{"doi":"10.1101/2023.12.02.569652","title":"The chemotherapy-induced senescence-associated secretome promotes cell detachment and metastatic dissemination through metabolic reprogramming","abstract":"ABSTRACT Cellular senescence, characterized by a stable cell cycle arrest, is a well-documented consequence of several widely used chemotherapeutics that has context-dependent roles in cancer. Although senescent cells are non-proliferative, they remain biologically active and secrete a complex and diverse array of factors collectively known as the se-nescence-associated secretome (SAS), which exerts pro-tumorigenic effects. Here, we aimed to mechanistically investigate how the SAS contributes to metastatic dissemination of high grade serous ovarian cancer (HGSOC) using standard-of-care cisplatin as a se-nescence inducer. Our findings demonstrate that the cisplatin-induced SAS enhances the dissemination of HGSOC in vivo without affecting cell proliferation or viability. We found that the SAS facilitates cell detachment, an effect that is mediated by a metabolic com-ponent. Using a metabolically focused CRISPR knockout screen, we identified complex I as the key driver of SAS-mediated cell detachment in bystander cells and validated that inhibition of complex I activity decreases HGSOC dissemination in vivo . Mechanistically, this effect was driven by SAS-mediated inhibition of an NAD + -SIRT-SREBP axis, leading to decreased plasma membrane cholesterol that increased cell detachment. Excitingly, we found that fructose is the key SAS component upstream of the NAD + -SIRT-SREBP-cholesterol axis mediating increased detachment of bystander cells, and a high fructose diet increases HGSOC dissemination in vivo . These findings reveal that the cisplatin-induced SAS reprograms the metabolic microenvironment in HGSOC, driving cancer cell detachment and promoting metastatic dissemination in a paracrine fashion. They also point to a previously unrecognized pro-tumorigenic effect of the SAS that may contribute to the high recurrence rate of HGSOC patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":401793,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9528,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":557914,"name":"Raquel Buj","orcid":"0000-0002-8355-6666","position":1,"is_corresponding":false},{"id":1167876,"name":"Apoorva Uboveja","orcid":"0000-0002-8037-9676","position":2,"is_corresponding":false},{"id":1179167,"name":"Evan Levasseur","orcid":null,"position":3,"is_corresponding":false},{"id":109228,"name":"Hui Wang","orcid":"0000-0003-2791-8981","position":4,"is_corresponding":false},{"id":266821,"name":"Katarzyna M. Kedziora","orcid":"0000-0001-6524-7731","position":5,"is_corresponding":false},{"id":1015886,"name":"Adam Chatoff","orcid":"0000-0002-7954-9527","position":6,"is_corresponding":false},{"id":1179168,"name":"Andrea Andress Huacachino","orcid":null,"position":7,"is_corresponding":false},{"id":1178179,"name":"Mariola M. Marcinkiewicz","orcid":null,"position":8,"is_corresponding":false},{"id":1167877,"name":"Amandine Amalric","orcid":"0000-0002-2856-1446","position":9,"is_corresponding":false},{"id":1168282,"name":"Baixue Yang","orcid":null,"position":10,"is_corresponding":false},{"id":653684,"name":"Naveen Kumar Tangudu","orcid":"0000-0001-9153-5825","position":11,"is_corresponding":false},{"id":1179169,"name":"Jeff Danielson","orcid":null,"position":12,"is_corresponding":false},{"id":893837,"name":"Amal T. Elhaw","orcid":"0000-0001-6547-3018","position":13,"is_corresponding":false},{"id":1179170,"name":"Sierra R. 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