Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2024

Open Access 01-12-2024 | Metastasis | Research

The incorporation of acetylated LAP-TGF-β1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis

Authors: Pei Yu, Yubao Han, Lulu Meng, Zengying Tang, Zhiwei Jin, Zhenzhen Zhang, Yunjiang Zhou, Jun Luo, Jianguang Luo, Chao Han, Chao Zhang, Lingyi Kong

Published in: Molecular Cancer | Issue 1/2024

Login to get access

Abstract

Triple-negative breast cancer (TNBC) stands as the breast cancer subtype with the highest recurrence and mortality rates, with the lungs being the common site of metastasis. The pulmonary microenvironment plays a pivotal role in the colonization of disseminated tumor cells. Herein, this study highlights the crucial role of exosomal LAP-TGF-β1, the principal form of exosomal TGF-β1, in reshaping the pulmonary vascular niche, thereby facilitating TNBC lung metastasis. Although various strategies have been developed to block TGF-β signaling and have advanced clinically, their significant side effects have limited their therapeutic application. This study demonstrates that in lung metastatic sites, LAP-TGF-β1 within exosomes can remarkably reconfigure the pulmonary vascular niche at lower doses, bolstering the extravasation and colonization of TNBC cells in the lungs. Mechanistically, under the aegis of the acetyltransferase TIP60, a non-canonical KFERQ-like sequence in LAP-TGF-β1 undergoes acetylation at the K304 site, promoting its interaction with HSP90A and subsequent transport into exosomes. Concurrent inhibition of both HSP90A and TIP60 significantly diminishes the exosomal burden of LAP-TGF-β1, presenting a promising therapeutic avenue for TNBC lung metastasis. This study not only offers fresh insights into the molecular underpinnings of TNBC lung metastasis but also lays a foundation for innovative therapeutic strategies.
Appendix
Available only for authorised users
Literature
1.
Leon-Ferre RA, Goetz MP. Advances in systemic therapies for triple negative breast cancer. BMJ. 2023;381:e071674.PubMedCrossRef
2.
Minn AJ, Gupta GP, Siegel PM, Bos PD, Shu W, Giri DD, Viale A, Olshen AB, Gerald WL, Massagué J. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24.PubMedPubMedCentralCrossRef
3.
Ogawa K, Lin Q, Li L, Bai X, Chen X, Chen H, Kong R, Wang Y, Zhu H, He F, et al. Aspartate beta-hydroxylase promotes pancreatic ductal adenocarcinoma metastasis through activation of SRC signaling pathway. J Hematol Oncol. 2019;12:144.PubMedPubMedCentralCrossRef
4.
Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol. 2022;87:17–31.PubMedCrossRef
5.
Yu W, Hu C, Gao H. Advances of nanomedicines in breast cancer metastasis treatment targeting different metastatic stages. Adv Drug Deliv Rev. 2021;178:113909.PubMedCrossRef
6.
Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, Brewer DS, Kallio HML, Hognas G, Annala M, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015;520:353–7.PubMedPubMedCentralCrossRef
7.
Blasco MT, Espuny I, Gomis RR. Ecology and evolution of dormant metastasis. Trends Cancer. 2022;8:570–82.PubMedCrossRef
8.
Brown D, Smeets D, Szekely B, Larsimont D, Szasz AM, Adnet PY, Rothe F, Rouas G, Nagy ZI, Farago Z, et al. Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations. Nat Commun. 2017;8:14944.PubMedPubMedCentralCrossRef
9.
Ullah I, Karthik GM, Alkodsi A, Kjallquist U, Stalhammar G, Lovrot J, Martinez NF, Lagergren J, Hautaniemi S, Hartman J, Bergh J. Evolutionary history of metastatic breast cancer reveals minimal seeding from axillary lymph nodes. J Clin Invest. 2018;128:1355–70.PubMedPubMedCentralCrossRef
