Interplay between Multiple Myeloma and mesenchymal stromal cells: insights into cellular traits related to dormancy, senescence and drug response

Multiple myeloma (MM) is a malignancy of terminally differentiated plasma cells which clonally expand in the bone marrow (BM). Mesenchymal stromal cells (MSCs) are prominent residents of the BM. MSCs from MM patients (MM-MSCs) exhibit functional and phenotypical alterations, related to MM-supportive behavior. MM-MSCs show traits of senescence, correlated to a pro-inflammatory secretory phenotype, characterized by an overproduction of factors essential for MM survival. Moreover, senescence in cancer cells occurs due to oncogene overactivation or as a result of treatment. Treated senescent cancer cells are in a continuous state of cell cycle arrest, during which they acquire traits of self-renewal and increased drug resistance. Since almost all MM patients relapse due to residual, drug resistant cells, the identification of dormant MM cells is essential for the improvement of current therapeutic approaches. This study investigated MM and MSCs interactions and bortezomib (BTZ) treatment. MSCs brought upon distinct, cell line dependent changes in MM cell proliferation, observed via expression of Ki67, p16 and p53. MSCs exhibited a MM-protective role, as effects seen in MM1.S cells on Ki67 expression and metabolic traits upon BTZ treatment seemed to be reverted when MSCs were present. BTZ caused an increase in the activity of senescence-associated β-galactosidase in both cell types, but no other senescent traits were detected. MSCs co-cultured with MM cells presented an altered cell cycle and dampened proliferation. When co-cultured MSCs were additionally treated with BTZ, a decrease in Ki67 expression was observed, contradictory to division rates and clonogenic results. The examination of MM cells drug response in a three-dimensional collagen culture system revealed a decreased response to BTZ, compared to standard two-dimensional cell culture, implying the importance of BM components in MM drug response. In conclusion, this study demonstrated a reciprocal impact MM cells and MSCs have on each other, in terms of proliferation, metabolism and drug response. The results presented in this thesis highlight the importance of investigating MM cells close to their original BM context, with the stomal, cellular component or with the addition of BM extracellular elements such as collagen.