Table Info

Table 2.

Association of TGF-β signaling with drug resistance across various cancer types

Effect of TGF-β signaling	Mechanism of drug resistance	Cancer type(s) implicated	Reference(s)
Overall association	Activation of TGF-β signaling often correlates with increased drug resistance.	Melanoma, non-small cell lung cancer, breast cancer, hepatocellular carcinoma, colorectal cancer, squamous cell carcinoma, osteosarcoma, and tumor-initiating cells.	[44, 73, 111–116]
Exosome-mediated transfer	Exosome-mediated transfer of TGF-β1 from resistant cells increases cell survival, reduces apoptosis, and enhances cell mobility.	Breast cancer.	[123]
Autophagy promotion	TGF-β promotes autophagy, leading to increased drug resistance.	Osteosarcoma (specifically, in mesenchymal stem cells), breast and pancreatic cancer cell lines.	[25, 124]
Quiescence/senescence	TGF-β activation leads to a population of slow-cycling cells resistant to cisplatin, potentially via NRF2 and p21 overexpression.	Squamous cell carcinoma.	[72]
Cancer stem cell induction	TGF-β can activate the AKT pathway, leading to increased expression of cancer stem cell markers (SOX2, ABCG2) and cisplatin resistance.	Squamous cell carcinoma.	[126]
Pathway downregulation	Downregulation of TGF-β signaling (e.g., MITF inhibition, SMAD2 downregulation, and SMAD4 loss) can paradoxically lead to drug resistance by upregulating anti-apoptotic proteins.	Melanoma, non-small cell lung cancer, and colorectal cancer.	[128–130]

TGF-β: transforming growth factor-β

Declarations

Author contributions

TR: Conceptualization, Investigation, Project administration, Supervision, Visualization, Writing—original draft, Writing—review & editing. NP: Data curation, Investigation, Writing—original draft, Writing—review & editing.

Conflicts of interest

The authors report no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Wan Z, Gao X, Dong Y, Zhao Y, Chen X, Yang G, et al. Exosome-mediated cell-cell communication in tumor progression. Am J Cancer Res. 2018;8:1661–73. [PubMed] [PMC]

Palmulli R, Couty M, Piontek MC, Ponnaiah M, Dingli F, Verweij FJ, et al. CD63 sorts cholesterol into endosomes for storage and distribution via exosomes. Nat Cell Biol. 2024;26:1093–109. [DOI] [PubMed]

Ghossoub R, Lembo F, Rubio A, Gaillard CB, Bouchet J, Vitale N, et al. Syntenin-ALIX exosome biogenesis and budding into multivesicular bodies are controlled by ARF6 and PLD2. Nat Commun. 2014;5:3477. [DOI] [PubMed]

Xu J, Zhang J, Zhang Z, Gao Z, Qi Y, Qiu W, et al. Hypoxic glioma-derived exosomes promote M2-like macrophage polarization by enhancing autophagy induction. Cell Death Dis. 2021;12:373. [DOI] [PubMed] [PMC]

Altea-Manzano P, Doglioni G, Liu Y, Cuadros AM, Nolan E, Fernández-García J, et al. A palmitate-rich metastatic niche enables metastasis growth via p65 acetylation resulting in pro-metastatic NF-κB signaling. Nat Cancer. 2023;4:344–64. [DOI] [PubMed] [PMC]

Castaneda M, den Hollander P, Kuburich NA, Rosen JM, Mani SA. Mechanisms of cancer metastasis. Semin Cancer Biol. 2022;87:17–31. [DOI] [PubMed]

Hosseini H, Obradović MMS, Hoffmann M, Harper KL, Sosa MS, Werner-Klein M, et al. Early dissemination seeds metastasis in breast cancer. Nature. 2016;540:552–8. [DOI] [PubMed] [PMC]

Bliss SA, Sinha G, Sandiford OA, Williams LM, Engelberth DJ, Guiro K, et al. Mesenchymal Stem Cell-Derived Exosomes Stimulate Cycling Quiescence and Early Breast Cancer Dormancy in Bone Marrow. Cancer Res. 2016;76:5832–44. [DOI] [PubMed]

Wu D, Yan J, Shen X, Sun Y, Thulin M, Cai Y, et al. Profiling surface proteins on individual exosomes using a proximity barcoding assay. Nat Commun. 2019;10:3854. [DOI] [PubMed] [PMC]

10.

Ji Y, Luo Z, Gao H, Dos Reis FCG, Bandyopadhyay G, Jin Z, et al. Hepatocyte-derived exosomes from early onset obese mice promote insulin sensitivity through miR-3075. Nat Metab. 2021;3:1163–74. [DOI] [PubMed] [PMC]

11.

Attaran S, Bissell MJ. The role of tumor microenvironment and exosomes in dormancy and relapse. Semin Cancer Biol. 2022;78:35–44. [DOI] [PubMed] [PMC]

12.

