for the opportunity to share our results uh presented the last as annual conference about the role of urging deprivation in macro environment to make multiple myeloma resistance to produce a minimation by metabolic rewiring as several groups showed clearly address this year the progression of multiple myeloma is not only a genomic event related to the selection of progressive Colonel that progressively acquire genomic events but also it's Associated to changes occur in the macro environment duri
ng a very important interplay between classic plasma cells and environment cells in this context we um we are working on those soluble factors that can change the interplay between myeloma cells and the environment in particular we discovered that several amino acids and one in particular arginine is progressively reduced in smoldering versus newly Diane is it versus reduction refactor in my lunar patients in the bone marrow and peripheral blood what is very important in this can occur if the bo
ne marrow where are several cells can I mean are required to live together and these cells are basically the myeloid suppressor there are cells the high density neutrophils which produce a lot amount of arginase which is the enzyme devoted into degradation of arginine um and T cells that should fight against myeloma cells recognizing them as new plastic ones but these cells are not able to synthetize or to produce Arginine on their own cells so for these reasons they cannot be properly activated
do some changes occur in the at the level of T cell receptors so basically our group really showed in the past that in the myeloma macro environment we have a very special situations for I mean devoting to reduce the amount of Virgin but with without the consequence of arginine low levels in the Boomer environment so or myeloma cells what we found very surprisingly is that the availability of extracellular arginine is not detrimental for maloma survival and immunoglobal in secretion so it means
that even if one amino acid is missing myeloma cells are not worried about that and can continue to do their job that means secreting the bad monoclonal component and proliferative and even the proliferation there are some little changes because we can have um a delay in the cell cycle progression but basically melanoma cells are alive just to be sure about that with just two to try to understand the molecular Machinery the molecular mechanism of myeloma adaptation surprisingly we found that th
ere's no relating to autophagy induction is not relating to these interactivations which which are the responses that usually other cells use to respond to uh men to to large in deprivation what we found is a new pathway which is called the information is not so different from ubiquitination or probably we are more familiar to the cutenation which is the um main target of protein inhibition and protagonal course and what we found is that basically myeloma cells prefer to recycle the ribosomes wh
ich are the organelles that are devoted to the synthesis of new RNA and this is very smart to do because the kernel cure entirely time points and consuming just a few energy a few HP molecules so it's very smart other than energetic point of view and this is because during other interpretation myeloma cells try to convey versus the low energy metabolic party which means to stop to use glycolysis stop to use mitochondria try to um save 80 bit like when you have a lot of them so you try to save mo
ney for what can happen in the future it is exactly what myeloma cells do and this is very important because it can convey a special adaptation pathway when you maintain in culture these cells for more than 10 days we learn amount of arginine what we found is the application of inflammosome Machinery which can be a chronic inflammation that means melanoma cells don't die but they produce tons of a better looking six cents are looking 18 and One beta that are required to continue to change the en
vironment to support themselves and this is very important because it's Associated also to the the very important very dangerous attempt to rearrange the DNA because um genomic instability can be acquired at that point to manage the high levels of reactive oxygen species and oxidative stress conveying DNA damage DNA liquid and formation of micronuclei identity in the past and again we saw to be connected to resistance to both bortez so to wrap up what we showed is that basically Argent deprivati
on can induce a low energy metabolic State poison myeloma cells interfunctional question State at the same time this can convey the negative DNA damage can further support the selection of new clothes that are resistant to protozo Inhibitors and at the same time this can induce the activation of inflammosomes promoting cytokine release that in turn can further affect the micro environment composition and signals for the other cells the implications of our work are pretty important not only to un
derstand new Pathways that could be potentially triggered to overcome Protestant I mean resistance to Protestant Inhibitors but it's really important also to use a Target Arginine to identify those niches in which it's easier to accumulate DNA damage that is very important for us to prevent or at least to identify those patients that can carry on a DNA damage with the risk of developing uh subliminal events So based on that please let me thank all people in my lab that are working to uh I mean i
n this field and let me thank International malama Foundation for their support um to go ahead with this video research thanks a lot all of you for your things [Music]
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