Project Funding Details

Over one billion individuals worldwide are affected by obesity, which is associated with a higher risk of several illnesses, including breast cancer (BC). In the presence of abundant adipose tissue (AT), breast gland undergoes multiple changes, characterized by chronic inflammation and oxidative stress, which are essential for the dynamic crosstalk between cancer and tumor microenvironment (TME) cells in BC progression. It has become increasingly clear that a subpopulation of neoplastic cells, termed cancer stem cells (CSCs), is responsible for recurrence, relapse, metastatic spread, and resistance to anti-cancer therapies. It has been demonstrated that CSCs benefit from: i) the presence of a dysfunctional microenvironment responsible for pro-inflammatory factor production; ii) induction of DNA damage and repair mechanisms; iii) immune cells recruitment, including macrophages; iv) metabolism rewiring and v) aberrant survival pathways' activation. Based on these preambles, understanding how AT cell components interact with breast CSCs (BCSCs) could lead to the identification of druggable biomarkers for advanced BC treatment. Of note, we observed that adipose stromal cells (ASCs), isolated from the AT of BC obese patients, enhance the proliferation, and boost the activation of chemotactic signals in BCSCs. In particular, ASCs prime the switch of infiltrating macrophages into M2-like cells, which are the prevalent immune subpopulation in the TME of obese BC patients. This proinflammatory microenvironment promotes DNA damage with a concomitant high proliferative index. Thus, we sought to determine whether pro-inflammatory stimuli could strengthen the dynamic interplay between BCSCs and TME components, contributing to aggressiveness in BCSCs. The development of ground-breaking treatments, based on the use of natural products with anti-inflammatory effects, could have a direct impact on sensitizing CSCs to standard therapeutic approaches. 1. Dissecting the dynamic interplay between BCSCs and ASCs 2. Explore the pro-inflammatory role of AT in the recruitment of macrophages in BC 3. Define the contribution of TME in the induction of DNA damage in BC 4. Evaluating effective therapeutic combinations using innovative tools Taking advantage of our collection of BCSCs and ASCs isolated from obese BC patients, we will investigate metabolic as well as transcriptomic changes occurring in tumor progression. We will perform spatial transcriptomic analysis to investigate the interaction between cancer cells and the infiltrating AT in xenograft-tumors generated by BCSCs, ASCs, and macrophages injection, and in matching BC obese patient specimens. 3D bioprinting of BCSCs and TME components will be exploited to test the combinatorial efficacy of natural compounds, endowed with anti-inflammatory properties, and currently available drugs interfering with DNA repair machinery. We expect to uncover the molecular mechanisms shaped by the evolving TME during BC progression. Cutting-edge technologies and 3D printing physio-mimetic models will enable the identification of therapeutic response predictive biomarkers and the design of more effective tailored treatments in advanced BC. Considering that obesity is a major hurdle worldwide, strictly associated with BC risk and progression, it is crucial to unveil pro-tumoral signals promoted by the inflammatory state dictated by AT. The combination of natural products with current standard therapies may accelerate bench-to-bedside processes.