Bhatia R, Chang J, Munoz JL, Walker ND. Forging New Therapeutic Targets: Efforts of Tumor Derived Exosomes to Prepare the Pre-Metastatic Niche for Cancer Cell Dissemination and Dormancy. Biomedicines. 2023;11:1614. [DOI] [PubMed] [PMC]

13.

Pan BT, Johnstone RM. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor. Cell. 1983;33:967–78. [DOI] [PubMed]

14.

Zhang Y, Liu Y, Liu H, Tang WH. Exosomes: biogenesis, biologic function and clinical potential. Cell Biosci. 2019;9:19. [DOI] [PubMed] [PMC]

15.

Brinton LT, Sloane HS, Kester M, Kelly KA. Formation and role of exosomes in cancer. Cell Mol Life Sci. 2015;72:659–71. [DOI] [PubMed] [PMC]

16.

You B, Xu W, Zhang B. Engineering exosomes: a new direction for anticancer treatment. Am J Cancer Res. 2018;8:1332–42. [PubMed] [PMC]

17.

Mathieu M, Névo N, Jouve M, Valenzuela JI, Maurin M, Verweij FJ, et al. Specificities of exosome versus small ectosome secretion revealed by live intracellular tracking of CD63 and CD9. Nat Commun. 2021;12:4389. [DOI] [PubMed] [PMC]

18.

Fuentes P, Sesé M, Guijarro PJ, Emperador M, Sánchez-Redondo S, Peinado H, et al. ITGB3-mediated uptake of small extracellular vesicles facilitates intercellular communication in breast cancer cells. Nat Commun. 2020;11:4261. [DOI] [PubMed] [PMC]

19.

Men Y, Yelick J, Jin S, Tian Y, Chiang MSR, Higashimori H, et al. Exosome reporter mice reveal the involvement of exosomes in mediating neuron to astroglia communication in the CNS. Nat Commun. 2019;10:4136. [DOI] [PubMed] [PMC]

20.

Al-Nedawi K, Meehan B, Micallef J, Lhotak V, May L, Guha A, et al. Intercellular transfer of the oncogenic receptor EGFRvIII by microvesicles derived from tumour cells. Nat Cell Biol. 2008;10:619–24. [DOI] [PubMed]

21.

Montermini L, Meehan B, Garnier D, Lee WJ, Lee TH, Guha A, et al. Inhibition of oncogenic epidermal growth factor receptor kinase triggers release of exosome-like extracellular vesicles and impacts their phosphoprotein and DNA content. J Biol Chem. 2015;290:24534–46. [DOI] [PubMed] [PMC]

22.

Di Giuseppe F, Carluccio M, Zuccarini M, Giuliani P, Ricci-Vitiani L, Pallini R, et al. Proteomic Characterization of Two Extracellular Vesicle Subtypes Isolated from Human Glioblastoma Stem Cell Secretome by Sequential Centrifugal Ultrafiltration. Biomedicines. 2021;9:146. [DOI] [PubMed] [PMC]

23.

Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527:329–35. [DOI] [PubMed] [PMC]

24.

García-Silva S, Benito-Martín A, Nogués L, Hernández-Barranco A, Mazariegos MS, Santos V, et al. Melanoma-derived small extracellular vesicles induce lymphangiogenesis and metastasis through an NGFR-dependent mechanism. Nat Cancer. 2021;2:1387–405. [DOI] [PubMed] [PMC]

25.

Mondal SK, Haas D, Han J, Whiteside TL. Small EV in plasma of triple negative breast cancer patients induce intrinsic apoptosis in activated T cells. Commun Biol. 2023;6:815. [DOI] [PubMed] [PMC]

26.

Madeo M, Colbert PL, Vermeer DW, Lucido CT, Cain JT, Vichaya EG, et al. Cancer exosomes induce tumor innervation. Nat Commun. 2018;9:4284. [DOI] [PubMed] [PMC]

27.

Cao M, Isaac R, Yan W, Ruan X, Jiang L, Wan Y, et al. Cancer-cell-secreted extracellular vesicles suppress insulin secretion through miR-122 to impair systemic glucose homeostasis and contribute to tumour growth. Nat Cell Biol. 2022;24:954–67. [DOI] [PubMed] [PMC]

28.

Gross JC, Chaudhary V, Bartscherer K, Boutros M. Active Wnt proteins are secreted on exosomes. Nat Cell Biol. 2012;14:1036–45. [DOI] [PubMed]

29.

Namburi S, Broxmeyer HE, Hong CS, Whiteside TL, Boyiadzis M. DPP4⁺ exosomes in AML patients’ plasma suppress proliferation of hematopoietic progenitor cells. Leukemia. 2021;35:1925–32. [DOI] [PubMed] [PMC]

30.

