Aberrant post-translational modifications in endosomal trafficking are potential therapeutic targets to avert therapy resistance in solid cancers: Dysregulation of PTM-regulated endosomal interactions presents an opportunity to block oncogenic signalling from multiple receptors by targeting common trafficking pathways: Dysregulation of PTM-regulated endosomal interactions presents an opportunity to block oncogenic signalling from multiple receptors by targeting common trafficking pathways.

Drugs targeting a single TK/RTK in the treatment of solid cancers has not had the same success seen in blood cancers. This is, in part, due to acquired resistance in solid cancers arising from a range of mechanisms including the upregulation of compensatory RTK signalling. Rather than attempting to inhibit individual compensatory RTK-requiring knowledge of which RTKs are upregulated in any given tumour-strategies to universally inhibit signalling from multiple RTKs may represent an effective alternative. Endosomal trafficking of RTKs is a common conduit that can regulate signalling from multiple RTKs simultaneously. As such, we posit that targeting endosomal trafficking-in particular, aberrant post-translational modifications in cancers that contribute to dysregulated endosomal trafficking-could inhibit oncogenic signalling driven by multiple RTKs and pave the way for the development of a novel class of inhibitors that shift the trafficking of RTKs to inhibit tumour growth.

Phosphorylation of PKCδ by FER tips the balance from EGFR degradation to recycling.

Receptor degradation terminates signaling by activated receptor tyrosine kinases. Degradation of EGFR occurs in lysosomes and requires the switching of RAB5 for RAB7 on late endosomes to enable their fusion with the lysosome, but what controls this critical switching is poorly understood. We show that the tyrosine kinase FER alters PKCδ function by phosphorylating it on Y374, and that phospho-Y374-PKCδ prevents RAB5 release from nascent late endosomes, thereby inhibiting EGFR degradation and promoting the recycling of endosomal EGFR to the cell surface. The rapid association of phospho-Y374-PKCδ with EGFR-containing endosomes is diminished by PTPN14, which dephosphorylates phospho-Y374-PKCδ. In triple-negative breast cancer cells, the FER-dependent phosphorylation of PKCδ enhances EGFR signaling and promotes anchorage-independent cell growth. Importantly, increased Y374-PKCδ phosphorylation correlating with arrested late endosome maturation was identified in ∼25% of triple-negative breast cancer patients, suggesting that dysregulation of this pathway may contribute to their pathology.

The tyrosine phosphatase PTPN14 (Pez) inhibits metastasis by altering protein trafficking.

Factors secreted by tumor cells shape the local microenvironment to promote invasion and metastasis, as well as condition the premetastatic niche to enable secondary-site colonization and growth. In addition to this secretome, tumor cells have increased abundance of growth-promoting receptors at the cell surface. We found that the tyrosine phosphatase PTPN14 (also called Pez, which is mutated in various cancers) suppressed metastasis by reducing intracellular protein trafficking through the secretory pathway. Knocking down PTPN14 in tumor cells or injecting the peritoneum of mice with conditioned medium from PTPN14-deficient cell cultures promoted the growth and metastasis of breast cancer xenografts. Loss of catalytically functional PTPN14 increased the secretion of growth factors and cytokines, such as IL-8 (interleukin-8), and increased the abundance of EGFR (epidermal growth factor receptor) at the cell surface of breast cancer cells and of FLT4 (vascular endothelial growth factor receptor 3) at the cell surface of primary lymphatic endothelial cells. We identified RIN1 (Ras and Rab interactor 1) and PRKCD (protein kinase C-δ) as binding partners and substrates of PTPN14. Similar to cells overexpressing PTPN14, receptor trafficking to the cell surface was inhibited in cells that lacked PRKCD or RIN1 or expressed a nonphosphorylatable RIN1 mutant, and cytokine secretion was decreased in cells treated with PRKCD inhibitors. Invasive breast cancer tissue had decreased expression of PTPN14, and patient survival was worse when tumors had increased expression of the genes encoding RIN1 or PRKCD. Thus, PTPN14 prevents metastasis by restricting the trafficking of both soluble and membrane-bound proteins.

The secretome in cancer progression.

The secretome is the collection of all macromolecules secreted by a cell, and is a vital aspect of cell-cell communication in eukaryotes. In cancer, tumour cells often display secretomes with altered composition compared to the normal tissue from which they are derived. These changes can contribute to the acquisition and maintenance of the recognised hallmarks of cancer. In addition, evidence is emerging for a more sophisticated role for the tumour secretome in cancer, with significant implications for malignant disease progression. In this review, we highlight recent advances in our understanding of factors contributing to secretome alterations in cancer, including genetic mutations, microRNA-based regulation and the influence of the tumour microenvironment. The contribution of secreted factors in maintenance and function of cancer stem cells, and of tumour-derived factors in specification of a pre-metastatic niche are also discussed. Collectively, evidence from the current literature suggests that the tumour secretome, consisting of factors derived from cancer stem cells, non-stem cells and the surrounding stroma, plays a deterministic role in cancer progression, and may constitute a key therapeutic target in many cancers. This article is part of a Special Issue entitled: An Updated Secretome.