bioRxiv - Cancer Biology最新文献_第3页

TopBP1 biomolecular condensates: a new therapeutic target in advanced-stage colorectal cancer. TopBP1 生物分子凝聚物：晚期结直肠癌的新治疗靶点。

bioRxiv - Cancer Biology Pub Date : 2024-09-15 DOI: 10.1101/2024.09.10.612204

Laura Morano, Nadia Vie, Adam Aissanou, Tom Egger, Antoine Aze, Solene Fiachetti, Herve Seitz, Louis-Antoine Milazzo, Veronique GARAMBOIS, Nathalie Bonnefoy-Berard, Celine Gongora, Angelos Constantinou, Jihane Basbous

{"title":"TopBP1 biomolecular condensates: a new therapeutic target in advanced-stage colorectal cancer.","authors":"Laura Morano, Nadia Vie, Adam Aissanou, Tom Egger, Antoine Aze, Solene Fiachetti, Herve Seitz, Louis-Antoine Milazzo, Veronique GARAMBOIS, Nathalie Bonnefoy-Berard, Celine Gongora, Angelos Constantinou, Jihane Basbous","doi":"10.1101/2024.09.10.612204","DOIUrl":"https://doi.org/10.1101/2024.09.10.612204","url":null,"abstract":"In cancer cells, ATR signaling is crucial to tolerate the intrinsically high damage levels that normally block replication fork progression. Assembly of TopBP1, a multifunctional scaffolding protein, into condensates is required to amplify ATR kinase activity to the levels needed to coordinate the DNA damage response and manage DNA replication stress. Many ATR inhibitors are tested for cancer treatment in clinical trials, but their overall effectiveness is often compromised by the emergence of resistance and toxicities. In this proof-of-concept study, we propose to disrupt the ATR pathway by targeting TopBP1 condensation. First, we screened a molecule-based library using a previously developed optogenetic approach and identified several TopBP1 condensation inhibitors. Amongst them, AZD2858 disrupted TopBP1 assembly induced by the clinically relevant topoisomerase I inhibitor SN-38, thereby inhibiting the ATR/Chk1 signaling pathway. We found that AZD2858 exerted its effects by disrupting TopBP1 self-interaction and binding to ATR in mammalian cells, and by increasing its chromatin recruitment in cell-free Xenopus laevis egg extracts. Moreover, AZD2858 prevented S-phase checkpoint induction by SN-38, leading to increased DNA damage and apoptosis in a colorectal cancer cell line. Lastly, AZD2858 showed synergistic effect in combination with the FOLFIRI chemotherapy regimen in a spheroid model of colorectal cancer.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"125 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249845","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics 利用化学蛋白质组学揭示 CRBN 分子胶隐藏的相互作用组

bioRxiv - Cancer Biology Pub Date : 2024-09-15 DOI: 10.1101/2024.09.11.612438

Khewoong Baek, Rebecca J Metivier, Shourya S Roy Burman, Jonathan W Bushman, Ryan J Lumpkin, Dinah M Abeja, Megha Lakshminarayan, Hong Yue, Samuel Ojeda, Alyssa L Verano, Nathanael Gray, Katherine A Donovan, Eric S Fischer

{"title":"Unveiling the hidden interactome of CRBN molecular glues with chemoproteomics","authors":"Khewoong Baek, Rebecca J Metivier, Shourya S Roy Burman, Jonathan W Bushman, Ryan J Lumpkin, Dinah M Abeja, Megha Lakshminarayan, Hong Yue, Samuel Ojeda, Alyssa L Verano, Nathanael Gray, Katherine A Donovan, Eric S Fischer","doi":"10.1101/2024.09.11.612438","DOIUrl":"https://doi.org/10.1101/2024.09.11.612438","url":null,"abstract":"Targeted protein degradation and induced proximity refer to strategies that leverage the recruitment of proteins to facilitate their modification, regulation or degradation. As prospective design of glues remains challenging, unbiased discovery methods are needed to unveil hidden chemical targets. Here we establish a high throughput affinity purification mass spectrometry workflow in cell lysates for the unbiased identification of molecular glue targets. By mapping the targets of 20 CRBN-binding molecular glues, we identify 298 protein targets and demonstrate the utility of enrichment methods for identifying novel targets overlooked using established methods. We use a computational workflow to estimate target confidence and perform a biochemical screen to identify a lead compound for the new non-ZF target PPIL4. Our study provides a comprehensive inventory of targets chemically recruited to CRBN and delivers a robust and scalable workflow for identifying new drug-induced protein interactions in cell lysates.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249800","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NEK9 ablation rewires docetaxel resistance through induction of ERK-mediated cancer cell pyroptosis NEK9 消融可通过诱导 ERK 介导的癌细胞热休克重塑多西他赛耐药性

