Mechanisms of invadopodia in tumor metastasis and frontiers in therapeutic translation

doi:10.3760/cma.j.cn371439-20251009-00015

Abstract

Abstract:

Invadopodia are core subcellular structures in which tumor cells degrade extracellular matrix， drive local infiltration and distant metastasis. Recent studies have not only analyzed the molecular composition and dynamic assembly mechanisms， but also gradually revealed their central role as hubs in integrating tumor microenvironment signals and mediating regulatory heterogeneity across cancer types. It is noteworthy that therapeutic interventions such as radiotherapy or chemotherapy may inadvertently induce the activation of invadopodia， thus contributing to the development of tumor adaptive resistance. In response， multi-dimensional intervention strategies targeting invadopodial scaffold proteins， protease delivery systems， and extracellular vesicle-mediated communication are gaining momentum. Coupled with drug repositioning and precision nanodelivery technologies， these approaches can provide important theoretical basis and translation direction for the development of next-generation anti-metastatic therapies.

Key words: Podosomes, Neoplasm metastasis, Tumor microenvironment, Matrix metalloproteinases, Molecular targeted therapy

Zhang Long, Li Jianzhen, Zhang Wei. Mechanisms of invadopodia in tumor metastasis and frontiers in therapeutic translation[J]. Journal of International Oncology, 2026, 53(2): 100-104.

