The WNT/ROR Pathway in Cancer: From Signaling to Therapeutic Intervention

Abstract

The WNT pathway is one of the major signaling cascades frequently deregulated in human cancer. While research had initially focused on signal transduction centered on β-catenin as a key effector activating a pro-tumorigenic transcriptional response, nowadays it is known that WNT ligands can also induce a multitude of β-catenin-independent cellular pathways. Traditionally, these comprise WNT/planar cell polarity (PCP) and WNT/Ca2+ signaling. In addition, signaling via the receptor tyrosine kinase-like orphan receptors (RORs) has gained increasing attention in cancer research due to their overexpression in a multitude of tumor entities. Active WNT/ROR signaling has been linked to processes driving tumor development and progression, such as cell proliferation, survival, invasion, or therapy resistance. In adult tissue, the RORs are largely absent, which has spiked the interest in them for targeted cancer therapy. Promising results in preclinical and initial clinical studies are beginning to unravel the great potential of such treatment approaches. In this review, we summarize seminal findings on the structure and expression of the RORs in cancer, their downstream signaling, and its output in regard to tumor cell function. Furthermore, we present the current clinical anti-ROR treatment strategies and discuss the state-of-the-art, as well as the challenges of the different approaches.

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

“…Consistent with genomic instability profiles in cancer [ 129 ], ALS [ 130 ], and Alzheimer’s disease [ 131 ], the ERVK interactome analysis identified each of these conditions as significant KEGG pathways. Despite differences in clinical presentation, the molecular underpinnings in cancer and neurodegenerative disease are remarkably similar and include alterations in DDR [ 129 , 130 , 132 ], 14-3-3 expression [ 133 , 134 ], p53 signaling [ 135 , 136 ], p38 signaling [ 137 , 138 ], and Wnt signaling [ 139 , 140 ]—which are all KEGG pathways enriched in the ERVK IN network. AGE-RAGE signaling was also identified as a potential pathway associated with the ERVK IN interactome.…”

“…133-137 in ERVK, MMTV, ENTV, and JRSV) that binds Pex13 and Pex14 for peroxisomal import [63], a SxIP motif (aa. [137][138][139][140][141][142][143][144][145][146][147][148][149][150] that binds to EBH domains in end-binding proteins involved in microtubule transport [64], and a tyrosine-based YXXØ sorting signal (aa. [75][76][77][78] for interaction with the µ-subunit of adaptor protein complex [65] and a PEXEL-like motif [66].…”

Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies

“…The serine/threonine-rich domain physically interacts with adaptor proteins, such as 14-3-3 zeta, leading to resistance to apoptosis (25). The detailed signaling activated by ROR1 has been reviewed recently (7). Although ROR1 is a member of the receptor tyrosine kinase superfamily, the function of the tyrosine kinase domain remains controversial.…”

“…In addition, ROR1 was found in CD34 + acute myeloid leukemia (AML) cells and can be targeted by mAbs (39).In addition to hematological malignancies, aberrant expression of ROR1 was also found in a wide range of solid tumors as a biomarker and therapeutic target (7,40). In breast cancer, ROR1 was found to be positive in tumor specimens but not normal breast tissues (41).…”

“…The Wnt family of proteins transduce signals through the canonical b-catenin-dependent and non-canonical b-catenin-independent pathways (7,8). Several Wnt ligands, including Wnt1, Wnt3a, and Wnt8, can bind to the Frizzled family of receptors to trigger the b-catenindependent Wnt signaling pathway.…”