Shan G, Gu J, Zhou D, Li L, Cheng W, Wang Y, et al. Cancer-associated fibroblast-secreted exosomal miR-423-5p promotes chemotherapy resistance in prostate cancer by targeting GREM2 through the TGF-β signaling pathway. Exp Mol Med. 2020;52:1809–22. [DOI] [PubMed] [PMC]

31.

Yong T, Zhang X, Bie N, Zhang H, Zhang X, Li F, et al. Tumor exosome-based nanoparticles are efficient drug carriers for chemotherapy. Nat Commun. 2019;10:3838. [DOI] [PubMed] [PMC]

32.

Lee YJ, Shin KJ, Chae YC. Regulation of cargo selection in exosome biogenesis and its biomedical applications in cancer. Exp Mol Med. 2024;56:877–89. [DOI] [PubMed] [PMC]

33.

Gonzalez MJ, Kweh MF, Biava PM, Olalde J, Toro AP, Goldschmidt-Clermont PJ, et al. Evaluation of exosome derivatives as bio-informational reprogramming therapy for cancer. J Transl Med. 2021;19:103. [DOI] [PubMed] [PMC]

34.

Bruno S, Collino F, Deregibus MC, Grange C, Tetta C, Camussi G. Microvesicles derived from human bone marrow mesenchymal stem cells inhibit tumor growth. Stem Cells Dev. 2013;22:758–71. [DOI] [PubMed]

35.

Zhou S, Abdouh M, Arena V, Arena M, Arena GO. Reprogramming Malignant Cancer Cells toward a Benign Phenotype following Exposure to Human Embryonic Stem Cell Microenvironment. PLoS One. 2017;12:e0169899. [DOI] [PubMed] [PMC]

36.

Hardin H, Helein H, Meyer K, Robertson S, Zhang R, Zhong W, et al. Thyroid cancer stem-like cell exosomes: regulation of EMT via transfer of lncRNAs. Lab Invest. 2018;98:1133–42. [DOI] [PubMed] [PMC]

37.

Esimbekova AR, Palkina NV, Zinchenko IS, Belenyuk VD, Savchenko AA, Sergeeva EY, et al. Focal adhesion alterations in G0-positive melanoma cells. Cancer Med. 2023;12:7294–308. [DOI] [PubMed] [PMC]

38.

Fluegen G, Avivar-Valderas A, Wang Y, Padgen MR, Williams JK, Nobre AR, et al. Phenotypic heterogeneity of disseminated tumour cells is preset by primary tumour hypoxic microenvironments. Nat Cell Biol. 2017;19:120–32. [DOI] [PubMed] [PMC]

39.

Gos M, Miloszewska J, Swoboda P, Trembacz H, Skierski J, Janik P. Cellular quiescence induced by contact inhibition or serum withdrawal in C3H10T1/2 cells. Cell Prolif. 2005;38:107–16. [DOI] [PubMed] [PMC]

40.

Carcereri de Prati A, Butturini E, Rigo A, Oppici E, Rossin M, Boriero D, et al. Metastatic Breast Cancer Cells Enter Into Dormant State and Express Cancer Stem Cells Phenotype Under Chronic Hypoxia. J Cell Biochem. 2017;118:3237–48. [DOI] [PubMed]

41.

Bragado P, Estrada Y, Parikh F, Krause S, Capobianco C, Farina HG, et al. TGF-β2 dictates disseminated tumour cell fate in target organs through TGF-β-RIII and p38α/β signalling. Nat Cell Biol. 2013;15:1351–61. [DOI] [PubMed] [PMC]

42.

Kye YC, Lee GW, Lee SW, Ju YJ, Kim HO, Yun CH, et al. STAT1 maintains naïve CD8⁺ T cell quiescence by suppressing the type I IFN-STAT4-mTORC1 signaling axis. Sci Adv. 2021;7:eabg8764. [DOI] [PubMed] [PMC]

43.

Khalil BD, Sanchez R, Rahman T, Rodriguez-Tirado C, Moritsch S, Martinez AR, et al. An NR2F1-specific agonist suppresses metastasis by inducing cancer cell dormancy. J Exp Med. 2022;219:e20210836. [DOI] [PubMed] [PMC]

44.

Batlle E, Massagué J. Transforming Growth Factor-β Signaling in Immunity and Cancer. Immunity. 2019;50:924–40. [DOI] [PubMed] [PMC]

45.

Massagué J. How cells read TGF-β signals. Nat Rev Mol Cell Biol. 2000;1:169–78. [DOI] [PubMed]

46.

Kubiczkova L, Sedlarikova L, Hajek R, Sevcikova S. TGF-β - an excellent servant but a bad master. J Transl Med. 2012;10:183. [DOI] [PubMed] [PMC]

47.

