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PO-220 Defining the role of heparanase in breast cancer progression using the PyMT-MMTV mouse model

Introduction Heparanase (HPSE) is a beta-d-endoglucuronidase and the only mammalian enzyme that cleaves heparan sulphate (HS), a major structural and regulatory component of the extracellular matrix (ECM) and the vascular basement membrane (BM). The expression of HPSE is tightly controlled and under physiological conditions is limited to immune cells, endothelial cells, placental trophoblasts and keratinocytes. However, during pathological conditions such as cancer, HPSE expression is dysregulated and high expression often correlates with poor patient survival. The cleavage of HS by HPSE expressing tumours degrades the ECM/BM and releases HS bound growth factors and cytokines, promoting cellular signalling in a positive feed-back mechanism. This in turn leads to enhanced primary tumour growth, metastasis, angiogenesis and inflammation. HPSE is therefore a critical promoter of the hallmarks of cancer and has generated significant interest as an anti-cancer drug target. However, despite decades of research, the precise mechanistic role of HPSE in the tumour microenvironment remains poorly defined. Breast cancer is the most prevalent malignancy in women worldwide. Clinical data reveals that the expression of HPSE in mammary tumours results in poor patient survival. Material and methods We recently generated a HPSE-deficient C57Bl/6 mouse strain (C57Bl/6xHPSE-/-) that were crossed with spontaneous mammary tumour developing PyMT-MMTV mice to generate the PyMT-MMTVxHPSE-/- strain, providing us with a valuable in vivo model to characterise the role of HPSE in early mammary tumour development, tumour progression and metastasis. Results and discussions Our data indicate that although HPSE promoted tumour angiogenesis, overall tumour development and metastasis between PyMT-MMTV and PyMT-MMTVxHPSE-/- mice remained comparable. By examination of the tumour microenvironment, we also demonstrate that the tumour stroma positively contributes to mammary tumour HPSE activity, promoting tumour angiogenesis. In contrast, HPSE expressed in the tumour-bearing host appeared to play no significant role in tumour growth and metastasis. These data suggest that in the PyMT-MMTV model and indeed, in certain cancer settings such as breast cancer, HPSE may not play as significant a role to what has been proposed over the last two decades. Conclusion These findings may have important implications for the ongoing development and application of HPSE inhibitors in the treatment of cancer.

Introduction Heparanase (HPSE) is a beta-d-endoglucuronidase and the only mammalian enzyme that cleaves heparan sulphate (HS), a major structural and regulatory component of the extracellular matrix (ECM) and the vascular basement membrane (BM). The expression of HPSE is tightly controlled and under physiological conditions is limited to immune cells, endothelial cells, placental trophoblasts and keratinocytes. However, during pathological conditions such as cancer, HPSE expression is dysregulated and high expression often correlates with poor patient survival. The cleavage of HS by HPSE expressing tumours degrades the ECM/BM and releases HS bound growth factors and cytokines, promoting cellular signalling in a positive feed-back mechanism. This in turn leads to enhanced primary tumour growth, metastasis, angiogenesis and inflammation. HPSE is therefore a critical promoter of the hallmarks of cancer and has generated significant interest as an anti-cancer drug target. However, despite decades of research, the precise mechanistic role of HPSE in the tumour microenvironment remains poorly defined. Breast cancer is the most prevalent malignancy in women worldwide. Clinical data reveals that the expression of HPSE in mammary tumours results in poor patient survival. Material and methods We recently generated a HPSE-deficient C57Bl/6 mouse strain (C57Bl/6xHPSE -/-) that were crossed with spontaneous mammary tumour developing PyMT-MMTV mice to generate the PyMT-MMTVxHPSE -/strain, providing us with a valuable in vivo model to characterise the role of HPSE in early mammary tumour development, tumour progression and metastasis.
Results and discussions Our data indicate that although HPSE promoted tumour angiogenesis, overall tumour development and metastasis between PyMT-MMTV and PyMT-MMTVxHPSE -/mice remained comparable. By examination of the tumour microenvironment, we also demonstrate that the tumour stroma positively contributes to mammary tumour HPSE activity, promoting tumour angiogenesis. In contrast, HPSE expressed in the tumour-bearing host appeared to play no significant role in tumour growth and metastasis. These data suggest that in the PyMT-MMTV model and indeed, in certain cancer settings such as breast cancer, HPSE may not play as significant a role to what has been proposed over the last two decades. Conclusion These findings may have important implications for the ongoing development and application of HPSE inhibitors in the treatment of cancer.

MOUSE MODELS OF LUNG SQUAMOUS CELL CARCINOMA FOR PRECLINICAL INTERVENTION STUDIES
1 G Ferone*, 2 JY Song, 3 K Sutherland, 1 R Bhaskaran, 1 J Van Der Vliet, 1 M Cozijnsen, Introduction Lung squamous cell carcinoma (LSCC) is a lethal disease accounting for 30% of all lung cancer cases. Currently, there are no effective treatments: patients are treated with a combination of surgery, chemotherapy and radiotherapy. So far numerous high-throughput screenings have been carried out in order to identify the representative mutations of this tumour. Their contribution is precious but remains descriptive. Material and methods Mice were engineered by using Flp-Recombinase mediated cassette exchange technology in ES cells. Mutations were activated by Intratracheal injection of adenoviruses carrying Cre recombinase under different promoters.
Genome profiling and histological analysis were performed on lung isolated from mice that showed signs of distress due to tumour development. Results and discussions We published that mice carrying SOX2 over-expression combined with PTEN and CDKN2AB loss (hereafter SOX2PC) developed central and peripheral LSCC according to the targeted cell-of-origin, fully mimicking the human counterpart.
To examine gene contribution, we uncoupled the inactivation of tumour suppressor genes and found that mice defective either of PTEN or CDKN2AB in combination with SOX2 over-expression, only showed epithelial hyperplasia, indicating that the combination is necessary for the tumour to progress.
In order to use SOX2PC autochthonous model for intervention studies, we attempted at reducing tumour latency by combining other oncogenes with SOX2 over-expression. Our data pointed at FGFR1 and NFE2L2 as candidate drivers of human LSCC. Surprisingly, FGFR1-SOX2PC mice were resistant to tumour formation, indicating that FGFR1 downstream pathways may be detrimental to squamous differentiation. However, NFE2L2, a transcription factor involved in the antioxidant pathway and found altered in 12% of human LSCC Abstracts ESMO Open 2018;3(Suppl 2):A1-A463 A313