10.
11.
Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, Yu Y, Chow A, O’Connor ST, Chin AR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. 2014;25:501–15.PubMedPubMedCentralCrossRef
12.
Lyden D, Ghajar CM, Correia AL, Aguirre-Ghiso JA, Cai S, Rescigno M, Zhang P, Hu G, Fendt SM, Boire A, et al. Metastasis. Cancer Cell. 2022;40:787–91.PubMedPubMedCentralCrossRef
13.
Qi M, Xia Y, Wu Y, Zhang Z, Wang X, Lu L, Dai C, Song Y, Xu K, Ji W, Zhan L. Lin28B-high breast cancer cells promote immune suppression in the lung pre-metastatic niche via exosomes and support cancer progression. Nat Commun. 2022;13:897.PubMedPubMedCentralCrossRef
14.
Fang T, Lv H, Lv G, Li T, Wang C, Han Q, Yu L, Su B, Guo L, Huang S, et al. Tumor-derived exosomal mir-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191.PubMedPubMedCentralCrossRef
15.
Liang M, Chen X, Wang L, Qin L, Wang H, Sun Z, Zhao W, Geng B. Cancer-derived exosomal TRIM59 regulates macrophage NLRP3 inflammasome activation to promote lung cancer progression. J Exp Clin Cancer Res. 2020;39:176.PubMedPubMedCentralCrossRef
16.
Reymond N, d’Água BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer. 2013;13:858–70.PubMedCrossRef
17.
Li DK, Chen XR, Wang LN, Wang JH, Li JK, Zhou ZY, Li X, Cai LB, Zhong SS, Zhang JJ, et al. Exosomal HMGA2 protein from EBV-positive NPC cells destroys vascular endothelial barriers and induces endothelial-to-mesenchymal transition to promote metastasis. Cancer Gene Ther. 2022;29:1439–51.PubMedPubMedCentralCrossRef
18.
Martinez VG, O’Neill S, Salimu J, Breslin S, Clayton A, Crown J, O’Driscoll L. Resistance to HER2-targeted anti-cancer drugs is associated with immune evasion in cancer cells and their derived extracellular vesicles. Oncoimmunology. 2017;6:e1362530.PubMedPubMedCentralCrossRef
19.
Tan C, Sun W, Xu Z, Zhu S, Hu W, Wang X, Zhang Y, Zhang G, Wang Z, Xu Y, Tang J. Small extracellular vesicles deliver TGF-beta1 and promote adriamycin resistance in breast cancer cells. Mol Oncol. 2021;15:1528–42.PubMedPubMedCentralCrossRef
20.
Halder LD, Jo EAH, Hasan MZ, Ferreira-Gomes M, Krüger T, Westermann M, Palme DI, Rambach G, Beyersdorf N, Speth C, et al. Immune modulation by complement receptor 3-dependent human monocyte TGF-β1-transporting vesicles. Nat Commun. 2020;11:2331.PubMedPubMedCentralCrossRef
21.
Nakayama F, Miyoshi M, Kimoto A, Kawano A, Miyashita K, Kamoshida S, Shimizu K, Hori Y. Pancreatic cancer cell-derived exosomes induce epithelial-mesenchymal transition in human pancreatic cancer cells themselves partially via transforming growth factor beta1. Med Mol Morphol. 2022;55:227–35.PubMedPubMedCentralCrossRef
22.
Yang X, Zhang Y, Zhang Y, Li H, Li L, Wu Y, Chen X, Qiu L, Han J, Wang Z. Colorectal cancer-derived extracellular vesicles induce liver premetastatic immunosuppressive niche formation to promote tumor early liver metastasis. Signal Transduct Target Ther. 2023;8:102.PubMedPubMedCentralCrossRef
23.
Da X, Li Z, Huang X, He Z, Yu Y, Tian T, Xu C, Yao Y, Wang QK. AGGF1 therapy inhibits thoracic aortic aneurysms by enhancing integrin alpha7-mediated inhibition of TGF-beta1 maturation and ERK1/2 signaling. Nat Commun. 2023;14:2265.PubMedPubMedCentralCrossRef
24.
Shelke GV, Yin Y, Jang SC, Lasser C, Wennmalm S, Hoffmann HJ, Li L, Gho YS, Nilsson JA, Lotvall J. Endosomal signalling via exosome surface TGFbeta-1. J Extracell Vesicles. 2019;8:1650458.PubMedPubMedCentralCrossRef
25.