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612209

Shamima Azma Ansari, Sibasish Mohanty, Pallavi Mohapatra, Rachna Rath, Dillip Muduli, Saroj Kumar Das Majumdar, Rajeeb K. Swain, Rupesh Dash

{"title":"NEK9 ablation rewires docetaxel resistance through induction of ERK-mediated cancer cell pyroptosis","authors":"Shamima Azma Ansari, Sibasish Mohanty, Pallavi Mohapatra, Rachna Rath, Dillip Muduli, Saroj Kumar Das Majumdar, Rajeeb K. Swain, Rupesh Dash","doi":"10.1101/2024.09.10.612209","DOIUrl":"https://doi.org/10.1101/2024.09.10.612209","url":null,"abstract":"Docetaxel alone or in combination with other drugs is the most common chemotherapy regimen for several neoplasms including advanced OSCC. Unfortunately, chemoresistance leads to relapse and continued tumor growth. It is therefore important to explore the causative factors for docetaxel resistance. In this study, we performed a CRISPR-based kinome screening that identified Never In Mitosis Gene-A Related Kinase-9 (NEK9) as a major player of docetaxel resistance in OSCC, prostate, and pancreatic cancer lines. NEK9 expression was upregulated in tumor samples of chemotherapy non-responders compared to responder OSCC patients. Our validation data suggests selectively knocking out NEK9 sensitizes cancer cells to docetaxel. Mechanistically, we found that ablation of NEK9 induces DNA damage, activating ERK(p-T202/Y204) that leads to Gasdermin-E mediated Cancer Cell pyroptosis. The in-vitro kinase activity assay identified fostamatinib as a potent inhibitor of NEK9. The xenograft data suggest that fostamatinib restores docetaxel sensitivity and facilitates a significant reduction of tumor burden. Overall, our data suggests a novel combination of fostamatinib and docetaxel needs further clinical investigation in advanced OSCC.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression BST2 在癌症进展过程中诱导血管平滑肌细胞可塑性和表型转换

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612298

Caitlin Bell, Richard Baylis, Nicolas Lopez, Wei Feng Ma, Hua Gao, Fudi Wang, Sharika Bamezai, Changhao Fu, Yoko Kojima, Shaunak Adkar, Lingfeng Luo, Clint Miller, Nicholas L Leeper

{"title":"BST2 induces vascular smooth muscle cell plasticity and phenotype switching during cancer progression","authors":"Caitlin Bell, Richard Baylis, Nicolas Lopez, Wei Feng Ma, Hua Gao, Fudi Wang, Sharika Bamezai, Changhao Fu, Yoko Kojima, Shaunak Adkar, Lingfeng Luo, Clint Miller, Nicholas L Leeper","doi":"10.1101/2024.09.10.612298","DOIUrl":"https://doi.org/10.1101/2024.09.10.612298","url":null,"abstract":"Background: Smooth muscle cell (SMC) plasticity and phenotypic switching play prominent roles in the pathogenesis of multiple diseases, but their role in tumorigenesis is unknown. We investigated whether and how SMC diversity and plasticity plays a role in tumor angiogenesis and the tumor microenvironment. Methods and Results: We use SMC-specific lineage-tracing mouse models and single cell RNA sequencing to observe the phenotypic diversity of SMCs participating in tumor vascularization. We find that a significant proportion of SMCs adopt a phenotype traditionally associated with macrophage-like cells. These cells are transcriptionally similar to resolution phase M2b macrophages, which have been described to have a role in inflammation resolution. Computationally predicted by the ligand-receptor algorithm CellChat, signaling from BST2 on the surface of tumor cells to PIRA2 on SMCs promote this phenotypic transition; in vitro SMC assays demonstrate upregulation of macrophage transcriptional programs, and increased proliferation, migration, and phagocytic ability when exposed to BST2. Knockdown of BST2 in the tumor significantly decreases the transition towards a macrophage-like phenotype, and cells that do transition have a comparatively higher inflammatory signal typically associated with anti-tumor effect. Conclusion: As BST2 is known to be a poor prognostic marker in multiple cancers where it is associated with an M2 macrophage-skewed TME, these studies suggest that phenotypically switched SMCs may have a previously unidentified role in this immunosuppressive milieu. Further translational work is needed to understand how this phenotypic switch could influence the response to anti-cancer agents and if targeted inhibition of SMC plasticity would be therapeutically beneficial.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249803","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

