Determinants of renal cell carcinoma invasion and metastatic competence

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.

Decoding the multicellular ecosystem of vena caval tumor thrombus in clear cell renal cell carcinoma by single-cell RNA sequencing

“…Previous studies demonstrated the ECM is important at initial stages of metastasis, where interactions between tumor cells and extracellular matrix induce an invasive phenotype [ 58 , 59 ]. Moreover, TT grade has been reported as an independent predictor for metastatic outcome irrespective of the grade of the PTs [ 60 ], which suggests the invasion ability of tumor cells in TTs is very important for metastatic potential. Our study demonstrated that ECM remodeling is crucial for both metastasis and tumor thrombus growth.…”

The changing role of natural killer cells in cancer metastasis

“…The process of collective migration conveys survival advantages to clusters of cancer cells as they invade and disseminate from the primary tumor, enter circulation, and seed distant sites (66). Clinically, circulating cancer cell clusters have been found in a variety of tumors, including breast, brain, lung, prostate, renal esophageal, and melanoma, and have been shown to correlate with worse survival outcomes (67)(68)(69)(70). And, as discussed further below, collective seeding of distant organs has been shown to increase metastatic efficiency.…”

Role of TELO2-interacting protein 1(TTI1) functions as an oncogene by regulating mTOR activity in the progression of non-small cell lung cancer

“…The activated mTOR signaling pathway is the key to promoting cell growth, and plays a variety of roles in human cancer, including cell survival, cytoskeleton rearrangement, invasion, metastasis, anti-apoptosis, and inhibition of autophagy[6, [17][18][19]. Recent studies have indicated that activated mTOR signaling could promote cancer cell proliferation, invasion and metastasis [20][21][22]. Kangsan Kim et found that augmented mTORC1 signaling determines metastatic potential in renal cell carcinoma [22].…”

“…Recent studies have indicated that activated mTOR signaling could promote cancer cell proliferation, invasion and metastasis [20][21][22]. Kangsan Kim et found that augmented mTORC1 signaling determines metastatic potential in renal cell carcinoma [22]. TTI1 and TTI2…”