Franzén P, Heldin CH, Miyazono K. The GS domain of the transforming growth factor-β type-I receptor is important in signal transduction. Biochem Biophys Res Commun. 1995;207:682–9. [DOI] [PubMed]

48.

Heldin CH, Miyazono K, ten Dijke P. TGF-β signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;390:465–71. [DOI] [PubMed]

49.

Cooley A, Zelivianski S, Jeruss JS. Impact of cyclin E overexpression on Smad3 activity in breast cancer cell lines. Cell Cycle. 2010;9:4900–7. [DOI] [PubMed] [PMC]

50.

Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-β signaling in health, disease and therapeutics. Signal Transduct Target Ther. 2024;9:61. [DOI] [PubMed] [PMC]

51.

Ji Z, Siu WS, Dueñas ME, Müller L, Trost M, Carvalho P. Suppression of TGF-β/SMAD signaling by an inner nuclear membrane phosphatase complex. Nat Commun. 2025;16:3474. [DOI] [PubMed] [PMC]

52.

Inoue Y, Imamura T. Regulation of TGF-β family signaling by E3 ubiquitin ligases. Cancer Sci. 2008;99:2107–12. [DOI] [PubMed] [PMC]

53.

Shi Y, Massagué J. Mechanisms of TGF-β Signaling from Cell Membrane to the Nucleus. Cell. 2003;113:685–700. [DOI] [PubMed]

54.

Zhang YE. Non-Smad pathways in TGF-β signaling. Cell Res. 2009;19:128–39. [DOI] [PubMed] [PMC]

55.

Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12:9–18. [DOI] [PubMed]

56.

Ungefroren H, Witte D, Lehnert H. The role of small GTPases of the Rho/Rac family in TGF-β-induced EMT and cell motility in cancer. Dev Dyn. 2018;247:451–61. [DOI] [PubMed]

57.

Sivadas VP, George NA, Kattoor J, Kannan S. Novel mutations and expression alterations in SMAD3/TGFBR2 genes in oral carcinoma correlate with poor prognosis. Genes Chromosomes Cancer. 2013;52:1042–52. [DOI] [PubMed]

58.

Principe DR, DeCant B, Mascariñas E, Wayne EA, Diaz AM, Akagi N, et al. TGFβ Signaling in the Pancreatic Tumor Microenvironment Promotes Fibrosis and Immune Evasion to Facilitate Tumorigenesis. Cancer Res. 2016;76:2525–39. [DOI] [PubMed] [PMC]

59.

Jung B, Staudacher JJ, Beauchamp D. Transforming Growth Factor β Superfamily Signaling in Development of Colorectal Cancer. Gastroenterology. 2017;152:36–52. [DOI] [PubMed] [PMC]

60.

Friese MA, Wischhusen J, Wick W, Weiler M, Eisele G, Steinle A, et al. RNA Interference Targeting Transforming Growth Factor-β Enhances NKG2D-Mediated Antiglioma Immune Response, Inhibits Glioma Cell Migration and Invasiveness, and Abrogates Tumorigenicity In vivo. Cancer Res. 2004;64:7596–603. [DOI] [PubMed]

61.

Wick A, Desjardins A, Suarez C, Forsyth P, Gueorguieva I, Burkholder T, et al. Phase 1b/2a study of galunisertib, a small molecule inhibitor of transforming growth factor-beta receptor I, in combination with standard temozolomide-based radiochemotherapy in patients with newly diagnosed malignant glioma. Invest New Drugs. 2020;38:1570–9. [DOI] [PubMed] [PMC]

62.

Morris JC, Tan AR, Olencki TE, Shapiro GI, Dezube BJ, Reiss M, et al. Phase I study of GC1008 (fresolimumab): a human anti-transforming growth factor-beta (TGFβ) monoclonal antibody in patients with advanced malignant melanoma or renal cell carcinoma. PLoS One. 2014;9:e90353. [DOI] [PubMed] [PMC]

63.

Bogdahn U, Hau P, Stockhammer G, Venkataramana NK, Mahapatra AK, Suri A, et al.; Trabedersen Glioma Study Group. Targeted therapy for high-grade glioma with the TGF-β2 inhibitor trabedersen: results of a randomized and controlled phase IIb study. Neuro Oncol. 2011;13:132–42. [DOI] [PubMed] [PMC]

64.

Chandramohan V, Mineva ND, Burke B, Jeay S, Wu M, Shen J, et al. c-Myc represses FOXO3a-mediated transcription of the gene encoding the p27^Kip1 cyclin dependent kinase inhibitor. J Cell Biochem. 2008;104:2091–106. [DOI] [PubMed]

65.

Lanvin O, Guglielmi P, Fuentes V, Gouilleux-Gruart V, Mazière C, Bissac E, et al. TGF-β1 modulates Fas (APO-1/CD95)-mediated apoptosis of human pre-B cell lines. Eur J Immunol. 2003;33:1372–81. [DOI] [PubMed]

66.

