Patient-derived models for breast cancer: a focus on the problems of metastasis and drug resistance
Alana Welm (University of Utah, Salt Lake City, UT, USA)
Yoko DeRose1, Maihi Fujita1, Alana L. Welm1
1 University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA
It is now appreciated that breast cancer patient-derived xenograft (PDX) models represent much of the diversity of human breast tumors, and are good models for tumor progression, drug resistance, and therapeutic response. PDX can be utilized to test new drugs and drug combinations to find therapeutic approaches that match with molecular features of various tumor types.
Material and Methods
The goal of our work is to utilize PDX to better understand pathways contributing to human metastatic breast cancer, and to identify new targets for therapy in advanced stage disease. A particular challenge with breast PDX is propagation and study of estrogen-dependent tumors, which are the most common type of metastatic breast cancer. We tested several conditions for growth of estrogen receptor-positive (ER+) breast PDX. Using optimized conditions, we tested several new therapies for their ability to prevent tumor growth and/or spontaneous metastasis.
Results and Discussion
We optimized conditions for growth of ER+ breast cancer PDX and expanded our collection of ER+ breast tumors. We found that inhibition of RON kinase and PI3K significantly impacts growth of metastatic breast tumors and blocks spontaneous metastasis in the mouse.
Data collected in breast PDX can be used in conjunction with data obtained in genetically-engineered, immunocompetent mouse models to reveal high-priority treatment strategies for future clinical trials in breast cancer patients.
Selected abstract: Optimized Mouse Models of Invasive Lobular Breast Carcinoma
George Sflomos (Federal Institute of Technology Lausanne, Switzerland)
Sflomos George1, Battista Laura1, Valentina Scabia1, Jeitziner Rachel1, Ayyanan Ayyakkannu1, Zaman Khalil2, Fiche Maryse1, Cathrin Brisken1
1 Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
2 Département d’oncologie UNIL-CHUV
Invasive lobular breast carcinoma (ILC) is the second most frequently occurring histological breast cancer subtype and accounts for 15% of all breast cancers. Over 90 % of ILC cases express estrogen receptor (ER) and is hard to detect through conventional diagnostic screenings. Intriguingly, ILC elicits characteristic invasive pattern and widespread metastatic colonization including ovaries, brain, and peritoneum. CDH1 and PIK3CA mutations are the most frequent genetic alterations in ILC. The molecular mechanisms that drive the development, progression and metastasis of ILC are not well characterized due to the lack of in vivo models that recapitulate the disease.
Material and Methods
In this study a recently described mouse intraductal transplantation methodology (MIND model) for ER+ breast cancers is used along with lentiviral technology to characterize and study the in vivo mechanisms of ILC development, progression and metastasis. We established xenografts and patient derived xenografts (PDXs) of ILC originated from diverse primary tumors. Resection specimens were received fresh from surgery.
Animal experiments were performed in accordance with protocols approved by the service de la consommation et des affaires vétérinaires of Canton de Vaud. NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice (NSG) were anesthetized by intraperitoneal injections with 10 mg/kg xylazine and 90 mg/kg ketamine and intraductal injections of single-cell suspensions were performed during the narcosis phase.
Results and Discussion
ILC-MIND xenografts and PDXs faithfully recapitulate the histopathologic and molecular characteristics of clinical ILCs including pagetoid spread, single-cell invasion into the surrounding stroma and the formation of elongated multicellular chains known as indian files. Interestingly, the peculiar metastatic behaviour frequently seen in human ILC metastases including ovaries, brain and peritoneum is well presented in this model. Analysis of global PDX gene-expression changes in ILC-MIND compared with NST-MIND showed that the two subtypes can be distinguished based on their unique transcriptomics profiles. Removal of ovaries to mimic aromatase inhibition had a profound decrease of ILC-MIND growth whereas E2 and P4 had synergistic effect favouring the exponential growth of ILCs. Finally, selective estrogen receptor downregulators efficiently blocked ILC progression and metastases.
In summary, we have successfully established a collection of ILC-MIND PDXs and the biobank is currently being expanded. The new ILC-MIND in vivo model provides a robust tool that resemble clinical ILC and will help to gain insights into the so far understudied ILC.