Andrea Miyahira: Hello, I am Andrea Miyahira on the Prostate Most cancers Basis. Right here with me are Medical doctors Irene Casanova-Salas and Joaquin Mateo from the Vall d’Hebron Institute of Oncology in Spain. They’ll share their latest publication in Most cancers Cell titled “Circulating Tumor Extracellular Vesicles to Monitor Metastatic Prostate Most cancers Genomic and Transcriptomic Evolution.” Thanks each for becoming a member of me at the moment.
Joaquin Mateo: Pleasure to be right here, Andrea.
Irene Casanova-Salas: Thanks, Andrea, for the sort introduction. We’re very glad to share with you the outcomes of our lately printed work, titled “Circulating Tumor Extracellular Vesicles to Monitor Metastatic Prostate Most cancers Genomic and Transcriptomic Evolution.” On this work, we intention to interrogate the molecular options of the tumor via the multi-omic profiling of extracellular vesicles. This class of vesicles is secreted by regular and tumor cells, and they’re key for most cancers cell communication. They’re implicated in a number of most cancers processes, corresponding to tumor metastasis. These extracellular vesicles secreted by tumors are present in excessive numbers in plasma and likewise different fluids corresponding to urine, CSF, or saliva. They’re an attention-grabbing supply of biomarkers as a result of they include a number of molecules as cargo, corresponding to DNA, RNA, proteins, and lipids. Nevertheless, the evaluation of the DNA and RNA compartment of those vesicles has not been broadly explored.
That is what we pursued in our latest examine, the place we carried out genomic and transcriptomic profiling of EV-DNA and EV-RNA in vitro and in vivo fashions of metastatic prostate most cancers and validated the ends in two cohorts of metastatic prostate most cancers sufferers present process systemic remedy with androgen receptor signaling inhibitors (ARSI) or taxane-based chemotherapy. Plasma samples had been collected longitudinally upon therapy, and twin EV-DNA and RNA, in addition to ctDNA extraction, had been carried out. We first characterised the DNA cargo inside these vesicles and located that the DNA inside these vesicles is protected against enzymatic degradation in distinction to ctDNA, and it’s also greater in dimension. We additionally carried out copy quantity profiling within the DNA cargo of those vesicles and confirmed the tumor origin of those vesicles. Moreover, we discovered that the EV-DNA tumor fraction correlated with outcomes in these sufferers.
Along with the genomic evaluation, we had been additionally fascinated about analyzing the RNA compartment in the identical plasma samples. So we developed a novel poly(A)-based seize methodology to research the EV-RNA in these sufferers. We discovered that the transcriptomic profiling of those vesicles exhibits that the teams may be categorized in response to their origin. We are able to see the PBMCs, the wholesome volunteers, or the sufferers relying on the expression of the EV-RNA genes. This truly exhibits that the affected person EV-RNA has a attribute transcriptomic profile, which is characterised by excessive expression of some attribute prostate-specific transcripts. We had been additionally fascinated about understanding if this tumor EV-RNA cargo may very well be related to patient-specific options. Apparently, we discovered that these sufferers that harbor, as an example, AR amplification, which is a key driver gene in metastatic prostate most cancers, additionally had greater expression of EV-RNA AR transcripts.
Equally, we additionally discovered a correlation between TP53 mutation standing and the degrees of TP53 transcripts in EV-RNA. These sufferers that harbor a deleterious mutation in TP53 had decrease expression of EV-RNA as effectively. Lastly, we had been additionally fascinated about learning the function of EV-RNA as a longitudinal response and resistance biomarker. To take action, we studied the adjustments in EV-RNA upon remedy with both androgen receptor signaling inhibitors or taxane-based chemotherapy. We discovered that already at 4 weeks upon therapy, the EV-RNA from sufferers within the ARSI cohort confirmed a downregulation of cell proliferation pathways and androgen signaling pathways, and an enrichment of basal-like and neuroendocrine options. Within the taxanes cohort, we discovered that the sufferers at 4 weeks of therapy had a downregulation of cell proliferation and apoptosis pathways, confirming that EV-RNA can truly seize these very early adjustments induced by the therapy.
Total, with this work, we have seen that EV profiling allows longitudinal interrogation of metastatic prostate most cancers, that the EV-DNA genomic profiling recapitulates tumor options and likewise associates with development, that RESCUE, the tactic we developed for this EV-RNA protein coding evaluation in circulating EVs, permits us to carry out transcriptomic profiling in liquid biopsies, and that EV-RNA additionally signifies early tumor adaptation adjustments throughout remedy in a non-invasive method. With this, I want to thanks for the chance to share our work, and I shall be joyful to reply any questions.