Schulz R, Vogel T, Dressel R, Krieglstein K. TGF-β superfamily members, ActivinA and TGF-β1, induce apoptosis in oligodendrocytes by different pathways. Cell Tissue Res. 2008;334:327–38. [DOI] [PubMed]

67.

Wang C, Yang S, Huang X, Lu Y, Zhang Y, Li M, et al. TGF-β1 reduces the differentiation of porcine IgA-producing plasma cells by inducing IgM⁺ B cells apoptosis via Bax/Bcl2-Caspase3 pathway. FASEB J. 2023;37:e23180. [DOI] [PubMed]

68.

Varveri A, Papadopoulou M, Papadovasilakis Z, Compeer EB, Legaki AI, Delis A, et al. Immunological synapse formation between T regulatory cells and cancer-associated fibroblasts promotes tumour development. Nat Commun. 2024;15:4988. [DOI] [PubMed] [PMC]

69.

Nan P, Dong X, Bai X, Lu H, Liu F, Sun Y, et al. Tumor-stroma TGF-β1-THBS2 feedback circuit drives pancreatic ductal adenocarcinoma progression via integrin α_vβ₃/CD36-mediated activation of the MAPK pathway. Cancer Lett. 2022;528:59–75. [DOI] [PubMed]

70.

Shen Y, TanTai J. Exosomes secreted by metastatic cancer cells promotes epithelial mesenchymal transition in small cell lung carcinoma: The key role of Src/TGF-β1 axis. Gene. 2024;892:147873. [DOI] [PubMed]

71.

Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H, et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol. 2013;15:807–17. [DOI] [PubMed] [PMC]

72.

Oshimori N, Oristian D, Fuchs E. TGF-β promotes heterogeneity and drug resistance in squamous cell carcinoma. Cell. 2015;160:963–76. [DOI] [PubMed] [PMC]

73.

Brown JA, Yonekubo Y, Hanson N, Sastre-Perona A, Basin A, Rytlewski JA, et al. TGF-β-Induced Quiescence Mediates Chemoresistance of Tumor-Propagating Cells in Squamous Cell Carcinoma. Cell Stem Cell. 2017;21:650–64.e8. [DOI] [PubMed] [PMC]

74.

Schober M, Fuchs E. Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-β and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci U S A. 2011;108:10544–9. [DOI] [PubMed] [PMC]

75.

Yumoto K, Eber MR, Wang J, Cackowski FC, Decker AM, Lee E, et al. Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep. 2016;6:36520. [DOI] [PubMed] [PMC]

76.

Johnson RW, Finger EC, Olcina MM, Vilalta M, Aguilera T, Miao Y, et al. Induction of LIFR confers a dormancy phenotype in breast cancer cells disseminated to the bone marrow. Nat Cell Biol. 2016;18:1078–89. [DOI] [PubMed] [PMC]

77.

Kucharzewska P, Christianson HC, Welch JE, Svensson KJ, Fredlund E, Ringnér M, et al. Exosomes reflect the hypoxic status of glioma cells and mediate hypoxia-dependent activation of vascular cells during tumor development. Proc Natl Acad Sci U S A. 2013;110:7312–7. [DOI] [PubMed] [PMC]

78.

Clayton A, Mitchell JP, Court J, Mason MD, Tabi Z. Human tumor-derived exosomes selectively impair lymphocyte responses to interleukin-2. Cancer Res. 2007;67:7458–66. [DOI] [PubMed]

79.

X Xiang X, Poliakov A, Liu C, Liu Y, Deng ZB, Wang J, et al. Induction of myeloid-derived suppressor cells by tumor exosomes. Int J Cancer. 2009;124:2621–33. [DOI] [PubMed] [PMC]

80.

Ludwig N, Yerneni SS, Azambuja JH, Pietrowska M, Widłak P, Hinck CS, et al. TGFβ⁺ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype. J Extracell Vesicles. 2022;11:e12294. [DOI] [PubMed] [PMC]

81.

Shelke GV, Yin Y, Jang SC, Lässer C, Wennmalm S, Hoffmann HJ, et al. Endosomal signalling via exosome surface TGFβ-1. J Extracell Vesicles. 2019;8:1650458. [DOI] [PubMed] [PMC]

82.

Xie F, Zhou X, Su P, Li H, Tu Y, Du J, et al. Breast cancer cell-derived extracellular vesicles promote CD8⁺ T cell exhaustion via TGF-β type II receptor signaling. Nat Commun. 2022;13:4461. [DOI] [PubMed] [PMC]

83.

Fu XH, Li JP, Li XY, Tan Y, Zhao M, Zhang SF, et al. M2-Macrophage-Derived Exosomes Promote Meningioma Progression through TGF-β Signaling Pathway. J Immunol Res. 2022;2022:8326591. [DOI] [PubMed] [PMC]

84.

