IMW 2021 | Proteomics in myeloma: mass spectrometry and novel approaches

So at the IMW meeting, I’m very happy to talk about the state of proteomics in myeloma. So, this concept that, essentially it’s a technology that you can use to look at many different proteins within the cell, which really are, again, those fundamental building blocks of cells, tumor cells in myeloma, but all biology.

And so, there’s really one major technique that’s made a ton of headway over the past 20 years, and that’s using an instrument called mass spectrometry. This has allowed us to monitor changes in thousands of proteins within a cell simultaneously, not just looking at their changes in abundance, basically how much of the protein, but looking specifically at their dynamics, thinking about synthesis, degradation, where they localize within the cells, what are the changes on proteins, post-translational modifications. All of these can really drive biology and it’s really invisible to any other techniques, and in particular, we can’t see these important biological changes looking at just a DNA or RNA, which are the more common, and what we call omic or cellular profiling techniques that are out there. So, this is one of the reasons that my lab does a lot of mass spec-based proteomics, is that we think it really is quite powerful for exploring myeloma biology.

And so within that, really over the past, again, few years, we’ve really seen really impactful findings in proteomics, basically trying to look at what we’ve looked at in our lab, drug resistance, other groups looking at mechanisms of drug action, looking at the interaction landscape, looking at how, basically, important proteins that drive myeloma oncogenesis interact with other proteins in the cells, and so this can reveal potential new therapeutic targets, new biology that helps us understand the disease better.

But one drawback of mass spec-based proteomics is that historically it has needed a fair amount of sample input to do any experiments using it. And so there actually has not been a lot done on profiling primary myeloma tumors, and so this is where we’re kind of seeing a few other techniques coming to the fore that I think are going to be much more promising to look at many proteins in myeloma tumor cells and primary samples. These are referred to as proteomic techniques. The big difference is they’re all dependent on antibodies, and so they can only profile, maybe, maximum 40, 50 proteins or protein targets at once. So, it’s very different than mass spectrometry-based proteomics where you can look at, again, several thousand proteins in the same sample. Here, you’re much more limited, much more targeted, but these new approaches do have the advantage of looking at single cells and mass spectrometry is much more bulk measurement. And so by looking at single cells, we can get much richer information, but for a smaller set of protein targets. But again, these are still considered proteomics.

One of the main ones that’s out there is called mass cytometry, or CyTOF. Essentially, it’s a very highly multiplexed flow cytometry approach that’s really had some interesting studies published already in myeloma and more are coming. And basically, I think it’s going to be incredibly important for looking at immune microenvironment alterations in myeloma. And then other ones we can combine antibody-based DNA barcoding with single-cell RNA seq, and many groups are already applying this, and then we have other approaches using so-called spatial proteomics. I haven’t seen this applied to yet so much in myeloma, but it’s really coming up in other tumor types, where we can look at, say, primary patient bone marrow biopsies, and looking at their relationship of myeloma plasma cells to other bone marrow microenvironment cells, that are immune or non-immune cells. And so, I think this is going to be a powerful protein-based multiplex platform for looking at this. And then there are other powerful biomarker discovery tools that are out there too, that are yet to be applied widely in myeloma, but I think really are advancing in their capabilities.

So, overall, I think that that’s what I’m going to talk about in terms of the current state of proteomics in myeloma. I think the future is bright and there’s many places that we can apply these technologies, either for biological discovery or applying to the patient samples.