Determinants of renal cell carcinoma invasion and metastatic competence

• DOI: 10.1038/s41467-021-25918-4
• Publication Date: 2021-10-04T17:16:57Z
• Authors: Kangsan Kim; Qinbo Zhou; Alana Christie; Christina Stevens; Yuanqing Ma; Oreoluwa Onabolu; Suneetha Chintala...; Tiffani Mckenzie; Vanina Toffessi T...; Layton Woolford; He Zhang; Nirmish Singla; Pravat Kumar Parida; Mauricio Marquez-...; Ivan Pedrosa; Vitaly Margulis; Arthur Sagalowsky; Zhiqun Xie; Tao Wang; Steffen Durinck; Zora Modrusan; Somasekar Seshagiri; Payal Kapur; James Brugarolas; Srinivas Malladi
• Keywords: Male; DNA Copy Number Variations; Science; Kidney; Article; Mice; 03 medical and health sciences; Risk Factors; Cell Line, Tumor; Exome Sequencing; Animals; Humans; Neoplasm Invasiveness; Prospective Studies; RNA-Seq; Carcinoma, Renal Cell; Aged; 0303 health sciences; Q; Thrombosis; Middle Aged; Kidney Neoplasms; 3. Good health; Gene Expression Regulation, Neoplastic; Female; Neoplasm Grading

AbstractMetastasis is the principal cause of cancer related deaths. Tumor invasion is essential for metastatic spread. However, determinants of invasion are poorly understood. We addressed this knowledge gap by leveraging a unique attribute of kidney cancer. Renal tumors invade into large vessels forming tumor thrombi (TT) that migrate extending sometimes into the heart. Over a decade, we prospectively enrolled 83 ethnically-diverse patients undergoing surgical resection for grossly invasive tumors at UT Southwestern Kidney Cancer Program. In this study, we perform comprehensive histological analyses, integrate multi-region genomic studies, generate in vivo models, and execute functional studies to define tumor invasion and metastatic competence. We find that invasion is not always associated with the most aggressive clone. Driven by immediate early genes, invasion appears to be an opportunistic trait attained by subclones with diverse oncogenomic status in geospatial proximity to vasculature. We show that not all invasive tumors metastasize and identify determinants of metastatic competency. TT associated with metastases are characterized by higher grade, mTOR activation and a particular immune contexture. Moreover, TT grade is a better predictor of metastasis than overall tumor grade, which may have implications for clinical practice.