Scientific Fellow - Breast Cancer Now
Cristina Branco is accepting applications for PhD students.
Endothelial Cell Physiology, Oxygen-sensitive metabolism and intercellular communication
Endothelial Cells and Vascular Function
Organ function relies on transport and delivery of remotely acquired or produced nutrients, signals, gases, as well as (and importantly) circulating cells, all of which occur via haematogenous mobilization. In addition to the systemic control of circulation, the success of the vasculature in supporting organ function relies heavily on specific cell types, which ultimately adjust the system to organ demand: parameters such as perfusion, blood pressure or vascular permeability, are organ-specific and vary widely within an organism. Endothelial cells are at the centre of this regulation, not only in the way they assemble and adhere to each other to form diverse capillary networks, but also by actively delivering signals and communicating with other cells types. We are interested in the molecular mechanisms that determine endothelial function in different organs, and whether (or in which circumstances) the distinct behaviour of microvascular endothelial cells is governed by intrinsic differences or environmentally conditioned.
How endothelial cells interact, respond and adapt can either protect or compromise vascular performance, and one of our aims is to understand molecular mechanisms affecting their behaviours, as well as the key molecular regulatory pathways.
We use in vivo and ex-vivo models to study endothelial cells in the context of hypoxia and cancer dissemination.
Endothelial Hypoxia inducible factors and Cancer
We are interested in the organic nature of tumors, namely their vascular and inflammatory components. Hypoxia Inducible Factors (HIF) are well-studied in tumor cells, as their activation correlates with poor prognosis. However, in the highly proliferative and poorly perfused tumor microenvironment, every cell is exposed to hypoxia, even if transiently. The study of HIF activation in different cells within the tumor is still incipient and incomplete, and we are interested in studying the role of HIF transcription factors in somatic cells, and how their stabilization affects tumor progression and dispersion. Most of our current work is focused on the role of these transcription factors in Endothelial Cells.
Vascular endothelium and cancer cell movement
Tumor cells in breast cancer migrate primarily via haematogenous dissemination. For that to happen, those cells need to transpose the endothelial layer to enter the blood circulation, and again to exit the blood vessels at a favourable secondary site, for further proliferation. We have shown that stabilization of different isoforms of HIF in endothelial cells results in opposing effects on endothelial permeability and inflammatory cell recruitment to the metastatic sites, which significantly affect metastatic pre-disposition and tumor dispersion. This was an exciting finding that opened several questions and possibilities with respect to approaches to target metastatic disease in breast and other cancer types. We are investigating the molecular mechanisms behind this phenomenon. (Figure 1)
Inflammatory and immune cell contribution to metastatic disease - acute and chronic hypoxia and vascular dysfunction as a pre-disposing factor
Inflammatory cells have been shown to be involved in vascular remodelling, shuttling of tumor cells in and out of the vasculature, as well as conditioning and suppression of protective immune response to tumor invasion. We are interested in scrutinizing role of the endothelial cells in conditioning the interactions between the blood vessels, circulating tumor cells and other cell types at the metastatic site, prior to and during secondary colonization. (Figure 2)
We have found that acute hypoxia results in increased levels of the HIF-1 isoform, and a pro-metastatic environment, whereas chronic hypoxia, which correlates with increased levels of another HIF isoform (2), does not, even though both conditions promote inflammation. The lung inflammatory profile of chronic and acute hypoxia responses is distinct, HIF isoform –dependent and conditions metastatic potential. We are investigating the role of the endothelium in the recruitment of pro- versus anti-inflammatory inflammatory cells.
Dr Renato Colaco (Research Assistant)
Moritz Reiterer (PhD Student, starting Michaelmas 2016)
PDN Part II - Genes and Physiology
Branco-Price C, Evans CE, Johnson RS, (2013), Endothelial hypoxic metabolism in carcinogenesis and dissemination: HIF-A isoforms are a NO metastatic phenomenon, Oncotarget, 2013 Dec;4(12):2567-76
Branco-Price C, Zhang N, Schnelle M, Evans C, Katschinski DM, Liao D, Ellies L, Johnson RS, (2012), Endothelial cell HIF-1α and HIF-2α differentially regulate metastatic success, Cancer Cell, 17;21(1):52-65, doi:10.1016/j.ccr.2011.11.017
Kim JW, Evans C, Weidemann A, Takeda N, Lee YS, Stockmann C, Branco-Price C, Brandberg F, Leone G, Ostrowski MC, Johnson RS, (2012), Loss of fibroblast HIF-1α accelerates tumorigenesis, Cancer Res, 72(13):3187-95. doi:10.1158/0008-5472.CAN-12-0534
Evans CE, Branco-Price C, Johnson RS, (2012), HIF-mediated endothelial response during cancer progression, Int J Hematol, 95(5):471-7. doi:10.1007/s12185-012-1072-3
Branco-Price C, Johnson RS, (2010), Tumor vessels are Eph-ing complicated, Cancer Cell, 2010,17(6):533-4. doi: 10.1016/j.ccr.2010.05.020