Stockis J, Dedobbeleer O, Lucas S. Role of GARP in the activation of latent TGF-beta1. Mol Biosyst. 2017;13:1925–35.PubMedCrossRef
26.
Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621–30.PubMedCrossRef
27.
28.
Javanmardi Y, Agrawal A, Malandrino A, Lasli S, Chen M, Shahreza S, Serwinski B, Cammoun L, Li R, Jorfi M, et al. Endothelium and subendothelial matrix mechanics modulate Cancer Cell Transendothelial Migration. Adv Sci (Weinh). 2023;10:e2206554.PubMedCrossRef
29.
Zeng Z, Li Y, Pan Y, Lan X, Song F, Sun J, Zhou K, Liu X, Ren X, Wang F, et al. Cancer-derived exosomal mir-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis. Nat Commun. 2018;9:5395.PubMedPubMedCentralCrossRef
30.
Rodrigues G, Hoshino A, Kenific CM, Matei IR, Steiner L, Freitas D, Kim HS, Oxley PR, Scandariato I, Casanova-Salas I, et al. Tumour exosomal CEMIP protein promotes cancer cell colonization in brain metastasis. Nat Cell Biol. 2019;21:1403–12.PubMedPubMedCentralCrossRef
31.
Lin Y, Zhang C, Xiang P, Shen J, Sun W, Yu H. Exosomes derived from HeLa cells break down vascular integrity by triggering endoplasmic reticulum stress in endothelial cells. J Extracell Vesicles. 2020;9:1722385.PubMedPubMedCentralCrossRef
32.
Lin Q, Chen X, Meng F, Ogawa K, Li M, Song R, Zhang S, Zhang Z, Kong X, Xu Q, et al. ASPH-notch Axis guided Exosomal delivery of Prometastatic Secretome renders breast Cancer multi-organ metastasis. Mol Cancer. 2019;18:156.PubMedPubMedCentralCrossRef
33.
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.PubMedCrossRef
34.
Martin CJ, Datta A, Littlefield C, Kalra A, Chapron C, Wawersik S, Dagbay KB, Brueckner CT, Nikiforov A, Danehy FT, et al. Selective inhibition of TGFβ1 activation overcomes primary resistance to checkpoint blockade therapy by altering tumor immune landscape. Sci Transl Med. 2020;12:eaay8456.PubMedCrossRef
35.
Derynck R, Turley SJ, Akhurst RJ. TGFβ biology in cancer progression and immunotherapy. Nat Reviews Clin Oncol. 2020;18:9–34.CrossRef
36.
van Niel G, D’Angelo G, Raposo G. Shedding light on the cell biology of extracellular vesicles. Nat Rev Mol Cell Biol. 2018;19:213–28.PubMedCrossRef
37.
Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, et al. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30. sup pp 11–13.PubMedCrossRef
38.
Baietti MF, Zhang Z, Mortier E, Melchior A, Degeest G, Geeraerts A, Ivarsson Y, Depoortere F, Coomans C, Vermeiren E, et al. Syndecan-syntenin-ALIX regulates the biogenesis of exosomes. Nat Cell Biol. 2012;14:677–85.PubMedCrossRef
39.
Zhang M, Liu L, Lin X, Wang Y, Li Y, Guo Q, Li S, Sun Y, Tao X, Zhang D, et al. A translocation pathway for vesicle-mediated unconventional protein secretion. Cell. 2020;181:637–e652615.PubMedCrossRef
40.
Zhong L, Liao D, Li J, Liu W, Wang J, Zeng C, Wang X, Cao Z, Zhang R, Li M, et al. Rab22a-NeoF1 fusion protein promotes osteosarcoma lung metastasis through its secretion into exosomes. Signal Transduct Target Ther. 2021;6:59.PubMedPubMedCentralCrossRef
41.
Nuchel J, Ghatak S, Zuk AV, Illerhaus A, Morgelin M, Schonborn K, Blumbach K, Wickstrom SA, Krieg T, Sengle G, et al. TGFB1 is secreted through an unconventional pathway dependent on the autophagic machinery and cytoskeletal regulators. Autophagy. 2018;14:465–86.PubMedPubMedCentralCrossRef
42.
43.
Villarroya-Beltri C, Baixauli F, Mittelbrunn M, Fernández-Delgado I, Torralba D, Moreno-Gonzalo O, Baldanta S, Enrich C, Guerra S. Sánchez-Madrid F: ISGylation controls exosome secretion by promoting lysosomal degradation of MVB proteins. Nat Commun. 2016;7:13588.PubMedPubMedCentralCrossRef
