Endocrine Control Mechanisms Group

Fluorescence stereograph of a mouse mammary gland 3 months after it was injected with human breast carcinoma cells. The mouse milk ducts are shown in green, the human tumor cells that colonize the mouse ducts are labelled in red. Credit: Patrick Aouad

Breast cancer is the most frequently diagnosed cancer worldwide. More than two thirds of all breast cancers are hormone-sensitive, they express the estrogen receptor and frequently the progesterone and the androgen receptor. They are typically slow growing and respond to endocrine therapy.

Progress in our understanding of the role of hormones and the development of hormone-sensitive tumors in a broader tissue context and under physiologically and clinically-relevant conditions has been hampered by the lack of models.

My group has recently overcome this hurdle and developed experimental approaches that allow us to study normal breast epithelial cells and hormone-sensitive breast cancer cells of different histological subtypes in a complex in vivo context. We achieve this by providing tumor cells with a physiological microenvironment by grafting then into the milk ducts (MIND) instead of injecting them into the subcutaneous fat.

Patient-derived tumor models; xenografts and organoids

The MIND modelling allows not only to grow hormone-sensitive breast cancer cell lines and patient-derived tumor cells with unprecedented engraftment rates but also to study critical stages of disease progression, including metastasis, in clinically-relevant endocrine conditions.

The In Vivo Modelling Group aims to establish a panel of intraductal xenograft models that reflects the clinical complexity of the disease both in terms of tumour subtypes and patient genetic ancestry. It promotes and supports the use of MIND models for preclinical and translational studies and seeks to develop them into tools for co-clinical trials and precision medicine. Through combined efforts with the Patient-Derived Organoids Group we seek to improve on existing approaches in drug discovery.

3D reconstruction of the human breast. In red cytokeratin 7 and in green smooth muscle antigen. Credit: Patrick Aouad

Lobular Carcinoma of the Breast

10 to 15% of breast cancers are of a special pathological type called lobular carcinoma. Lobular carcinomas are typically slow growing, very sensitive to hormones and have a high risk of late recurrence and a unique metastatic pattern. They tend not to respond well to standard therapies. Progress in our understanding of this particular type of breast cancer has been hampered by the lack of models to study it.

We have recently shown that lobular breast cancer cells either from cell lines or from patient tumors when grafted directly to the milk ducts of immunocompromised female mice, grow, invade, and metastasize in a similar way as they do in patients.

Molecular analysis of purified lobular carcinoma cells from intraductal xenografts revealed that these tumor cells actively secrete and modulate extracellular matrix.

Blocking the secreted enzyme, LOXL1 that is critical for this modulation interferes with tumor growth and progression (Sflomos G et al, EMBO Mol Med. 2021).

We will test whether this tumor cell-derived matrix provides a vulnerability that can be exploited therapeutically.

The intraductal (MIND) system reveals lobular carcinoma-specific biology and vulnerabilities. Adapted from Kozma et al. 

New Patient-Derived In Vivo Models

In close collaboration with clinical partners we aim to establish a panel of patient-derived MIND models that reflects the clinical complexity of the disease both in terms of tumour subtypes and patient genetic ancestry.

Workflow of the MIND patient-derived model establishment. Courtesy Valentina Scabia.

Resources

• Professor Brisken's laboratory at EPFL
• Preclinical Models course
• ITN PhD training network in cancer prevention (coordinated by Professor Brisken)

References

Sflomos, G., Battista, L., Aouad, P., DeMartino, F., Scabia, V., Ayyanan, A., Ifticene-Treboux, A, RLS, Bucher, P., Ambrosini, G., Fiche, M.,, Brisken, C. Intraductal Xenografts Model Lobular Carcinoma of the Breast and Reveal Matrix Remodeling by LOXL1 as a Targetable Hallmark. EMBO Mol Med. 2021.