On the design and stability of cancer adaptive therapy cycles: deterministic and stochastic models 论癌症适应性治疗周期的设计和稳定性：确定性模型和随机模型

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612338

Yuri G. Vilela, Artur C. Fassoni, Armando G. M. Neves

{"title":"On the design and stability of cancer adaptive therapy cycles: deterministic and stochastic models","authors":"Yuri G. Vilela, Artur C. Fassoni, Armando G. M. Neves","doi":"10.1101/2024.09.10.612338","DOIUrl":"https://doi.org/10.1101/2024.09.10.612338","url":null,"abstract":"Adaptive therapy is a promising paradigm for treating cancers, that exploits competitive interactions between drug-sensitive and drug-resistant cells, thereby avoiding or delaying treatment failure due to evolution of drug resistance within the tumor. Previous studies have shown the mathematical possibility of building cyclic schemes of drug administration which restore tumor composition to its exact initial value in deterministic models. However, algorithms for cycle design, the conditions on which such algorithms are certain to work, as well as conditions for cycle stability remain elusive. Here, we state biologically motivated hypotheses that guarantee existence of such cycles in two deterministic classes of mathematical models already considered in the literature: Lotka-Volterra and adjusted replicator dynamics. We stress that not only existence of cyclic schemes, but also stability of such cycles is a relevant feature for applications in real clinical scenarios. We also analyze stochastic versions of the above deterministic models, a necessary step if we want to take into account that real tumors are composed by a finite population of cells subject to randomness, a relevant feature in the context of low tumor burden. We argue that the stability of the deterministic cycles is also relevant for the stochastic version of the models. In fact, Dua, Ma and Newton [Cancers (2021)] and Park and Newton [Phys. Rev. E (2023)] observed breakdown of deterministic cycles in a stochastic model (Moran process) for a tumor. Our findings indicate that the breakdown phenomenon is not due to stochasticity itself, but to the deterministic instability inherent in the cycles of the referenced papers. We then illustrate how stable deterministic cycles avoid for very large times the breakdown of cyclic treatments in stochastic tumor models.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

RAD50 is a potential biomarker for breast cancer diagnosis and prognosis RAD50 是乳腺癌诊断和预后的潜在生物标志物

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.07.611821

Kunwer S. Chhatwal, Hengrui Liu

引用次数: 0

Identifying, Prioritizing, and Visualizing Functional Promoter SNVs with the Recurrence-agnostic REMIND-Cancer Pipeline and pSNV Hunter 利用具有复发诊断功能的 REMIND-Cancer Pipeline 和 pSNV 猎人识别、优先排序和可视化功能启动子 SNV

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612212

Nicholas Allen Baclig Abad, Irina Glas, Chen Hong, Yoann Pageaud, Barbara Hutter, Benedikt Brors, Cindy Korner, Lars Feuerbach