References 38

[1]	Wang YQ, Wang AJ, Zhang TT, et al. Association of alpha-fetoprotein and metastasis for small hepatocellular carcinoma: a propensity-matched analysis[J]. Sci Rep, 2022, 12(1): 15676. DOI: 10.1038/s41598-022-19531-8.
[2]	Li YL, Hung WC. Reprogramming of sentinel lymph node microenvironment during tumor metastasis[J]. J Biomed Sci, 2022, 29(1): 84. DOI: 10.1186/s12929-022-00868-1.
[3]	Ueshima S, Fang J. Histone H3K9 methyltransferase SETDB1 augments invadopodia formation to promote tumor metastasis[J]. Oncogene, 2022, 41(24): 3370-3380. DOI: 10.1038/s41388-022-02345-3. pmid: 35546351
[4]	Manuelli V, Cahill F, Wylie H, et al. Invadopodia play a role in prostate cancer progression[J]. BMC Cancer, 2022, 22(1): 386. DOI: 10.1186/s12885-022-09424-4.
[5]	Perrin L, Gligorijevic B. Proteolytic and mechanical remodeling of the extracellular matrix by invadopodia in cancer[J]. Phys Biol, 2022, 20(1): 015001. DOI: 10.1088/1478-3975/aca0d8.
[6]	Niland S, Riscanevo AX, Eble JA. Matrix metalloproteinases shape the tumor microenvironment in cancer progression[J]. Int J Mol Sci, 2021, 23(1): 146. DOI: 10.3390/ijms23010146.
[7]	Djediai S, Gonzalez Suarez N, El Cheikh-Hussein L, et al. MT1-MMP cooperates with TGF-β receptor-mediated signaling to trigger SNAIL and induce epithelial-to-mesenchymal-like transition in U87 glioblastoma cells[J]. Int J Mol Sci, 2021, 22(23): 13006. DOI: 10.3390/ijms222313006.
[8]	Linder S, Cervero P, Eddy R, et al. Mechanisms and roles of podosomes and invadopodia[J]. Nat Rev Mol Cell Biol, 2023, 24(2): 86-106. DOI: 10.1038/s41580-022-00530-6.
[9]	Loureiro FJA, Balbinot KM, da Silva Kataoka MS, et al. Invadopodia related-proteins expression in mucoepidermoid carcinoma[J]. Oral Dis, 2025, 31(8): 2427-2440. DOI: 10.1111/odi.15312.
[10]	Mishra YG, Manavathi B. Focal adhesion dynamics in cellular function and disease[J]. Cell Signal, 2021, 85: 110046. DOI: 10.1016/j.cellsig.2021.110046.
[11]	Xia XD, Alabi A, Wang M, et al. Membrane-type Ⅰ matrix metalloproteinase (MT1-MMP), lipid metabolism, and therapeutic implications[J]. J Mol Cell Biol, 2021, 13(7): 513-526. DOI: 10.1093/jmcb/mjab048.
[12]	Gil-Henn H, Girault JA, Lev S. PYK2, a hub of signaling networks in breast cancer progression[J]. Trends Cell Biol, 2024, 34(4): 312-326. DOI: 10.1016/j.tcb.2023.07.006.
[13]	Legrand M, Mousson A, Carl P, et al. Protein dynamics at invadopodia control invasion-migration transitions in melanoma cells[J]. Cell Death Dis, 2023, 14(3): 190. DOI: 10.1038/s41419-023-05704-4.
[14]	Quilaqueo-Millaqueo N, Brown-Brown DA, Vidal-Vidal JA, et al. NOX proteins and ROS generation: role in invadopodia formation and cancer cell invasion[J]. Biol Res, 2024, 57(1): 98. DOI: 10.1186/s40659-024-00577-z.
[15]	Mgrditchian T, Sakalauskaite G, Müller T, et al. The multiple roles of actin-binding proteins at invadopodia[J]. Int Rev Cell Mol Biol, 2021, 360: 99-132. DOI: 10.1016/bs.ircmb.2021.03.004. pmid: 33962752
[16]	Jiang Y, Zhang H, Wang J, et al. Targeting extracellular matrix stiffness and mechanotransducers to improve cancer therapy[J]. J Hematol Oncol, 2022, 15(1): 34. DOI: 10.1186/s13045-022-01252-0.
[17]	Kumar R, Tiwari V, Dey S. Role of proline-rich tyrosine kinase 2 (Pyk2) in the pathogenesis of Alzheimer's disease[J]. Eur J Neurosci, 2022, 56(9): 5442-5452. DOI: 10.1111/ejn.15569.
[18]	Patwardhan S, Mahadik P, Shetty O, et al. ECM stiffness-tuned exosomes drive breast cancer motility through thrombospondin-1[J]. Biomaterials, 2021, 279: 121185. DOI: 10.1016/j.biomaterials.2021.121185.
[19]	Prakash J, Shaked Y. The interplay between extracellular matrix remodeling and cancer therapeutics[J]. Cancer Discov, 2024, 14(8): 1375-1388. DOI: 10.1158/2159-8290.Cd-24-0002. pmid: 39091205