Previewed: Kozma KJ, Done SJ, Egan SE. The tumor cell-derived matrix of lobular breast cancer: a new vulnerability. EMBO Mol Med. (2021)

Koch, C, .Kuske, A., Josse, S.A., Yigit, G., Sflomos, G., Thaler, S., Smit, D.J., Werner, S., Borgmann, K., Gärtner, S., Mohammadi, P.M., Battista, L., Cayrefourcq ,L., Altmüller, J., Salinas-Riester, G., Raithatha, K., Zibat, A., Goy, Y., Ott, L., Bartkowiak, K., Tan, Z. T., Speicher, M.R., Müller, V., Jücker, M., Thiery, J.P., Brisken, C.*, Riethdorf, S.*, Alix-Panabières, C*., Pantel, K.  Characterization of circulating breast cancer cells with tumorigenic and metastatic capacity *equal contribution. EMBO Mol Med. (2021) Sep 7;12(9):e11908.

Cartaxo, AL., Estrada, M., Domenici, G., Roque, R., Silva, F., Gualda, EJ., Loza-Alvarez, P., Sflomos, G., and Brisken, C. , Alves, PM., André, S., Brito, C. A novel culture method that sustains ERα signaling in human breast cancer tissue microstructures. J Exp Clin Cancer Res 2020 Aug 17;39(1):161.

Siersbæk, R., Scabia, V., Chernukhin, I., Papachristou, E., Broome, R., Green, A., Joosten, S., Kumar, S., Alvarez, R., Nagarajan, S., Glont, S., Omarjee S., Aitken, S., Kishore,K., Rakha, E., D’Santos, C., Zwart, W., Russell, A., Brisken, C, Carroll, J. IL6/STAT3 co-opts ER regulatory elements to drive metastasis in breast cancer. Cancer Cell. 2020 Jul 6:S1535-6108(20)30311-1.

Laszlo, C. F., De Martino, F., Montoya, J. P., Shamseddin, M., Beguin, A., Nellen, R., Bruce, S., Moniatte, M., Henry, H., and Brisken, C. A high resolution LC-MS targeted method for the concomitant analysis of 11 contraceptive progestins and 4 steroids. J Pharm Biomed Anal. 2019 Oct 25;175:112756.

Vincent, GP., Nacht, AS, Ferrari, R., Zaurin, R., Scabia, V., Carbonell, J., Le Dily, F., Quilez, J., Leopoldi, A., Brisken, C, Beato, M. C/EBPα mediates the growth inhibitory effect of progestins on breast cancer cells. EMBO J. 2019 Sep 16;38(18):e101426.

Fiche, M., Scabia, V., Aouad, P., Battista, L., Treboux, A., Stravodimou, A., Zaman, K., RLS, Ayyanan, A., Sflomos, G., and Brisken, C. Intraductal patient derived xenografts of ER+ breast cancer recapitulate the histopathological spectrum and metastatic potential of human lesions. J Pathol. 2019 Mar;247(3):287-292.

Sflomos, G., Dormoy, V., T. Metsalu, T., Jeitziner, R., Battista, L., Scabia, V., Raffoul, W., Delaloye, J.-F., Treboux, A., Vilo,J., Fiche, M., Ayyanan, A., Brisken C. (2016) A robust preclinical model for ERα positive breast cancer points to the mammary epithelial microenvironment as critical determinant of luminal phenotype and hormone response. Cancer Cell, 2016 Mar 14; 29(3):407-422.

Previewed: Haricharan S, Lei J, Ellis M. Mammary Ductal Environment Is Necessary for Faithful Maintenance of Estrogen Signaling in ER(+) Breast Cancer. Cancer Cell. 2016 14;29(3):249-50.

Featured in: Research Watch: Bledsoe, K. Milk Duct Engraftment Allows Preclinical Modeling of ER+ Breast Cancer Milk Duct Engraftment Allows Preclinical Modeling of ER+ Breast Cancer. Cancer Discovery. 2016