Andrea Miyahira: Thanks a lot for sharing this actually attention-grabbing examine with us. How does EV-DNA examine with ctDNA for predicting tumor burden and prognosis of subtypes corresponding to NEPC?
Irene Casanova-Salas: So I feel I can begin with this one, Joaquin. After we examine straight ctDNA and EV-DNA, we observe kind of the identical sensitivity and specificity for the detection of mutations. Nevertheless, what we expect is extra attention-grabbing about our work is that with the EV compartment, we are able to additionally interrogate the RNA expression, which permits us to carry out a greater affected person stratification and subclassification for several types of tumors, corresponding to neuroendocrine tumors. In an analogous method to what the neighborhood is attempting to do with the methylation patterns in ctDNA, we expect that with the transcriptomic signatures, we might doubtlessly additionally use that for affected person stratification. Thus far, now we have only a few circumstances that had been clearly recognized as neuroendocrine in our cohorts. Nevertheless, we are able to see that these sufferers that had been handled with ARSI ultimately develop these extra neuroendocrine or basal-like options, and we are able to seize that within the EV-RNA.
Andrea Miyahira: Okay, thanks. So what scientific and analysis functions would you anticipate for EVs sooner or later, Dr. Mateo?
Joaquin Mateo: Effectively, I feel the brief reply is we’re nonetheless within the early days of understanding how a lot info we are able to get out of it. Clearly, essentially the most worth that we see right here is the potential of interrogating tumor RNA via a liquid biopsy. We all know that cell-free DNA is a really highly effective software, however cell-free RNA is definitely far more difficult as a result of RNA degrades in circulation. So that is providing us the potential of monitoring RNA profiles in liquid biopsies. And that is crucial as a result of, as we all know, prostate most cancers evolves not essentially via the buildup of mutations however primarily via transcriptomic adjustments. So I feel that this may very well be the beginning of a brand new software that permits us to watch tumor adaptation via liquid biopsies.
Andrea Miyahira: Okay. So thrilling. What recommendation would you give to others hoping to check EVs from most cancers sufferers?
Irene Casanova-Salas: Yeah, I imply, I feel it has loads of potential, and it’ll actually assist us to develop these sorts of multi-omic approaches or composite biomarkers. I feel among the challenges with the EV area is the heterogeneity. So there are several types of EVs and several types of contents. Regular cells may even secrete EVs. So I feel the problem comes with the deconvolution of all that sign. In our work, we have developed some pipelines for cell deconvolution that can enable us to verify the tumor origin. However for certain, it is a area that can want some additional analysis, and we’re focusing a few of our tasks on that angle as effectively.
Andrea Miyahira: Okay. Thanks. And-
Joaquin Mateo: Yeah. If I could add, Andrea, additionally to say that you simply requested, “What recommendation can we give to others?” I imply, there was a studying curve right here, and loads of work was put in by Irene and the staff into the event of the moist lab, but additionally the dry lab a part of it. And we’re very happy to debate with anybody within the area and to ascertain collaborations to push the sector ahead.
Andrea Miyahira: Okay, that is actually fantastic to listen to. And should you might simply give extra particulars on what are your subsequent steps in these research?
Irene Casanova-Salas: So I feel this was a really sort of pilot and pioneer examine within the area of transcriptomic evaluation in liquid biopsies. Our outcomes are very thrilling, however we actually need to validate these in greater cohorts of sufferers and likewise to validate if we see comparable outcomes after we apply them to broader therapy sorts. So I feel that is in all probability the primary purpose that we want to discover. On a separate observe, from the useful perspective, we additionally need to do some work in our PDX platform within the lab to verify the adjustments that we observe in therapy adaptation and the way we are able to higher goal them sooner or later.
Joaquin Mateo: Yeah, I feel that is an vital level as a result of we solely have so many samples from sufferers. So now we have very inflexible time factors, and if we’re learning evolution, we need to actually perceive what’s the impact of the therapy within the early days. So in all probability right here, the PDX fashions are going to assist us to grasp the adjustments upon therapy publicity in a extra exact approach.
Andrea Miyahira: Okay. Effectively, thanks each for approaching at the moment and sharing this actually thrilling examine with us.
Joaquin Mateo: Thanks.
Andrea Miyahira: Thanks.