44.
Scott CC, Vacca F, Gruenberg J. Endosome maturation, transport and functions. Semin Cell Dev Biol. 2014;31:2–10.PubMedCrossRef
45.
Zhang M, Kenny SJ, Ge L, Xu K, Schekman R. Translocation of interleukin-1beta into a vesicle intermediate in autophagy-mediated secretion. Elife. 2015;4:e11205.PubMedPubMedCentralCrossRef
46.
Kim SH, Kang JG, Kim CS, Ihm S-H, Choi MG, Yoo HJ, Lee SJ. Synergistic cytotoxicity of BIIB021 with triptolide through suppression of PI3K/Akt/mTOR and NF-κB signal pathways in thyroid carcinoma cells. Biomed Pharmacother. 2016;83:22–32.PubMedCrossRef
47.
Huang Y, Song N, Ding Y, Yuan S, Li X, Cai H, Shi H, Luo Y. Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. Cancer Res. 2009;69:7529–37.PubMedCrossRef
48.
Bridgeman VL, Vermeulen PB, Foo S, Bilecz A, Daley F, Kostaras E, Nathan MR, Wan E, Frentzas S, Schweiger T, et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. J Pathol. 2017;241:362–74.PubMedCrossRef
49.
Holash J. Vessel cooption, regression, and growth in tumors mediated by Angiopoietins and VEGF. Science. 1999;284:1994–8.PubMedCrossRef
50.
Reymond N, d’Agua BB, Ridley AJ. Crossing the endothelial barrier during metastasis. Nat Rev Cancer. 2013;13:858–70.PubMedCrossRef
51.
Tsukita S, Furuse M. Occludin and claudins in tight-junction strands: leading or supporting players? Trends Cell Biol. 1999;9:268–73.PubMedCrossRef
52.
Jiang WG, Martin TA, Matsumoto K, Nakamura T, Mansel RE. Hepatocyte growth factor/scatter factor decreases the expression of occludin and transendothelial resistance (TER) and increases paracellular permeability in human vascular endothelial cells. J Cell Physiol. 1999;181:319–29.PubMedCrossRef
53.
Martin TA, Mansel RE, Jiang WG. Antagonistic effect of NK4 on HGF/SF induced changes in the transendothelial resistance (TER) and paracellular permeability of human vascular endothelial cells. J Cell Physiol. 2002;192:268–75.PubMedCrossRef
54.
Ma W, Han W, Greer PA, Tuder RM, Toque HA, Wang KK, Caldwell RW, Su Y. Calpain mediates pulmonary vascular remodeling in rodent models of pulmonary hypertension, and its inhibition attenuates pathologic features of disease. J Clin Invest. 2011;121:4548–66.PubMedPubMedCentralCrossRef
55.
Pittet JF, Griffiths MJ, Geiser T, Kaminski N, Dalton SL, Huang X, Brown LA, Gotwals PJ, Koteliansky VE, Matthay MA, Sheppard D. TGF-beta is a critical mediator of acute lung injury. J Clin Invest. 2001;107:1537–44.PubMedPubMedCentralCrossRef
56.
Epstein FH, Blobe GC, Schiemann WP, Lodish HF. Role of transforming growth factor beta in human disease. N Engl J Med. 2000;342:1350–8.CrossRef
57.
Sanchez-Capelo A. Dual role for TGF-beta1 in apoptosis. Cytokine Growth Factor Rev. 2005;16:15–34.PubMedCrossRef
58.
Sánchezcapelo A, Colin P, Guibert B, Biguet NF, Mallet J. Transforming growth factor beta1 overexpression in the nigrostriatal system increases the dopaminergic deficit of MPTP mice. Mol Cell Neurosci. 2003;23:614–25.PubMedCrossRef
59.
Monteleone G, Boirivant M, Pallone F, MacDonald TT. TGF-beta1 and Smad7 in the regulation of IBD. Mucosal Immunol. 2008;1(Suppl 1):S50–53.PubMedCrossRef
60.
Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, Ramirez F, Sakai LY, Dietz HC. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet. 2003;33:407–11.PubMedCrossRef
61.
Wyss-Coray T, Masliah E, Mallory M, Mcconlogue L, Johnson-Wood K, Lin C, Mucke L. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer’s disease. Nature, 389:603–6.
62.
