Systems Pathology and Cancer

Why do some patients respond to therapy and some don’t? There is a growing need to personalise therapeutic treatments because human diseases are somewhat unique to the individual patient. Diagnostic assays detecting specific features (biomarkers) of a disease provide a framework to classify diseases according to their underlying molecular defects. In turn, the patient-specific molecular profile guides the clinician’s choice for therapy. Cancer is a remarkably heterogeneous disease and the increasing complexity of molecular changes that occur during tumour evolution highlights the importance of identifying events that drive this process. In pregnancy, cells from the fetus invade maternal tissue and this process has many similarities to how cancer spreads. During pregnancy, fetal placental trophoblast cells invade the maternal uterine decidua without being rejected by the maternal immune system - the pregnancy paradox. The maternal decidua harbours multiple populations of maternal immune cells, all of which extensively interact with the fetal trophoblasts. Up to 40% of decidual cells are leukocytes, and accumulating evidence suggests that fetal immune tolerance is established locally at the placenta to counteract these maternal immune cells. The immune system also restrains the growth of many early cancer lesions by the process of immune surveillance, where lesions are detected and removed. However, cancers that develop further into clinical disease escape immune surveillance and it is increasingly appreciated that overcoming immune surveillance is a critical acquired attribute of tumourigenesis.

The Reynolds lab is interested in identifying those molecular changes which drive disease with particular emphasis on 1) factors that mediate tumour invasion and 2) factors that mediate placental invasion. We are employing biochemistry, molecular biology and cell biology approaches to investigate the nature and context of these factors and how they impact upon human health.

Stromal Factors in Cancer Resistance

The tumour microenvironment (TME; or tumour stroma) is the noncancerous portion of solid tumours that contains a complex mixture of cell types including fibroblasts, endothelial and immune cells, and matrix components, that confer biochemical and biophysical cues which modulate cell behaviour. It is not only a physical support for mutated epithelial cells but is also an important modulator and even driver of tumourigenesis. It provides the environment in which the fittest cancer cells are selected in the absence of therapy and these same factors can also modulate the strong selective pressures applied by chemo- and radiotherapy. Cancer treatments can also directly affect many of the cellular components of the microenvironment and further alter the context in which cancer evolution occurs. We are investigating a novel type I membrane protein which is highly expressed on the cell surface of stromal fibroblasts in a number of common cancers.

Factors in Placental Invasion

During pregnancy, fetal placental trophoblast cells invade the maternal uterine decidua without being rejected by the maternal immune system - the pregnancy paradox. In both mice and humans, the placenta develops from the trophectoderm of the blastocyst. During implantation, invading placental trophoblast cells anchor the blastocyst to the decidua, on which placentation occurs. Since trophoblasts are the only fetal-derived cells that come into direct contact with maternal immune cells at the maternal-fetal interface, trophoblasts serve an essential role in mediating maternal tolerance towards the embryo. Therefore, research in this area has largely focused on elucidating how these trophoblast cells contribute to local immune suppression. We are investigating a novel type I membrane protein which is naturally expressed in placenta. Our study aims to investigate the precise location of this protein over the course of pregnancy from initial implantation to birth. We are using advanced state-of-the-art tissue imaging methods and laboratory cell models of placenta to investigate how our protein is involved in placental function.

M.A.; Ph.D.

Pathology; Tumour Microenvironment; Immuno-oncology; Carcinoma Associated Fibroblasts; Cancer Drug Resistance.