Pre-metastatic niche: vascular and immune compliance with invasive and metastatic breast cancer

Prof Randall Johnson, Department of Physiology, Development and Neuroscience is a second Co-Investigator for this project.

This PhD project aims to identify and characterize novel molecular mechanisms and cellular processes governing the invasion of breast cancer to distant secondary organs, by identifying the contribution of the non-tumour cells in the establishment of metastases. It provides a unique opportunity for a highly motivated individual to conduct research within a multi-disciplinary group of physiologists and pathologists with expertise in mammary cell development, breast cancer and intercellular communication.

Background and Objectives
Metastases are the main cause of mortality associated with cancer. In breast cancer, secondary tumours can occur in different organs, often several years after initial diagnosis. Considering that recent evidence shows that there are tumour cells in circulation from early stages of malignancy, it is clear that early diagnosis alone cannot be a consistent predictor of better outcomes. Consequently, prognoses can be uncertain in this disease, as in so many forms of cancer. Current therapies are focused on direct elimination of tumour cells, a strategy proven insufficient: frequently, tumour cells succeed in circumventing those treatments, and resistant cells eventually generate more tumours. Currently, there are no therapeutic strategies that specifically target metastatic disease.

Our research1,2 and that of others 3 have shown that tumour development and dissemination rely both on properties of the tumour cells and on the physiological context in the host organ. Tumour progression is thus a function of the individual cell types in the microenvironment of the primary tumour and metastatic sites. This project focuses on the role of somatic cells at metastatic sites, and how the micro-environmental milieu affects the establishment of secondary tumours.

Breast cancer metastasizes mostly via hematogenous dissemination, under which circumstances tumour cells rely on direct interaction with the vascular endothelium to exit the circulation into a new seeding site. It has also been demonstrated that physical interaction with a capillary is a requirement for a metastasized tumour cell to proliferate. Hypoxia inducible factors are associated with poor prognosis in most cancer types, yet we have shown that their role in endothelial cells is isoform-specific: activation of HIF-1a in endothelial cells results in increased tumour cell migration and lung metastases, whereas that of HIF-2a has the opposite effect1, and when it is expressed, tumour cells are less successful at both extravasating and proliferating. This is a very intriguing phenomenon that revealed a decisive role for the endothelium in allowing or preventing metastatic success. Our hypothesis is that cell and isoform-specific HIF stabilization in the pre-metastatic niche regulates secondary tumour formation.

The aims of this project are to determine:
1. which HIF-a isoform is preferentially stabilized at pre-metastatic organs during tumour progression, and in which cell types
2. how does HIF stabilization affect metastatic success
3. what causes the stabilization of HIF at metastatic organs (hypoxia? Tumour-derived signals?)
4. how does tumour stage correlate with metastatic pre-disposition (relevant to adjust timing and duration of potentially promising therapeutic intervention)
5. what physiological factors relevant for metastatic success are affected by HIF-mediated processes (e.g. permeability, angiogenesis, inflammatory response, immune cell recruitment and polarization, immunosuppression…)
Understanding the mechanisms downstream of HIF activity will open an array of possible therapeutic targets that, in addition to the strategy of eliminating tumour cells, will potentially contribute to fill two main voids in the current therapeutic practice: 1) addressing metastatic disease and 2) the host response (i.e.: by enhancing resistance or opposing compliance).
Therefore, it is beneficial to approach targeting of non-malignant cells, known to greatly contribute to cancer progression and outcome, in order to reduce host cell permissiveness to tumour cell extravasation, seeding and proliferation at secondary sites.

For full project details please see http://www.cambridgecancercentre.org.uk/studentships