Determinants of renal cell carcinoma invasion and metastatic competence

Kangsan Kim, Qinbo Zhou, Alana Christie, Christina Stevens, Yuanqing Ma, Oreoluwa Onabolu, Suneetha Chintalapati, Tiffani Mckenzie, Vanina Toffessi Tcheuyap, Layton Woolford, He Zhang, Nirmish Singla, Pravat Kumar Parida, Mauricio Marquez-Palencia, Ivan Pedrosa, Vitaly Margulis, Arthur Sagalowsky, Zhiqun Xie, Tao Wang, Steffen DurinckZora Modrusan, Somasekar Seshagiri, Payal Kapur, James Brugarolas, Srinivas Malladi

Research output: Contribution to journalArticlepeer-review

Abstract

Metastasis 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.

Original languageEnglish (US)
Article number5760
JournalNature communications
Volume12
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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