Project Funding Details
- Title
- Fighting inflammation in multiple myeloma: amyloid aggregation a new molecular target
- Alt. Award Code
- 2025-30307-17045
- Funding Organization
- Fondazione AIRC
- Budget Dates
- 2025-01-02 to 2026-04-01
- Principal Investigator
-
Ricagno, Stefano
0000000166785873
(ORCiD iD) - Institution
- Università degli Studi di Milano (University of Milan)
- Region
- Europe & Central Asia
- Location
- Milano, IT
Collaborators
View People MapThis project funding has either no collaborators or the information is not available.
Technical Abstract
Multiple myeloma (MM) is a B-cell neoplasm characterized by infiltration and expansion of malignant plasma cells in the bone marrow. In the aging European population, the incidence of MM is expected to rise, especially since 70% of MM patients are over 65 years old. Advances in therapy have significantly improved overall survival. However, the response of MM cells to drug treatment is often weakened by the presence of bone marrow stromal cells and, specifically, of tumour-associated macrophages (TAMs). We have recently shown that the secretion of pro-inflammatory cytokines sustaining tumour survival and progression is caused by NLRP3 inflammasome activation, which is in turn caused by b2m amyloid aggregation in lysosomes of TAMs. Our data from cell cultures, samples from MM patients, and a MM mouse model strongly support the pivotal role of b2m as a macrophagic NLRP3 inflammasome activator and its contribution to MM progression. The inflammation mediated by b2m aggregation strongly correlates with the levels of pro-inflammatory cytokines in MM patients, facilitating MM progression. Blocking this process is likely to make MM cells more susceptible to cytotoxic treatments. The molecular mechanisms underlying b2m-mediated inflammation in TAMs remain unclear, and no strategies are available to inhibit this process. To address these issues, BAg-MM has three integrated aims: 1) Elucidate the molecular events that occur following b2m internalisation in macrophages, resulting in the secretion of pro-inflammatory cytokines. 2) Characterise the molecular species and the architecture of b2m deposits in macrophagic lysosomes. 3) Identify specific b2m binders that can prevent b2m-mediated pro-inflammatory response in macrophages. BAg-MM is divided into three integrated aims with different experimental approaches. Fist we will investigate the cellular events following b2m phagocytosis in M2 macrophages. We will characterise b2m internalisation, aggregation, lysosomal damage, inflammasome activation and IL-1b/-18 secretion. In the second aim, a proteomic approach will clarify the lysosomal content of TAMs from MM patients. In parallel, by combining confocal microscopy and FT-IR spectroscopy we will study lysosomal membrane modifications and characterize in situ b2m aggregates in macrophages and TAMs. Finally, aim 3 will identify specific inhibitors of lysosomal b2m aggregation which will be benchmarked in vitro, in cellular and in in vivo models. BAg-MM will provide a detailed understanding of the molecular events triggered by the b2m aggregation in macrophages and the consequent release of pro-inflammatory cytokines. BAg-MM will also deliver the characterisation of b2m aggregates in lysosomes and of the damage to lysosomal membranes. Finally, b2m binders interfering with IL-1b/-18 secretion mediated by macrophages will be identified. Inflammation plays a crucial role in the onset and progression of tumours. It was recently demonstrated that b2m aggregation promotes inflammation in the MM environment by inducing the secretion of IL-1b/-18 from TAMs. BAg-MM will deliver a detailed understanding of the cross-talk between b2m amyloid aggregation and IL-1b/-18-mediated inflammation. Moreover, it will identify specific b2m binders that may reduce b2m-derived inflammation. In other words, Bag-MM will provide all the molecular understanding and hit molecules necessary to develop efficient strategies to counteract this pathological process supporting MM resilience against chemotherapies.
Cancer Types
- Myeloma
Common Scientific Outline (CSO) Research Areas
- 5.3 Treatment Systemic Therapies - Discovery and Development
- 4.1 Early Detection, Diagnosis, and Prognosis Technology Development and/or Marker Discovery