BACKGROUNDMetastases are the hallmark of lethal cancer, though underlying mechanisms that drive metastatic spread to specific organs remain poorly understood. Renal cell carcinoma (RCC) is known to have distinct sites of metastases, with lung, bone, liver, and lymph nodes being more common than brain, gastrointestinal tract, and endocrine glands. Previous studies have shown varying clinical behavior and prognosis associated with the site of metastatic spread; however, little is known about the molecular underpinnings that contribute to the differential outcomes observed by the site of metastasis.METHODSWe analyzed primary renal tumors and tumors derived from metastatic sites to comprehensively characterize genomic and transcriptomic features of tumor cells as well as to evaluate the tumor microenvironment at both sites.RESULTSWe included a total of 657 tumor samples (340 from the primary site [kidney] and 317 from various sites of metastasis). We show distinct genomic alterations, transcriptomic signatures, and immune and stromal tumor microenvironments across metastatic sites in a large cohort of patients with RCC.CONCLUSIONWe demonstrate significant heterogeneity among primary tumors and metastatic sites and elucidate the complex interplay between tumor cells and the extrinsic tumor microenvironment that is vital for developing effective anticancer therapies.
The Journal of clinical investigation. 2024 May 30*** epublish ***
Shuchi Gulati, Pedro C Barata, Andrew Elliott, Mehmet Asim Bilen, Earle F Burgess, Toni K Choueiri, Sourat Darabi, Nancy Ann Dawson, Benjamin Adam Gartrell, Hans J Hammers, Elisabeth I Heath, Daniel Magee, Arpit Rao, Charles J Ryan, Przemyslaw Twardowski, Shuanzeng Wei, James Brugarolas, Tian Zhang, Matthew R Zibelman, Chadi Nabhan, Rana R McKay
UC Davis Comprehensive Cancer Center, Sacramento, California, USA., University Hospitals Seidman Cancer Center, Cleveland, Ohio, USA., Caris Life Sciences, Irving, Texas, USA., Emory University School of Medicine, Atlanta, Georgia, USA., Levine Cancer Institute, Charlotte, North Carolina, USA., Dana Farber Cancer Institute, Boston, Massachusetts, USA., Hoag Memorial Hospital Presbyterian, Newport Beach, California, USA., Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, USA., Montefiore Medical Center and Albert Einstein College of Medicine, New York, New York, USA., UT Southwestern Medical Center, Dallas, Texas, USA., Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan, USA., Baylor College of Medicine, Houston, Texas, USA., University of Minnesota, Minneapolis, Minnesota, USA., Saint John's Cancer Institute at Providence Saint John's Health Center, Santa Monica, California, USA., Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA., University of California San Diego, La Jolla, California, USA.