{"doi":"10.1101/2021.09.20.460963","title":"Extracellular Vesicles Carry Distinct Proteo-Transcriptomic Signatures That are Different from Their Cancer Cell of Origin","abstract":"Abstract Circulating extracellular vesicles (EVs) contain molecular footprints from their cell of origin and may provide potential non-invasive access for detection, characterization, and monitoring of numerous diseases. Despite their growing promise, the integrated proteo-transcriptomic landscape of EVs and their donor cells remain poorly understood. To assess their cargo, we conducted small RNA sequencing and mass spectrometry (LC-MS/MS) of EVs isolated from in vitro cancer cell culture and prostate cancer patients’ serum. Here, we report that EVs enrich for distinct molecular cargo, and their proteo-transcriptome is predominantly different from their cancer cell of origin, implicating a coordinated disposal and delivery mechanism. We have discovered that EVs package their cargo in a non-random fusion, as their most enriched RNAs and proteins are not the most abundant cargo from their donor cells. We show that EVs enrich for 4 times more cytoskeletal and 2 times extracellular proteins than their donor cells. While the donor cells carry 10 times more mitochondrial and 3 times nuclear proteins than their EVs. EVs predominantly (40-60%) enrich for small RNA (~15-200 nucleotides) molecules that implicate cell differentiation, development, and signaling signatures. Finally, our integrated proteo-transcriptomic analyses reveal that EVs are enriched of RNAs (RNY3, vtRNA, and MIRLET-7) and their complementary proteins (YBX1, IGF2BP2, SRSF1/2), implicating an interrelated mechanism that may protect and regulate transcripts until a biological function is achieved. Based on these results, we envision that the next-generation clinical assays will take an integrative multi-omic (proteomic and transcriptomic) approach for liquid biopsy in numerous diseases.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2021,"id":216123,"datarank":0.3391626625811547,"base_score":1.791759469228055,"endowment":1.791759469228055,"self_citation_contribution":0.26876392038420827,"citation_network_contribution":0.07039874219694643,"self_endowment_contribution":0.26876392038420827,"citer_contribution":0.07039874219694643,"corpus_percentile":null,"corpus_rank":null,"citation_count":5,"citer_count":4,"citers_with_citation_signal":3,"citers_with_endowment":3,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9511,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":566982,"name":"Edgar Gonzalez‐Kozlova","orcid":"0000-0002-6948-0626","position":1,"is_corresponding":false},{"id":811535,"name":"Taliah Soleymani","orcid":"0000-0003-3732-0334","position":2,"is_corresponding":false},{"id":312151,"name":"Sabrina La Salvia","orcid":"0000-0002-2988-137X","position":3,"is_corresponding":false},{"id":264835,"name":"Natasha Kyprianou","orcid":"0000-0002-8713-3599","position":4,"is_corresponding":false},{"id":545863,"name":"Susmita Sahoo","orcid":"0000-0002-7279-1564","position":5,"is_corresponding":false},{"id":72996,"name":"Ashutosh Tewari","orcid":"0000-0002-3146-4524","position":6,"is_corresponding":false},{"id":13006,"name":"Carlos Cordon‐Cardo","orcid":"0000-0003-0858-5624","position":7,"is_corresponding":false},{"id":12562,"name":"Gustavo Stolovitzky","orcid":"0000-0002-9618-2819","position":8,"is_corresponding":false},{"id":264834,"name":"Navneet Dogra","orcid":"0000-0002-4602-3991","position":9,"is_corresponding":false},{"id":811534,"name":"Tzu-Yi Chen","orcid":"0009-0005-9332-709X","position":0,"is_corresponding":true}],"reference_count":33,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-18T23:53:00.192353Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}