T Teixeira AF, Wang Y, Iaria J, Ten Dijke P, Zhu HJ. Simultaneously targeting extracellular vesicle trafficking and TGF-β receptor kinase activity blocks signaling hyperactivation and metastasis. Signal Transduct Target Ther. 2023;8:456. [DOI] [PubMed] [PMC]

85.

Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol. 2017;216:3799–816. [DOI] [PubMed] [PMC]

86.

Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98. [DOI] [PubMed]

87.

Kumar P, Smith T, Raeman R, Chopyk DM, Brink H, Liu Y, et al. Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells. J Biol Chem. 2018;293:12781–92. [DOI] [PubMed] [PMC]

88.

Chakravarthy A, Khan L, Bensler NP, Bose P, De Carvalho DD. TGF-β-associated extracellular matrix genes link cancer-associated fibroblasts to immune evasion and immunotherapy failure. Nat Commun. 2018;9:4692. [DOI] [PubMed] [PMC]

89.

Webber J, Steadman R, Mason MD, Tabi Z, Clayton A. Cancer exosomes trigger fibroblast to myofibroblast differentiation. Cancer Res. 2010;70:9621–30. [DOI] [PubMed]

90.

Ringuette Goulet C, Bernard G, Tremblay S, Chabaud S, Bolduc S, Pouliot F. Exosomes Induce Fibroblast Differentiation into Cancer-Associated Fibroblasts through TGFβ Signaling. Mol Cancer Res. 2018;16:1196–204. [DOI] [PubMed]

91.

Gu J, Qian H, Shen L, Zhang X, Zhu W, Huang L, et al. Gastric cancer exosomes trigger differentiation of umbilical cord derived mesenchymal stem cells to carcinoma-associated fibroblasts through TGF-β/Smad pathway. PLoS One. 2012;7:e52465. [DOI] [PubMed] [PMC]

92.

Baglio SR, Lagerweij T, Pérez-Lanzón M, Ho XD, Léveillé N, Melo SA, et al. Blocking Tumor-Educated MSC Paracrine Activity Halts Osteosarcoma Progression. Clin Cancer Res. 2017;23:3721–33. [DOI] [PubMed]

93.

Shang A, Gu C, Wang W, Wang X, Sun J, Zeng B, et al. Exosomal circPACRGL promotes progression of colorectal cancer via the miR-142-3p/miR-506-3p- TGF-β1 axis. Mol Cancer. 2020;19:117. [DOI] [PubMed] [PMC]

94.

Tuncer E, Calçada RR, Zingg D, Varum S, Cheng P, Freiberger SN, et al. SMAD signaling promotes melanoma metastasis independently of phenotype switching. J Clin Invest. 2019;129:2702–16. [DOI] [PubMed] [PMC]

95.

Webber JP, Spary LK, Sanders AJ, Chowdhury R, Jiang WG, Steadman R, et al. Differentiation of tumour-promoting stromal myofibroblasts by cancer exosomes. Oncogene. 2015;34:290–302. [DOI] [PubMed]

96.

Jafarzadeh N, Safari Z, Pornour M, Amirizadeh N, Forouzandeh Moghadam M, Sadeghizadeh M. Alteration of cellular and immune-related properties of bone marrow mesenchymal stem cells and macrophages by K562 chronic myeloid leukemia cell derived exosomes. J Cell Physiol. 2019;234:3697–710. [DOI] [PubMed]

97.

Aksenenko MB, Palkina NV, Sergeeva ON, Yu Sergeeva E, Kirichenko AK, Ruksha TG. miR-155 overexpression is followed by downregulation of its target gene, NFE2L2, and altered pattern of VEGFA expression in the liver of melanoma B16-bearing mice at the premetastatic stage. Int J Exp Pathol. 2019;100:311–9. [DOI] [PubMed] [PMC]

98.

Costa-Silva B, Aiello NM, Ocean AJ, Singh S, Zhang H, Thakur BK, et al. Pancreatic cancer exosomes initiate pre-metastatic niche formation in the liver. Nat Cell Biol. 2015;17:816–26. [DOI] [PubMed] [PMC]

99.

Li C, Qiu S, Liu X, Guo F, Zhai J, Li Z, et al. Extracellular matrix-derived mechanical force governs breast cancer cell stemness and quiescence transition through integrin-DDR signaling. Signal Transduct Target Ther. 2023;8:247. [DOI] [PubMed] [PMC]

100.

Hsu YL, Huang MS, Hung JY, Chang WA, Tsai YM, Pan YC, et al. Bone-marrow-derived cell-released extracellular vesicle miR-92a regulates hepatic pre-metastatic niche in lung cancer. Oncogene. 2020;39:739–53. [DOI] [PubMed]

101.