Ferreira JV, Soares ADR, Ramalho J, Carvalho CM, Cardoso MH, Pintado P, Carvalho AS, Beck HC, Matthiesen R, Zuzarte M. LAMP2A regulates the loading of proteins into exosomes. Sci Adv. 2022;8:eabm1140.PubMedPubMedCentralCrossRef
63.
Colombo M, Raposo GA, Théry C. Biogenesis, secretion, and intercellular interactions of exosomes and other extracellular vesicles. Annu Rev Cell Dev Biol. 2014;30:255–89.PubMedCrossRef
64.
Derynck R, Akhurst RJ, Balmain A. TGF- beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–29.PubMedCrossRef
65.
Walton KL, Makanji Y, Chen J, Wilce MC, Chan KL, Robertson DM, Harrison CA. Two distinct regions of latency-associated peptide coordinate stability of the latent transforming growth factor-beta1 complex. J Biol Chem. 2010;285:17029–37.PubMedPubMedCentralCrossRef
66.
Buscemi L, Ramonet D, Klingberg F, Formey A, Smith-Clerc J, Meister J-J, Hinz B. The single-molecule mechanics of the latent TGF-β1 complex. Curr Biol. 2011;21:2046–54.PubMedCrossRef
67.
68.
Ghossoub R, Lembo F, Rubio A, Gaillard CB, Bouchet J, Vitale N, Slavik J, Machala M, Zimmermann P. Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun. 2014;5:3477.PubMedCrossRef
69.
Kashyap R, Balzano M, Lechat B, Lambaerts K, Egea-Jimenez AL, Lembo F, Fares J, Meeussen S, Kugler S, Roebroek A, et al. Syntenin-knock out reduces exosome turnover and viral transduction. Sci Rep. 2021;11:4083.PubMedPubMedCentralCrossRef
70.
Ageta H, Ageta-Ishihara N, Hitachi K, Karayel O, Onouchi T, Yamaguchi H, Kahyo T, Hatanaka K, Ikegami K, Yoshioka Y, et al. UBL3 modification influences protein sorting to small extracellular vesicles. Nat Commun. 2018;9:3936.PubMedPubMedCentralCrossRef
71.
Hou PP, Luo LJ, Chen HZ, Chen QT, Bian XL, Wu SF, Zhou JX, Zhao WX, Liu JM, Wang XM, et al. Ectosomal PKM2 promotes HCC by inducing macrophage differentiation and remodeling the Tumor Microenvironment. Mol Cell. 2020;78:1192–e12061110.PubMedCrossRef
72.
Xie F, Su P, Pan T, Zhou X, Li H, Huang H, Wang A, Wang F, Huang J, Yan H et al. Engineering Extracellular vesicles enriched with palmitoylated ACE2 as COVID-19 therapy. Adv Mater 2021:e2103471.
73.
74.
Liang X, Wang X, He Y, Wu Y, Zhong L, Liu W, Liao D, Kang T. Acetylation dependent functions of Rab22a-NeoF1 Fusion protein in Osteosarcoma. Theranostics. 2020;10:7747–57.PubMedPubMedCentralCrossRef
Metadata
Title
The incorporation of acetylated LAP-TGF-β1 proteins into exosomes promotes TNBC cell dissemination in lung micro-metastasis
Authors
Pei Yu
Yubao Han
Lulu Meng
Zengying Tang
Zhiwei Jin
Zhenzhen Zhang
Yunjiang Zhou
Jun Luo
Jianguang Luo
Chao Han
Chao Zhang
Lingyi Kong
Publication date
01-12-2024
Publisher
BioMed Central
Keyword
Metastasis
Published in
Molecular Cancer / Issue 1/2024
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-024-01995-z

Other articles of this Issue 1/2024

Molecular Cancer 1/2024 Go to the issue

Correction

Correction: Aurora kinase targeting in lung cancer reduces KRAS-induced transformation

Review

Drug resistance mechanisms and treatment strategies mediated by Ubiquitin-Specific Proteases (USPs) in cancers: new directions and therapeutic options

Review

R-loop and diseases: the cell cycle matters

Correspondence

Pan-cancer characterization of cell-free immune-related miRNA identified as a robust biomarker for cancer diagnosis

Research

Targeted deletion of CD244 on monocytes promotes differentiation into anti-tumorigenic macrophages and potentiates PD-L1 blockade in melanoma

Correction

Correction: Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits