R-spondin-3 promotes proliferation and invasion of breast cancer cells independently of Wnt signaling.

We recently identified R-spondin-3 (RSPO3) as a novel driver of breast cancer associating with reduced patient survival, expanding its clinical value as potential therapeutic target that had been recognized mostly for colorectal cancer so far. (Pre)clinical studies exploring RSPO3 targeting in colorectal cancer approach this indirectly with Wnt inhibitors, or directly with anti-RSPO3 antibodies. Here, we address the clinical relevance of RSPO3 in breast cancer and provide insight in the oncogenic activities of RSPO3.

LGR6-dependent conditional inactivation of E-cadherin and p53 leads to invasive skin and mammary carcinomas in mice.

Tissue-specific inactivation of E-cadherin combined with tumor suppressor loss leads to invasive and metastatic cancers in mice. While epidermal E-cadherin loss in mice induces squamous cell carcinomas, inactivation of E-cadherin in the mammary gland leads to invasive lobular carcinoma. To further explore the carcinogenic consequences of cell-cell adhesion loss in these compartments, we developed a new conditional mouse model inactivating E-cadherin (Cdh1) and p53 (Trp53) simultaneously in cells expressing the leucine-rich repeat-containing G-protein coupled receptor 6 (Lgr6), a putative epithelial stem cell marker in the skin and alveolar progenitor marker in the mammary gland.

R-spondin-3 is an oncogenic driver of poorly differentiated invasive breast cancer.

R-spondins (RSPOs) are influential signaling molecules that promote the Wnt/β-catenin pathway and self-renewal of stem cells. Currently, RSPOs are emerging as clinically relevant oncogenes, being linked to cancer development in multiple organs. Although this has instigated the rapid development and testing of therapeutic antibodies targeting RSPOs, functional evidence that RSPO causally drives cancer has focused primarily on the intestinal tract.

The role of R-spondin proteins in cancer biology.

R-spondin (RSPO) proteins constitute a family of four secreted glycoproteins (RSPO1-4) that have appeared as multipotent signaling ligands. The best-known molecular function of RSPOs lie within their capacity to agonize the Wnt/β-catenin signaling pathway. As RSPOs act upon cognate receptors LGR4/5/6 that are typically expressed by stem cells and progenitor cells, RSPO proteins importantly potentiate Wnt/β-catenin signaling especially within these proliferative stem cell compartments.

Recent advances in understanding the role of protein-tyrosine phosphatases in development and disease.

Protein-tyrosine phosphatases (PTPs) remove phosphate groups from tyrosine residues, and thereby propagate or inhibit signal transduction, and hence influence cellular processes such as cell proliferation and differentiation. The importance of tightly controlled PTP activity is reflected by the numerous mechanisms employed by the cell to control PTP activity, including a variety of post-translational modifications, and restricted subcellular localization. This review highlights the strides made in the last decade and discusses the important role of PTPs in key aspects of embryonic development: the regulation of stem cell self-renewal and differentiation, gastrulation and somitogenesis during early embryonic development, osteogenesis, and angiogenesis.