The Stacker laboratory has an interest in the growth factors, growth factor receptors and signalling pathways that control cells in the tumour microenvironment, in particular those of the blood vessels, lymphatic vessels and stroma.
Currently the laboratory is addressing the following questions:
- What controls the remodelling of blood and lymphatic vessels in human disease?
- What biomarkers exist to predict or monitor these events?
- How do we improve the use of existing anti-angiogenic therapies?
- What changes occur to organ-specific vessels and how might they affect organ-specific diseases?
- How can we understand the different responses of the hierarchy of vessels in the vascular system (both blood and lymphatic vessels)?
- Can we find new and improved targets for angiogenesis/lymphangiogenesis or vessel remodelling, and are there existing drugs that modulate their function?
- How does the broader tumour microenvironment signal to coordinate the interaction of blood vessels, lymphatic vessels, stroma and immune cells to drive tumour progression?
- Can we discover new signalling pathways to control cancer or resistance to current anti-cancer therapeutics?
Role of novel growth factor receptors in cancer
RYK is a Wnt-binding receptor tyrosine kinase that is involved in the growth and differentiation of mammalian cells. We have previously shown a role for this receptor in planar cell polarity signalling. Our current interest is defining the role RYK plays in transducing signals within tumour cells that might be involved in driving resistance to known therapeutic drugs.
Signaling pathways controlling lymphangiogenesis and lymphatic vessel remodeling
Changes to lymphatic vessels potentially underlie the development of various human pathologies. We have previously shown the key role that lymphangiogenesis plays in modifying lymphatic vessels in primary tumours and lymph nodes during cancer progression and metastasis. Using in vitro assays for endothelial cell migration and tube formation, we have interrogated the human genome for genes involved in lymphatic endothelial cell migration, a key aspect of lymphangiogenesis and lymphatic vessel remodelling. Examining candidates from these screens has provided both cellular targets and biomarkers that are currently under investigation.
Resistance to anti-angiogenic drugs
Avastin (bevacizumab; anti-VEGF-A) is therapeutic antibody that inhibits the action of VEGF-A, blocks the formation of new blood vessels and is used to treat a variety of cancers. While Avastin represents a major targeted therapy, many patients do not gain any benefit from Avastin treatment, and those that do ultimately develop resistance. We have established sophisticated in vitro model systems to understand the role of blood endothelial cells in this resistance, and have employed siRNA screening approaches to identify molecules and signalling pathways that mediate the resistance.
Role of collecting lymphatic vessels in cancer metastasis
We have led studies that have examined the role of collecting lymphatic vessels and the cells that line these vessels, so-called collecting lymphatic endothelial cells (cLECs), in cancer metastasis. We are interested in their unique cell biology and how they interact with the prostaglandin pathway to modulate the host response to tumour progression and metastasis.
He MY, Halford MM, Liu R, Roy JP, Grant ZL, Coultas L, Thio N, Gilan O, Chan YC, Dawson MA, Achen MG, Stacker SA. Three-dimensional CRISPR screening reveals epigenetic interaction with anti-angiogenic therapy. (2021) Commun Biol. 15;4(1):878.
Farnsworth RH, Karnezis T, Maciburko SJ, Mueller SN, Stacker SA. The Interplay Between Lymphatic Vessels and Chemokines. (2019) Front Immunol. 12;10:518.
Karnezis T, Farnsworth RH, Harris NC, Williams SP, Caesar C, Byrne DJ, Herle P, Macheda ML, Shayan R, Zhang YF, Yazar S, Takouridis SJ, Gerard C, Fox SB, Achen MG, Stacker SA. CCL27/CCL28-CCR10 Chemokine Signaling Mediates Migration of Lymphatic Endothelial Cells. (2019) Cancer Res. 1;79(7):1558-1572.
Roy JP, Halford MM, Stacker SA. The biochemistry, signalling and disease relevance of RYK and other WNT-binding receptor tyrosine kinases. (2018) Growth Factors. Apr;36(1-2):15-40.
Farnsworth RH, Achen MG, Stacker SA. The evolving role of lymphatics in cancer metastasis. (2018) Curr Opin Immunol. Aug;53:64-73.
Williams SP, Odell AF, Karnezis T, Farnsworth RH, Gould CM, Li J, Paquet-Fifield S, Harris NC, Walter A, Gregory JL, Lamont SF, Liu R, Takano EA, Nowell CJ, Bower NI, Resnick D, Smyth GK, Coultas L, Hogan BM, Fox SB, Mueller SN, Simpson KJ, Achen MG, Stacker SA. (2017) Genome-wide functional analysis reveals central signaling regulators of lymphatic endothelial cell migration and remodeling. Sci Signal. Oct 3;10(499):eaal2987.
Le CP, Nowell CJ, Kim-Fuchs C, Botteri E, Hiller JG, Ismail H, Pimentel MA,Chai MG, Karnezis T, Rotmensz N, Renne G, Gandini S, Pouton CW, Ferrari D, Möller A, Stacker SA, Sloan EK (2016). Chronic stress in mice remodels lymph vasculature to promote tumour cell dissemination. Nat Commun. 7:10634.
Stacker SA, Williams SP, Karnezis T, Shayan R, Fox SB, Achen MG (2014). Lymphangiogenesis and lymphatic vessel remodelling in cancer. Nat Rev Cancer.14(3):159-72.
Farnsworth RH, Lackmann M, Achen MG, Stacker SA (2014). Vascular remodeling in cancer. Oncogene.33(27):3496-505.
Halford MM, Macheda ML, Parish CL, Takano EA, Fox S, Layton D, Nice E, Stacker SA (2013). A fully human inhibitory monoclonal antibody to the Wnt receptor RYK. PLoS One.8(9):e75447.
Macheda ML, Sun WW, Kugathasan K, Hogan BM, Bower NI, Halford MM, Zhang YF, Jacques BE, Lieschke GJ, Dabdoub A, Stacker SA (2012). The Wnt receptor Ryk plays a role in mammalian planar cell polarity signaling. J Biol Chem.287(35):29312-23.
Karnezis T, Shayan R, Caesar C, Roufail S, Harris NC, Ardipradja K, Zhang YF, Williams SP, Farnsworth RH, Chai MG, Rupasinghe TW, Tull DL, Baldwin ME, Sloan EK, Fox SB, Achen MG, Stacker SA (2012). VEGF-D promotes tumor metastasis by regulating prostaglandins produced by the collecting lymphatic endothelium. Cancer Cell.21(2):181-95.
Farnsworth RH, Karnezis T, Shayan R, Matsumoto M, Nowell CJ, Achen MG, Stacker SA (2011). A role for bone morphogenetic protein-4 in lymph node vascular remodeling and primary tumor growth. Cancer Res.71(20):6547-57.
The Stacker laboratory provides training opportunities for the following students:
- Undergraduate Research Program (UROP)
- BSc (Hons)