and Genetically Engineered Modified Mouse samples will be collected from ACTREC Mumbai and Kidney Cancer Program, UT Southwestern Medical Center.