Targeting Breast Cancer Stemness through Manipulation of IL

Stem cell programs contribute to the initiation and growth of various tumor entities, including breast cancer. Hence, manipulation of such programs is an attractive therapeutic concept holding the potential to cure cancer. However, as tumor stemness is also linked to drug resistance, direct targeting approaches are less expedient, providing the rationale for innovative strategies of stemness-directed treatment, for instance via non-transformed cell types of the tumor stroma. In this research project, specialized models of breast cancer will be used to investigate the significance of defined stromal cell populations for tumor stemness and growth. The proposed research is based on the hypotheses that (i) stemness of breast cancer cells is enhanced by specific cell types of the tumor stroma and that (ii) manipulation of these cells can impinge on breast cancer cells, thereby leading to tumor regression. Experimentally, the study will make use of specific mouse models susceptible to toxin-mediated elimination of tumor fibroblasts, in which the impact of cell ablation on breast cancer stemness will be determined using different cell- and molecular-biological readouts. Furthermore, the particular properties of tumor fibroblasts will be characterized so as to identify novel potential targets for breast cancer treatment. The proposed research is expected to reveal (i) whether and to which extent breast cancer growth depends on tumor fibroblasts and (ii) whether specific factors in these cells can be utilized to interfere with breast tumor stemness. Positive results will open new avenues for breast cancer treatment and will ultimately contribute to improved clinical management of this life-threatening disease.

Cancer-associated fibroblasts are key components of the tumor microenvironment and foster tumor growth based on different mechanisms. In this Erwin Schrödinger Fellowship-funded study, it was shown that a specific population of cancer-associated fibroblasts promotes the progression of breast cancer, thus serving as a potential target for novel cancer therapies. These connective tissue cells produce a plurality of tumor-promoting growth factors and further constitute a niche for the so-called cancer stem cells, which are implicated in metastasis and relapse. Employing various cell- and molecular-biological techniques, it was shown that the tumor-promoting effects of the fibroblasts were elicited by a specific secretory molecule whose receptor is targetable with a pharmacological compound already in clinical use. The study paves the way for the development of innovative cancer therapies targeting the supporting microenvironment, rather than the tumor cells themselves. The ultimate goal is to eliminate cancer stem cells in long-term through a niche deprivation effect. Realization of such therapeutic concepts should largely prevent metastatic progression and disease recurrence, thus significantly improving the prognosis of breast cancer and other tumor types.