RAB27B-regulated exosomes mediate LSC maintenance via resistance to senescence and crosstalk with the microenvironment

Lytle NK, Barber AG, Reya T. Stem cell fate in cancer growth, progression and therapy resistance. Nat Rev Cancer. 2018;18:669–80.

Article  CAS  PubMed  PubMed Central  Google Scholar 

MacPherson L, Anokye J, Yeung MM, Lam EYN, Chan Y, Weng C, et al. Hbo1 is required for the maintenance of leukaemia stem cells. Nature. 2020;577:266–70.

Article  CAS  PubMed  Google Scholar 

Shlush LI, Mitchell A, Heisler L, Abelson S, Ng S, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104–8.

Article  CAS  PubMed  Google Scholar 

Trumpp A, Haas S. Cancer stem cells: the adventurous journey from hematopoietic to leukemic stem cells. Cell. 2022;185:1266–70.

Article  CAS  PubMed  Google Scholar 

Gorgoulis V, Adams PD, Alimonti A, Bennett DC, Bischof O, Bishop C, et al. Cellular senescence: defining a path forward. Cell. 2019;179:813–27.

Article  CAS  PubMed  Google Scholar 

Ruscetti M, Morris JP, Mezzadra R, Russell J, Leibold J, Romesser PB, et al. Senescence-induced vascular remodeling creates therapeutic vulnerabilities in pancreas cancer. Cell. 2020;181:424–41.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Schmitt CA, Wang B, Demaria M. Senescence and cancer - role and therapeutic opportunities. Nat Rev Clin Oncol. 2022;19:619–36.

Article  PubMed  PubMed Central  Google Scholar 

Wang L, Lankhorst L, Bernards R. Exploiting senescence for the treatment of cancer. Nat Rev Cancer. 2022;22:340–55.

Article  CAS  PubMed  Google Scholar 

Niu J, Peng D, Liu L. Drug resistance mechanisms of acute myeloid leukemia stem cells. Front Oncol. 2022;12:896426.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bourdeau V, Ferbeyre G. Engaging a senescent response to cure leukemia. Nat Med. 2014;20:123–4.

Article  CAS  PubMed  Google Scholar 

Peng D, Wang H, Li L, Ma X, Chen Y, Zhou H, et al. Mir-34c-5p promotes eradication of acute myeloid leukemia stem cells by inducing senescence through selective rab27b targeting to inhibit exosome shedding. Leukemia. 2018;32:1180–8.

Article  CAS  PubMed  Google Scholar 

Abdul-Aziz AM, Sun Y, Hellmich C, Marlein CR, Mistry J, Forde E, et al. Acute myeloid leukemia induces protumoral p16ink4a-driven senescence in the bone marrow microenvironment. Blood. 2019;133:446–56.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kumar B, Garcia M, Weng L, Jung X, Murakami JL, Hu X, et al. Acute myeloid leukemia transforms the bone marrow niche into a leukemia-permissive microenvironment through exosome secretion. Leukemia. 2018;32:575–87.

Article  CAS  PubMed  Google Scholar 

Lim M, Pang Y, Ma S, Hao S, Shi H, Zheng Y, et al. Altered mesenchymal niche cells impede generation of normal hematopoietic progenitor cells in leukemic bone marrow. Leukemia. 2016;30:154–62.

Article  CAS  PubMed  Google Scholar 

Geyh S, Rodriguez-Paredes M, Jager P, Khandanpour C, Cadeddu RP, Gutekunst J, et al. Functional inhibition of mesenchymal stromal cells in acute myeloid leukemia. Leukemia. 2016;30:683–91.

Article  CAS  PubMed  Google Scholar 

Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, et al. Rab27a and rab27b control different steps of the exosome secretion pathway. Nat Cell Biol. 2010;12:19–30.

Article  CAS  PubMed  Google Scholar 

Yang J, Zhang G, Zhang Q, Zhang Y, Zhang Z, Ni X, et al. Zip4 promotes muscle wasting and cachexia in mice with orthotopic pancreatic tumors by stimulating rab27b-regulated release of extracellular vesicles from cancer cells. Gastroenterology. 2019;156:722–34.

Article  CAS  PubMed  Google Scholar 

Song L, Tang S, Han X, Jiang Z, Dong L, Liu C, et al. Kibra controls exosome secretion via inhibiting the proteasomal degradation of rab27a. Nat Commun. 2019;10:1639.