[20]	Dalton CJ, Lemmon CA. Fibronectin: molecular structure, fibrillar structure and mechanochemical signaling[J]. Cells, 2021, 10(9): 2443. DOI: 10.3390/cells10092443.
[21]	Sorvina A, Antoniou M, Esmaeili Z, et al. Unusual suspects: bone and cartilage ECM proteins as carcinoma facilitators[J]. Cancers (Basel), 2023, 15(3): 791. DOI: 10.3390/cancers15030791.
[22]	Ding XC, Wang LL, Zhang XD, et al. The relationship between expression of PD-L1 and HIF-1 αin glioma cells under hypoxia[J]. J Hematol Oncol, 2021, 14(1): 92. DOI: 10.1186/s13045-021-01102-5.
[23]	Wang JZ, Zhu W, Han J, et al. The role of the HIF-1α/ALYREF/PKM2 axis in glycolysis and tumorigenesis of bladder cancer[J]. Cancer Commun (Lond), 2021, 41(7): 560-575. DOI: 10.1002/cac2.12158.
[24]	Rimal R, Desai P, Daware R, et al. Cancer-associated fibroblasts: origin, function, imaging, and therapeutic targeting[J]. Adv Drug Deliv Rev, 2022, 189: 114504. DOI: 10.1016/j.addr.2022.114504.
[25]	Li M, Yang Y, Xiong L, et al. Metabolism, metabolites, and macrophages in cancer[J]. J Hematol Oncol, 2023, 16(1): 80. DOI: 10.1186/s13045-023-01478-6.
[26]	Wang Y, Wang W, Wu H, et al. The essential role of PRAK in tumor metastasis and its therapeutic potential[J]. Nat Commun, 2021, 12(1): 1736. DOI: 10.1038/s41467-021-21993-9.
[27]	Shen J, Huang Q, Jia W, et al. YAP1 induces invadopodia formation by transcriptionally activating TIAM1 through enhancer in breast cancer[J]. Oncogene, 2022, 41(31): 3830-3845. DOI: 10.1038/s41388-022-02344-4. pmid: 35773411
[28]	孟珂心, 陆海军. 口腔菌群:口腔鳞状细胞癌诊断和预后的生物标志物[J]. 国际肿瘤学杂志, 2024, 51(8): 515-519. DOI: 10.3760/cma.j.cn371439-20240304-00086.
[29]	Mitre GP, Balbinot KM, Ribeiro ALR, et al. Key proteins of invadopodia are overexpressed in oral squamous cell carcinoma suggesting an important role of MT1-MMP in the tumoral progression[J]. Diagn Pathol, 2021, 16(1): 33. DOI: 10.1186/s13000-021-01090-7.
[30]	Gou Q, Zheng LL, Huang H. Unravelling the roles of autophagy in OSCC: a renewed perspective from mechanisms to potential applications[J]. Front Pharmacol, 2022, 13: 994643. DOI: 10.3389/fphar.2022.994643.
[31]	杜爱超, 程厚翔, 代军强, 等. 肿瘤电场治疗在胶质母细胞瘤中的研究进展[J]. 国际肿瘤学杂志, 2024, 51(10): 639-644. DOI: 10.3760/cma.j.cn371439-20240407-00107.
[32]	Whitehead CA, Fang H, Su H, et al. Small extracellular vesicles promote invadopodia activity in glioblastoma cells in a therapy-dependent manner[J]. Cell Oncol (Dordr), 2023, 46(4): 909-931. DOI: 10.1007/s13402-023-00786-w. pmid: 37014551
[33]	Whitehead CA, Morokoff AP, Kaye AH, et al. Invadopodia associated thrombospondin-1 contributes to a post-therapy pro-invasive response in glioblastoma cells[J]. Exp Cell Res, 2023, 431(1): 113743. DOI: 10.1016/j.yexcr.2023.113743.
[34]	Yu Y, Peng XD, Qian XJ, et al. Fis1 phosphorylation by Met promotes mitochondrial fission and hepatocellular carcinoma metastasis[J]. Signal Transduct Target Ther, 2021, 6(1): 401. DOI: 10.1038/s41392-021-00790-2.
[35]	Hao Z, Zhang M, Du Y, et al. Invadopodia in cancer metastasis: dynamics, regulation, and targeted therapies[J]. J Transl Med, 2025, 23(1): 548. DOI: 10.1186/s12967-025-06526-y.
[36]	Li F, Yang BB. Non-coding RNAs in invadopodia: new insights into cancer metastasis[J]. Front Oncol, 2021, 11: 681576. DOI: 10.3389/fonc.2021.681576.
[37]	Chen SH, Chao CN, Chen SY, et al. Flunarizine, a drug approved for treating migraine and vertigo, exhibits cytotoxicity in GBM cells[J]. Eur J Pharmacol, 2021, 892: 173756. DOI: 10.1016/j.ejphar.2020.173756.
[38]	Kreider-Letterman G, Castillo A, Mahlandt EK, et al. ARHGAP17 regulates the spatiotemporal activity of Cdc42 at invadopodia[J]. J Cell Biol, 2023, 222(2): e202207020. DOI: 10.1083/jcb.202207020.