{"title":"Identifying, Prioritizing, and Visualizing Functional Promoter SNVs with the Recurrence-agnostic REMIND-Cancer Pipeline and pSNV Hunter","authors":"Nicholas Allen Baclig Abad, Irina Glas, Chen Hong, Yoann Pageaud, Barbara Hutter, Benedikt Brors, Cindy Korner, Lars Feuerbach","doi":"10.1101/2024.09.10.612212","DOIUrl":"https://doi.org/10.1101/2024.09.10.612212","url":null,"abstract":"Cancer is a heterogeneous disease that arises due to mutations that drive cancer progression. However, the identification of these functional mutations has typically focused only on protein-coding DNA. Among non-coding mutations, only a few have been clearly associated with cancer. We hypothesize that this gap in discovery is partly due to the limitations of current methods requiring high recurrence of mutations. To support candidate selection for experimental validation of lowly recurrent and singleton promoter mutations, new computational approaches for the integrated analysis of multi-omics data are required. To address this challenge, the REMIND-Cancer Pipeline leverages whole-genome sequencing and RNA-Seq data to extract and prioritize functional promoter mutations, regardless of their recurrence status. Subsequently, pSNV Hunter aggregates and visualizes comprehensive information for each candidate. We demonstrate the functionality of both tools by applying it to the PCAWG dataset. This workflow successfully identified and prioritized known highly-recurrent mutations, as well as, novel singletons and lowly recurrent candidates. Hence, the output of our workflow directly supports hypothesis generation for subsequent experimental validation to overcome limitations of recurrence-based approaches.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metastatic tumor cells in bone marrow differ from paired neuroblastoma tumor and contain subsets with therapy-resistant characteristics 骨髓中的转移性肿瘤细胞与配对的神经母细胞瘤肿瘤不同，包含具有抗药性特征的亚群

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.13.612231

Caroline Hochheuser, Arjan Boltjes, Kaylee M Keller, Simon Tol, Marieke van de Mheen, Caroline Pita Barros, Zeinab van Gestel-Fadaie, André B.P. van Kuilenburg, Sander van Hooff, Carlijn Voermans, Jan J. Molenaar, Godelieve A.M. Tytgat, Ilse Timmerman

{"title":"Metastatic tumor cells in bone marrow differ from paired neuroblastoma tumor and contain subsets with therapy-resistant characteristics","authors":"Caroline Hochheuser, Arjan Boltjes, Kaylee M Keller, Simon Tol, Marieke van de Mheen, Caroline Pita Barros, Zeinab van Gestel-Fadaie, André B.P. van Kuilenburg, Sander van Hooff, Carlijn Voermans, Jan J. Molenaar, Godelieve A.M. Tytgat, Ilse Timmerman","doi":"10.1101/2024.09.13.612231","DOIUrl":"https://doi.org/10.1101/2024.09.13.612231","url":null,"abstract":"Bone marrow (BM) is a common site for solid tumor metastasis, often causing poor outcome. Here, we define the characteristics of BM-disseminated tumor cells (DTCs) using neuroblastoma as a model. We combined single-cell RNA-sequencing (scRNA-seq) and cell-surface protein analysis using 7 paired BM and primary tumor (PT) samples and found that DTCs contain a higher percentage of cycling cells and higher expression of neurodevelopmental genes compared to corresponding PT cells. In 6 patients, the copy number variation profile differed between PT cells and DTCs, indicating spatial heterogeneity. Within the BM, we detected dormant DTCs with potentially reduced chemosensitivity; this population contained cells expressing low levels of the immunotherapeutic antigen GD2 and increased NGFR expression. In conclusion, we characterized DTCs that are particularly challenging to target, offering new avenues for developing therapeutic strategies designed to target all subpopulations within the highly complex metastatic site, thereby preventing the development of drug-resistant clones.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"65 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249838","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Primary cilia promote EMT-induced triple-negative breast tumor heterogeneity and resistance to therapy 原发性纤毛促进 EMT 诱导的三阴性乳腺肿瘤的异质性和抗药性

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612175

Camille Tessier, Jennifer Derrien, Aurore Dupuy, Thomas Pele, Martin Moquet, Julie Roul, Elise Douillard, Camille El Harrif, Xavier Pinson, Matthieu Le Gallo, Florence Godey, Patrick Tas, Roselyne Viel, Claude Prigent, Eric Letouze, Peggy Suzanne, Patrick Dallemagne, Mario Campone, Robert Weinberg, Jacqueline Lees, Philippe Juin, Vincent Guen

