Characterization of the mutually interaction between adipose-derived mesenchymal stem/stromal cells and breast cancer cells in obesity: Functional impact on tumor development and metastasis in vivo

• Applicant: Dr. Andreas Ritter
• Subject Area: Gynaecology and Obstetrics ; Cell Biology
• Term: since 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 413992926

The dramatic increase in the prevalence of obesity poses a grave challenge worldwide and obesity is associated with progression of multiple malignancies including breast cancer. Further, breast cancer is the most frequently diagnosed cancer and a common cause of cancer-related death in women. It is well recognized that obesity, predominantly in postmenopausal woman, is tightly associated with an enhanced risk of more aggressive breast cancer as well as reduced patient survival. Breast adipose tissue-derived mesenchymal stromal/stem cells (bASCs) are key components of the tumor microenvironment and fuel the tumor progression. A key step initially involved in this process might be the de-differentiation of bASCs into a tumor supporting phenotype. In the first grant period, we isolated bASCs from adipose tissues adjacent to the tumor (aT bASCs) from lean- (ln-aT bASCs, BMI <= 25) and obese breast cancer patients (ob-aT bASCs, BMI >=35), and found that ln-aT bASCs are susceptible to be transformed into an inflammatory cancer-associated phenotype, whereas ob-aT bASCs are prone to be cancer-educated into a myofibroblastic phenotype. Both ln-aT- and ob-aT bASCs compromise their physiological adipo-, osteo- and chondrogenic differentiation capacity, and upregulate metastasis-promoting factors such as CC-chemokine-ligand 2, C-X-C motif ligand 1-3 and interleukin 6. While ln-aT bASCs, but not their distant counterparts, stimulate proliferation, motility and chemoresistance towards tamoxifen and docetaxel by inducing epithelial-mesenchymal transition of low malignant BT474 and MCF7 breast cancer cells, ob-aT bASCs trigger more efficiently a cancer stem cell phenotype in highly malignant MDA-MB-231 cells. In this follow-up proposal we want to achieve the following goals: 1st verifying the distinct cancer-educated phenotypes by single cell sequencing (scRNA seq) in isolated bASCs and patient derived mammary adipose tissue. 2nd an in-depth functional characterization of iCAF-/myCAF-like bASCs sorted by FACS concerning monocytes/macrophages polarization, BC organoid migration, invasion, proliferation, and chemoresistance. 3rd exploring the function of both subgroups on an orthotopic firefly luciferase xenograft breast organoid tumor mouse model followed by isolation of the xenograft derived breast cancer cells and RNA seq analyses. 4th we plan to do molecular intervention studies on key signaling proteins found in the xenograft RNA seq data in comparison to the results obtained in the first grant period on breast cancer organoids and analyzes of key proteins in a comprehensive breast cancer tissue cohort (300 breast cancer tissue samples). Taken together, we hypothesis that the functional and genetical alterations in obese bASCs have a significant impact on the breast cancer development and progression. Therefore, it is of utmost importance to understand their role in the TME on a molecular level and to study molecular intervention targets.

• DFG Programme: Research Grants