Tumour extracellular vesicles and breast cancer metastasis
Dr Miki De Palma, École Polytechnique Eédérale de Lausanne
In spite of significant improvements in treatments and survival rates, metastatic breast cancer remains one of the leading causes of cancer-related deaths in women worldwide. Taxanes are microtubule-stabilizing agents largely employed as cytotoxic agents for breast cancer treatment, both in the adjuvant and neoadjuvant setting. Increasing evidence suggests that the cancer cells of primary tumors release extracellular vesicles (tEVs), which can facilitate the homing of metastatic cells to target organs. We found that paclitaxel – a lead taxane – enhances tEV release from murine breast cancer cells, both in vitro and in vivo. I will present the functional implications of this phenomenon in the context of breast cancer. Furthermore, I will discuss the determinants of microRNA sorting to EVs, and the significance of EV-mediated microRNA transfer to acceptor cells.
An apoptosis-driven 'onco-regenerative niche': roles of tumour-associated macrophages and extracellular vesicles
Professor Christopher D Gregory, MRC Centre for Inflammation Research
Apoptosis is a well-established anti-oncogenic cell-death programme. Paradoxically, high apoptosis indices in tumours are closely coupled with poor prognosis. Indeed, where it has been studied, cell loss is a striking feature of high-grade cancers, illustrating the importance of considering malignant disease as an imbalance between cell gain and cell loss rather than as a unidirectional disorder of cell gain alone. In addition to orchestrating cell loss, apoptosis can signal regenerative responses; for example compensatory proliferation in other cells. Accumulating evidence suggests that normal tissue repair and regenerative processes are hijacked in the malignant tissue microenvironment such that cancer may be likened to a “wound that fails to stop repairing”.
We have proposed that a critical requirement for the successful growth, progression and re-growth of malignant tumours is a complex niche, conceptually termed the “onco-regenerative niche”, which is composed, in addition to transformed neoplastic cells, of normal cells and factors activated as if in tissue repair and regeneration. Our work is based around the hypothesis that tumour cell apoptosis, macrophage activation and endothelial activation are key, interlinked elements of the onco-regenerative niche and that apoptotic tumour cell-derived extracellular vesicles (Apo-EVs) provide critical intercellular communication vehicles of the niche. In aggressive B-cell lymphoma, tumour cell apoptosis promotes both angiogenesis and the accumulation of pro-tumour macrophages in the lymphoma microenvironment. Furthermore, lymphoma-derived apo-EVs have potent pro-tumour potential. These findings have important implications for the roles of apoptosis in regulation of malignant diseases and for the efficacy of apoptosis-inducing anti-cancer therapies.
Cellular stress sensors mTORC1 switches exosome biogenesis and secretion pathways to influence the tumour microenvironment
Contributory talk given by Associate Professor Deborah Goberdhan.
Cancer cells can adapt to nutrient starvation and growth inhibitory drugs by communicating with their neighbours via secreted soluble factors, exosomes and other extracellular vesicles. Exosomes are commonly believed to originate in late endosomal multivesicular bodies, but the intracellular mechanisms modulating their functions remain poorly characterised. Here a new type of exosome biogenesis pathway involving Rab11-positive recycling endosomes is identified that releases exosomes with enhanced reprogramming activities. This pathway is present in both human cancer cells and an in vivo Drosophila model of exosome secretion. Using the fly model the biogenesis of these different exosome subtypes can be visualised in living tissue for the first time.
Inhibiting the glutamine-sensing PAT4 amino acid transporter blocks a specific form of mTORC1 signalling, leading to the preferential release of exosomes from recycling endosomes. Functionally, these stress-induced exosomes orchestrate signalling in recipient cells, which promotes pro-tumorigenic microenvironmental changes and cancer growth. Therefore in cancer cells the mTORC1 signalling hub senses microenvironmental stresses and then modulates exosome secretory pathways to drive tumour adaptation. These findings may partly explain why mTORC1 inhibitors often have poor clinical efficacy, and highlight the importance of distinguishing exosomal sub-types when defining their effects on the tumour microenvironment.
Contributory talk given by James Edgar
Edgar et al demonstrate that exosome release can be induced in HeLa cells upon inhibition of the V-ATPase, and that exosomes are observed in clusters at the plasma membrane. Such clustering shows striking similarities to clusters of retroviruses, which are attached to the plasma membrane by tetherin. To determine whether tetherin also attaches exosomes, it was knocked out and this resulted in a 4-fold reduction in plasma membrane-associated exosomes, with a concomitant increase in exosomes discharged into the medium. Such phenotype could be rescued by expression of wild-type tetherin but not tetherin lacking its GPI anchor. Edgar et al propose that tetherin may play a key role in exosome fate, determining whether they participate in long-range or short-range interactions.
Can glioblastoma extracellular vesicles drive normal astrocytes towards a tumour-enhancing phenotype?
Dr Michael Graner, University of Colorado Denver
Glioblastomas (GBMs, WHO grade IV astrocytomas) are the worst of the central nervous system tumors; despite maximum (and damaging) therapeutic intervention, median survival time for patients is <15 months, and overall quality of life is poor. These abysmal outcomes have changed little in 20 years. Clearly, our current therapies are inadequate; we need innovative strides in understanding GBM biology to rectify this situation. One “hot” research area is that of the impact of tumor extracellular vesicles (EVs) on normal recipient cells. Tumor EVs have extraordinary abilities to manipulate tumor microenvironments and recipient cells both proximally and distally. Tumor EVs prepare the “metastatic niche” for circulating tumor cells prior to colonization of a target organ, deflect immune responses, and alter normal cells. Thus, tumor EVs impact recipient cells to support tumor growth and progression, which undoubtedly holds true for GBMs as well. However, little is known about effects of GBM EVs on normal astrocytes—do GBM EVs drive astrocyte phenotypic changes, potentially making the astrocytes into tumor promotors? The answers could re-shape our paradigms on gliomagenesis, particularly for recurrent tumors. Here we show that GBM EVs activate cancer-type signaling pathways in recipient astrocytes, promoting astrocyte migration towards the EVs, as well as astrocyte anchorage-independent growth in soft agar. Astrocytes release of various factors to generate a tumor-promoting milieu with increased tumor cell growth. We discuss the consequences of these phenomena in the context of our current therapies with a view towards therapeutic improvement.