{"title":"Primary cilia promote EMT-induced triple-negative breast tumor heterogeneity and resistance to therapy","authors":"Camille Tessier, Jennifer Derrien, Aurore Dupuy, Thomas Pele, Martin Moquet, Julie Roul, Elise Douillard, Camille El Harrif, Xavier Pinson, Matthieu Le Gallo, Florence Godey, Patrick Tas, Roselyne Viel, Claude Prigent, Eric Letouze, Peggy Suzanne, Patrick Dallemagne, Mario Campone, Robert Weinberg, Jacqueline Lees, Philippe Juin, Vincent Guen","doi":"10.1101/2024.09.10.612175","DOIUrl":"https://doi.org/10.1101/2024.09.10.612175","url":null,"abstract":"Tumor heterogeneity and plasticity, driven by Epithelial-Mesenchymal Transition (EMT), enable cancer therapeutic resistance. We previously showed that EMT promotes primary cilia formation, which enables stemness and tumorigenesis in triple-negative breast cancer (TNBC). Here, we establish a role for primary cilia in human TNBC chemotherapeutic resistance. We developed patient-derived organoids, and showed that these recapitulated the cellular heterogeneity of TNBC biopsies. Notably, one of the identified cell states bore a quasi-mesenchymal phenotype, primary cilia, and stemness signatures. We treated our TNBC organoids with chemotherapeutics and observed partial killing. The surviving cells with organoid-reconstituting capacity showed selective enrichment for the quasi-mesenchymal ciliated cell subpopulation. Genomic analyses argue that this enrichment reflects a combination of pre-existing cells and ones that arose through drug-induced cellular plasticity. We developed a family of small-molecule inhibitors of ciliogenesis and show that these, or genetic ablation of primary cilia, suppress chemoresistance. We conclude that primary cilia help TNBC to evade chemotherapy.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Platelet PI3Kβ regulates breast cancer metastasis 血小板 PI3Kβ 调控乳腺癌转移

bioRxiv - Cancer Biology Pub Date : 2024-09-14 DOI: 10.1101/2024.09.10.612261

Ryan C Graff, Adam Haimowitz, Jennifer Aguilan, Adriana Levine, Jinghang Zhang, Wenlin Yuan, Merone Roose-Girma, Somesekar Seshagiri, Steven A Porcelli, Matthew J Gamble, Simone Sidoli, Anne R Bresnick, Jonathan Backer

{"title":"Platelet PI3Kβ regulates breast cancer metastasis","authors":"Ryan C Graff, Adam Haimowitz, Jennifer Aguilan, Adriana Levine, Jinghang Zhang, Wenlin Yuan, Merone Roose-Girma, Somesekar Seshagiri, Steven A Porcelli, Matthew J Gamble, Simone Sidoli, Anne R Bresnick, Jonathan Backer","doi":"10.1101/2024.09.10.612261","DOIUrl":"https://doi.org/10.1101/2024.09.10.612261","url":null,"abstract":"Platelets promote tumor metastasis by several mechanisms. Platelet-tumor cell interactions induce the release of platelet cytokines, chemokines, and other factors that promote tumor cell epithelial-mesenchymal transition and invasion, granulocyte recruitment to circulating tumor cells (CTCs), and adhesion of CTCs to the endothelium, assisting in their extravasation at metastatic sites. Previous studies have shown that platelet activation in the context of thrombus formation requires the Class IA PI 3-kinase PI3Kβ. We now define a role for platelet PI3Kβ in breast cancer metastasis. Platelet PI3Kβ is essential for platelet-stimulated tumor cell invasion through Matrigel. Consistent with this finding, in vitro platelet-tumor cell binding and tumor cell-stimulated platelet activation are reduced in platelets isolated from PI3Kβ mutant mice. RNAseq and proteomic analysis of human breast epithelial cells co-cultured with platelets revealed that platelet PI3Kβ regulates the expression of EMT and metastasis-associated genes in these cells. The EMT and metastasis-associated proteins PAI-1 and IL-8 were specifically downregulated in co-cultures with PI3Kβ mutant platelets. PI3Kβ mutant platelets are impaired in their ability to stimulate YAP and Smad2 signaling in tumor cells, two pathways regulating PAI-1 expression. Finally, we show that mice expressing mutant PI3Kβ show reduced spontaneous metastasis, and platelets isolated from these mice are less able to stimulate experimental metastasis in WT mice. Taken together, these data support a role for platelet PI3Kβ in promoting breast cancer metastasis and highlight platelet PI3Kβ as a potential therapeutic target.","PeriodicalId":501233,"journal":{"name":"bioRxiv - Cancer Biology","volume":"190 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142249806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0