Article  PubMed  PubMed Central  Google Scholar 

Fujii M, Kawai Y, Endoh M, Hossain MN, Nakabayashi K, Ayusawa D. Expression of rab27b is up-regulated in senescent human cells. Mech Ageing Dev. 2006;127:639–42.

Article  CAS  PubMed  Google Scholar 

Crescitelli R, Lässer C, Szabó TG, Kittel A, Eldh M, Dianzani I, et al. Distinct rna profiles in subpopulations of extracellular vesicles: apoptotic bodies, microvesicles and exosomes. J Extracell Vesicles. 2013;2:20677.

Article  Google Scholar 

Wen J, Chen Y, Liao C, Ma X, Wang M, Li Q, et al. Engineered mesenchymal stem cell exosomes loaded with mir-34c-5p selectively promote eradication of acute myeloid leukemia stem cells. Cancer Lett. 2023;575:216407.

Article  CAS  PubMed  Google Scholar 

Jing B, Qian R, Jiang D, Gai Y, Liu Z, Guo F, et al. Extracellular vesicles-based pre-targeting strategy enables multi-modal imaging of orthotopic colon cancer and image-guided surgery. J Nanobiotechnology. 2021;19:151.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mercier FE, Shi J, Sykes DB, Oki T, Jankovic M, Man CH, et al. In vivo genome-wide crispr screening in murine acute myeloid leukemia uncovers microenvironmental dependencies. Blood Adv. 2022;6:5072–84.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Ng SW, Mitchell A, Kennedy JA, Chen WC, McLeod J, Ibrahimova N, et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature. 2016;540:433–7.

Article  CAS  PubMed  Google Scholar 

van Galen P, Hovestadt V, Wadsworth IM, Hughes TK, Griffin GK, Battaglia S, et al. Single-cell rna-seq reveals aml hierarchies relevant to disease progression and immunity. Cell. 2019;176:1265–81.

Article  PubMed  PubMed Central  Google Scholar 

Saul D, Kosinsky RL, Atkinson EJ, Doolittle ML, Zhang X, LeBrasseur NK, et al. A new gene set identifies senescent cells and predicts senescence-associated pathways across tissues. Nat Commun. 2022;13:4827.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Leidal AM, Huang HH, Marsh T, Solvik T, Zhang D, Ye J, et al. The lc3-conjugation machinery specifies the loading of rna-binding proteins into extracellular vesicles. Nat Cell Biol. 2020;22:187–99.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zeng Q, Saghafinia S, Chryplewicz A, Fournier N, Christe L, Xie Y, et al. Aberrant hyperexpression of the rna binding protein fmrp in tumors mediates immune evasion. Science. 2022;378:eabl7207.

Article  CAS  PubMed  Google Scholar 

Guo D, Lui G, Lai SL, Wilmott JS, Tikoo S, Jackett LA, et al. Rab27a promotes melanoma cell invasion and metastasis via regulation of pro-invasive exosomes. Int J Cancer. 2019;144:3070–85.

Article  CAS  PubMed  Google Scholar 

Borghesan M, Fafián-Labora J, Eleftheriadou O, Carpintero-Fernández P, Paez-Ribes M, Vizcay-Barrena G, et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein ifitm3. Cell Rep. 2019;27:3956–71.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang M, Liu L, Lin X, Wang Y, Li Y, Guo Q, et al. A translocation pathway for vesicle-mediated unconventional protein secretion. Cell. 2020;181:637–52.

Article  CAS  PubMed  Google Scholar 

Jeppesen DK, Fenix AM, Franklin JL, Higginbotham JN, Zhang Q, Zimmerman LJ, et al. Reassessment of exosome composition. Cell. 2019;177:428–45.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28:436–53.

Article  CAS  PubMed  Google Scholar 

Weng Z, Wang Y, Ouchi T, Liu H, Qiao X, Wu C, et al. Mesenchymal stem/stromal cell senescence: hallmarks, mechanisms, and combating strategies. Stem Cells Transl Med. 2022;11:356–71.

Article  PubMed  PubMed Central  Google Scholar 

Duy C, Li M, Teater M, Meydan C, Garrett-Bakelman FE, Lee TC, et al. Chemotherapy induces senescence-like resilient cells capable of initiating aml recurrence. Cancer Discov. 2021;11:1542–61.

Article  CAS  PubMed  PubMed Central 

Comments (0)

No login
gif