Ror2, a developmentally regulated kinase, promotes tumor growth potential in renal cell carcinoma

Abstract

Inappropriate kinase expression and subsequent promiscuous activity defines the transformation of many solid tumors including renal cell carcinoma (RCC). Thus, the expression of novel tumor-associated kinases has the potential to dramatically shape tumor cell behavior. Further, identifying tumor-associated kinases can lend insight into patterns of tumor growth and characteristics. Here, we report the identification of Ror2, a new tumor-associated kinase in RCC cell lines and primary tumors. Ror2 is an orphan receptor tyrosine kinase with physiological expression normally seen in the embryonic kidney. However, in RCC, Ror2 expression correlated with expression of genes involved at the extracellular matrix, including Twist and matrix metalloprotease-2 (MMP2). Expression of MMP2 in RCC cells was suppressed by Ror2 knockdown, placing Ror2 as a mediator of MMP2 regulation in RCC and a potential regulator of extracellular matrix remodeling. The suppression of Ror2 not only inhibited cell migration, but also inhibited anchorage independent growth in soft agar and growth in an orthotopic xenograft model. These findings suggest a novel pathway of tumor-promoting activity by Ror2 within a subset of renal carcinomas, with significant implications for unraveling the tumorigenesis of RCC.

Identification of Ror2 as a Hypoxia-inducible Factor Target in von Hippel-Lindau-associated Renal Cell Carcinoma

“…We previously reported that Ror2 expression has a distinct role in RCC tumor cell biology (7) and has the potential to be important for components of tumor invasion. We have since demonstrated a mechanism of Ror2 regulation that, with respect to clear cell RCC, can be linked to VHL loss and is a component of the HIF-dependent transcriptional program in clear cell RCC cell lines.…”

“…We have identified Ror2 expression as a characteristic of many renal cell carcinoma (RCC) 2 cell lines and human tumors (7), where its expression is associated with increased cell migration and anchorage-independent growth. Ror2 also plays a prominent role in osteosarcoma (8) and has recently been identified in squamous cell carcinoma of the head and neck, where expression parallels the development of invasive features of these tumors (9).…”

Primordial germ cell migration and the Wnt signaling pathway

“…Recent publications have further implicated Wnt5a-Ror2 in various processes of mammalian cell migration including mediation of chemotactic responses, convergent extension, and cell invasiveness in the palate, gut, and osteosarcoma lines, respectively (He et al, 2008;Enomoto et al, 2009;Yamada et al, 2010). Ror2 as a biomarker and therapeutic target for metastatic cancers is also an active area of research (Morioka et al, 2009;Wright et al, 2009;Debebe and Rathmell, 2015).…”

Exploitation of Aberrant Signalling Pathways as Useful Targets for Renal Clear Cell Carcinoma Therapy

“…Ror2 is found heavily phosphorylated in the kidney of RCC patients and is expressed highly in human RCC cell lines indicating a role for Ror2 in the pathology of RCC (Wright et al, 2009). In fact suppressed expression of Ror2 results in reduced expression of matrix metalloproteinase (MMP)-2, whose upregulation correlates with advanced stages of RCCs (Slaton et al, 2001).…”