Li Q, Hutchins AP, Chen Y, Li S, Shan Y, Liao B, et al. A sequential EMT-MET mechanism drives the differentiation of human embryonic stem cells towards hepatocytes. Nat Commun. 2017;8:15166. [DOI] [PubMed] [PMC]

102.

Esposito M, Mondal N, Greco TM, Wei Y, Spadazzi C, Lin SC, et al. Bone vascular niche E-selectin induces mesenchymal-epithelial transition and Wnt activation in cancer cells to promote bone metastasis. Nat Cell Biol. 2019;21:627–39. [DOI] [PubMed] [PMC]

103.

Feng X, Liu X, Xiang J, Xu J, Yin N, Wang L, et al. Exosomal ITGB6 from dormant lung adenocarcinoma cells activates cancer-associated fibroblasts by KLF10 positive feedback loop and the TGF-β pathway. Transl Lung Cancer Res. 2023;12:2520–37. [DOI] [PubMed] [PMC]

104.

Li W, Zhang X, Wang J, Li M, Cao C, Tan J, et al. TGFβ1 in fibroblasts-derived exosomes promotes epithelial-mesenchymal transition of ovarian cancer cells. Oncotarget. 2017;8:96035–47. [DOI] [PubMed] [PMC]

105.

Xia Y, Zhang Q, Zhen Q, Zhao Y, Liu N, Li T, et al. Negative regulation of tumor-infiltrating NK cell in clear cell renal cell carcinoma patients through the exosomal pathway. Oncotarget. 2017;8:37783–95. [DOI] [PubMed] [PMC]

106.

Long GV, Fung C, Menzies AM, Pupo GM, Carlino MS, Hyman J, et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat Commun. 2014;5:5694. [DOI] [PubMed]

107.

Komina AV, Palkina NV, Aksenenko MB, Lavrentev SN, Moshev AV, Savchenko AA, et al. Semaphorin-5A downregulation is associated with enhanced migration and invasion of BRAF-positive melanoma cells under vemurafenib treatment in melanomas with heterogeneous BRAF status. Melanoma Res. 2019;29:544–8. [DOI] [PubMed]

108.

Giddings EL, Champagne DP, Wu MH, Laffin JM, Thornton TM, Valenca-Pereira F, et al. Mitochondrial ATP fuels ABC transporter-mediated drug efflux in cancer chemoresistance. Nat Commun. 2021;12:2804. [DOI] [PubMed] [PMC]

109.

Goyal Y, Busch GT, Pillai M, Li J, Boe RH, Grody EI, et al. Diverse clonal fates emerge upon drug treatment of homogeneous cancer cells. Nature. 2023;620:651–9. [DOI] [PubMed] [PMC]

110.

Han X, Sui J, Nie K, Zhao Y, Lv X, Xie J, et al. Tumor evolution analysis uncovered immune-escape related mutations in relapse of diffuse large B-cell lymphoma. Leukemia. 2024;38:2276–80. [DOI] [PubMed]

111.

Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature. 2014;508:118–22. [DOI] [PubMed]

112.

Soucheray M, Capelletti M, Pulido I, Kuang Y, Paweletz CP, Becker JH, et al. Intratumoral Heterogeneity in EGFR-Mutant NSCLC Results in Divergent Resistance Mechanisms in Response to EGFR Tyrosine Kinase Inhibition. Cancer Res. 2015;75:4372–83. [DOI] [PubMed] [PMC]

113.

Palomeras S, Diaz-Lagares Á, Viñas G, Setien F, Ferreira HJ, Oliveras G, et al. Epigenetic silencing of TGFBI confers resistance to trastuzumab in human breast cancer. Breast Cancer Res. 2019;21:79. [DOI] [PubMed] [PMC]

114.

Bhagyaraj E, Ahuja N, Kumar S, Tiwari D, Gupta S, Nanduri R, et al. TGF-β induced chemoresistance in liver cancer is modulated by xenobiotic nuclear receptor PXR. Cell Cycle. 2019;18:3589–602. [DOI] [PubMed] [PMC]

115.

Quan Q, Zhong F, Wang X, Chen K, Guo L. PAR2 Inhibition Enhanced the Sensitivity of Colorectal Cancer Cells to 5-FU and Reduced EMT Signaling. Oncol Res. 2019;27:779–88. [DOI] [PubMed] [PMC]

116.

Wang T, Wang D, Zhang L, Yang P, Wang J, Liu Q, et al. The TGFβ-miR-499a-SHKBP1 pathway induces resistance to EGFR inhibitors in osteosarcoma cancer stem cell-like cells. J Exp Clin Cancer Res. 2019;38:226. [DOI] [PubMed] [PMC]

117.

Taniguchi S, Elhance A, Van Duzer A, Kumar S, Leitenberger JJ, Oshimori N. Tumor-initiating cells establish an IL-33-TGF-β niche signaling loop to promote cancer progression. Science. 2020;369:eaay1813. [DOI] [PubMed] [PMC]

118.

Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, et al. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015;47:320–9. [DOI] [PubMed]

119.

Okada Y, Wang T, Kasai K, Suzuki K, Takikawa Y. Regulation of transforming growth factor is involved in the efficacy of combined 5-fluorouracil and interferon alpha-2b therapy of advanced hepatocellular carcinoma. Cell Death Discov. 2018;4:42. [DOI] [PubMed] [PMC]

120.

Zhuang X, Wang J. Correlations of MRP1 gene with serum TGF-β1 and IL-8 in breast cancer patients during chemotherapy. J BUON. 2018;23:1302–8. [PubMed]

121.

Tauriello DVF. From poor prognosis to promising treatment. Science. 2019;363:1051. [DOI] [PubMed]

122.

Guo B, Wu S, Zhu X, Zhang L, Deng J, Li F, et al. Micropeptide CIP2A-BP encoded by LINC00665 inhibits triple-negative breast cancer progression. EMBO J. 2020;39:e102190. [DOI] [PubMed] [PMC]

123.

Tan C, Sun W, Xu Z, Zhu S, Hu W, Wang X, et al. Small extracellular vesicles deliver TGF-β1 and promote adriamycin resistance in breast cancer cells. Mol Oncol. 2021;15:1528–42. [DOI] [PubMed] [PMC]

124.

Feng H, Zhang Q, Zhao Y, Zhao L, Shan B. Leptin acts on mesenchymal stem cells to promote chemoresistance in osteosarcoma cells. Aging (Albany NY). 2020;12:6340–51. [DOI] [PubMed] [PMC]

125.

Lambies G, Miceli M, Martínez-Guillamon C, Olivera-Salguero R, Peña R, Frías CP, et al. TGFβ-Activated USP27X Deubiquitinase Regulates Cell Migration and Chemoresistance via Stabilization of Snail1. Cancer Res. 2019;79:33–46. [DOI] [PubMed] [PMC]

126.

Li K, Yang L, Li J, Guan C, Zhang S, Lao X, et al. TGFβ induces stemness through non-canonical AKT-FOXO3a axis in oral squamous cell carcinoma. EBioMedicine. 2019;48:70–80. [DOI] [PubMed] [PMC]

127.

Bugide S, Parajuli KR, Chava S, Pattanayak R, Manna DLD, Shrestha D, et al. Loss of HAT1 expression confers BRAFV600E inhibitor resistance to melanoma cells by activating MAPK signaling via IGF1R. Oncogenesis. 2020;9:44. [DOI] [PubMed] [PMC]

128.

Vu T, Yang S, Datta PK. MiR-216b/Smad3/BCL-2 Axis Is Involved in Smoking-Mediated Drug Resistance in Non-Small Cell Lung Cancer. Cancers (Basel). 2020;12:1879. [DOI] [PubMed] [PMC]

129.

Smith MP, Ferguson J, Arozarena I, Hayward R, Marais R, Chapman A, et al. Effect of SMURF2 targeting on susceptibility to MEK inhibitors in melanoma. J Natl Cancer Inst. 2013;105:33–46. [DOI] [PubMed] [PMC]

130.

Zhang B, Chen X, Bae S, Singh K, Washington MK, Datta PK. Loss of Smad4 in colorectal cancer induces resistance to 5-fluorouracil through activating Akt pathway. Br J Cancer. 2014;110:946–57. [DOI] [PubMed] [PMC]

131.

Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554:544–8. [DOI] [PubMed] [PMC]

132.

Ji Q, Zhou L, Sui H, Yang L, Wu X, Song Q, et al. Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nat Commun. 2020;11:1211. [DOI] [PubMed] [PMC]

133.

Mirzaei S, Gholami MH, Aghdaei HA, Hashemi M, Parivar K, Karamian A, et al. Exosome-mediated miR-200a delivery into TGF-β-treated AGS cells abolished epithelial-mesenchymal transition with normalization of ZEB1, vimentin and Snail1 expression. Environ Res. 2023;231:116115. [DOI] [PubMed]

134.

Chatterjee S, Chatterjee A, Jana S, Dey S, Roy H, Das MK, et al. Transforming growth factor beta orchestrates PD-L1 enrichment in tumor-derived exosomes and mediates CD8 T-cell dysfunction regulating early phosphorylation of TCR signalome in breast cancer. Carcinogenesis. 2021;42:38–47. [DOI] [PubMed]

135.

Singh DK, Carcamo S, Farias EF, Hasson D, Zheng W, Sun D, et al. 5-Azacytidine- and retinoic-acid-induced reprogramming of DCCs into dormancy suppresses metastasis via restored TGF-β-SMAD4 signaling. Cell Rep. 2023;42:112560. [DOI] [PubMed] [PMC]