癌症轉移是造成癌症病患死亡的主要原因。愈來愈多證據顯示，存在著一群具有幹細胞特性的癌細胞，這些細胞具有較強的自我更新、分化及形成腫瘤能力特徵的細胞。這些細胞稱為”腫瘤起始細胞”或”癌幹細胞”。癌幹細胞受到細胞內在性及細胞外在性因子的偕同作用下，其性狀可在上皮樣及間質樣狀態間轉換。其中，間質樣癌幹細胞具有非常高度的移動能力並且非常具侵犯性，被認為是造成癌症轉移的主要原因。
具侵略性及惡性的癌幹細胞會在其侵略端前緣的特殊構造表現並釋出多種蛋白酶，這一特殊構造稱為”侵犯足”。這一個獨特且高脂筏含量的微小結構，由細胞膜延伸突起，具有能將細胞外基質分解的能力。愈來愈多證據顯示，侵犯足的形成對於癌症轉移是必要的。侵犯足的形成需要許多細胞膜的脂筏上的分子共同作用，這些分子包括癌幹細胞表面標誌、膜周邊蛋白，以及分解基質的蛋白酶。
α-烯醇化酶已被發現存在於細胞表面上，並與脂筏上的分子有作用。在細胞表面上，α-烯醇化酶主要作為纖維蛋白溶酶原受體，協助將纖維蛋白溶酶原轉換為纖維蛋白溶酶。α-烯醇化酶的表現與多種癌症轉移及較差預後高度相關。這個發現驅使我們推測α-烯醇化酶可能會被表現在惡性轉移癌幹細胞的侵犯足表面上，並且幫助癌幹細胞的轉移。
由於胃癌以及攝護腺癌是屬於高度復發以及較易遠端轉移的癌症，於此我們在這篇研究中主要使用這兩種癌症作為研究對象。首先，先偵測α-烯醇化酶在這兩種癌幹細胞上的表現，並且檢查α-烯醇化酶的表現與否在癌幹細胞的侵犯性以及轉移潛在能力的差異(Aim 1)。接下來，藉由影像分析、功能性實驗以及癌症轉移模式探討侵犯足表面的α-烯醇化酶在侵犯足的形成及功能上的角色，我們更進一步利用癌症轉移動物模式來檢查細胞表面α-烯醇化酶在癌幹細胞轉移的重要性(Aim 2)。第三，利用分子及生化實驗去尋找調控α-烯醇化酶轉移到細胞膜表面的分子機制(Aim 3)。更進一步衍生我們所發現的結果，我們計畫使用蛋白質體學篩選的方式來尋找在癌幹細胞上與癌症侵犯及轉移相關且新穎的侵犯足蛋白質(Aim 4)。
在這個研究中，我們在高度轉移的癌幹細胞族群中找到了一群在侵犯足表面表現α-烯醇化酶的高度轉移性癌幹細胞。研究中展現了這群細胞具有較強的間質樣細胞特性，並且具有較強的侵犯足生成能力、侵犯力以及癌症遠端轉移的能力。我們更進一步提供了α-烯醇化酶轉移到細胞表面的分子機制，主要是由脂筏分子微囊蛋白1的協助造成。
總結來說，本篇研究發現了癌幹細胞其侵犯足侵犯能力的機制，並且可做為一個新穎的藥物標的分子，藉由阻斷侵犯足的生成來防止癌症轉移，將可以減少癌症病患治療後轉移的發生並增進其癌症治療的效果。

Cancer metastasis is the major cause of cancer death. A growing body of evidence shows that rare populations of stem-cell-like cancer cells have heightened capacities to self-renew, differentiate, and initiate tumor growth, which are termed “tumor-initiating cells (TICs)” or “cancer stem cells (CSCs)”. CSCs exist in interconvertible phenotypes between epithelial-like and mesenchymal-like states, that is orchestrated by cell-intrinsic or cell-extrinsic factors. Among them, mesenchymal-like CSCs are characterized by their highly motile and invasive properties and thereby may mediate cancer invasiveness and metastasis.
Invasive and pro-metastatic CSCs express multiple proteases at their invasive front on a cellular structure called “invadopodium”. These unique, lipid raft-enriched microstructures protrude from the plasma membrane and have an ability to digest surrounding extracellular matries (ECM). There is now substantial evidence that invadopodia are required for cancer metastasis. The formation of invadopodia requires the cooperation among molecule clustered in the lipid rafts, including such as certain CSC surface markers, membrane proteins, and proteases, which function cooperatively to active ECM-degradative proteases.
Alpha-enolase (ENO1) has been identified to exist on the cell surface where it interacts with components of lipid rafts, and functions as a plasminogen receptor, promoting the conversion of plasminogen to plasmin. The expression of ENO1 has been associated with cancer metastasis and poor prognosis in different types of cancers. These findings prompted us to speculate that ENO1 is present on the surface of invadopodia on metastatic CSCs and may play a functional role in cancer metastasis.
We choose gastric cancer and prostate cancer as the disease models in my research as both cancers are associated with a high rate of recurrence and distant metastasis. We first explored the expression profile of ENO1 on the surface of CSCs in gastric cancer and prostate cancers and examined the invasive behaviors and pro-metastatic potentials of surface ENO1 (sENO1)+ CSCs and their sENO1- counterparts (Aim 1). Next, we investigated the functional role of sENO1 in the invadopodia of CSCs using a series of imaging, in vitro functional assays, and cancer metastasis models (Aim 2). Third, we explored the regulatory mechanisms that mediate the expression of ENO1 on the invadopodia of CSCs using molecular and biochemical studies (Aim 3). To further substantiate these findings, we propose a proteomic screening to identify additional invadopodial proteins on CSCs that may also play an important role in cancer invasion and metastasis (Aim 4).
In this study, we identified a highly metastatic subpopulation of CSCs that are characterized by the expression of ENO1 on the surface of their invadopodia. we demonstrated that sENO1+ CSCs have stronger mesenchymal-like properties and are proficient in generating invadopodia, invasion, and causing distant metastasis. We also provided a mechanistic insight into the localization of ENO1 to the invadopodial surface of CSCs, which is mainly mediated by the essential component of lipid rafts, Caveolin-1 (CAV1).
Taken together, my study presents a novel mechanistic explanation for the invasive property of invasive CSCs and their invadopodia, and a novel and druggable molecular target that may provide an avenue for treated cancer metastasis through blocking invadopodia functions in metastatic CSCs, which hold great promise in improving the outcome of patients with highly metastatic cancers.

1 Luzzi, K. J. et al. Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. Am J Pathol 153, 865-873, doi:10.1016/S0002-9440(10)65628-3 (1998).
2 Fares, J., Fares, M. Y., Khachfe, H. H., Salhab, H. A. & Fares, Y. Molecular principles of metastasis: a hallmark of cancer revisited. Signal Transduct Target Ther 5, 28, doi:10.1038/s41392-020-0134-x (2020).
3 Anderberg, C. et al. Deficiency for endoglin in tumor vasculature weakens the endothelial barrier to metastatic dissemination. J Exp Med 210, 563-579, doi:10.1084/jem.20120662 (2013).
4 Reymond, N., d'Agua, B. B. & Ridley, A. J. Crossing the endothelial barrier during metastasis. Nat Rev Cancer 13, 858-870, doi:10.1038/nrc3628 (2013).
5 Karagiannis, G. S. et al. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res 10, 1403-1418, doi:10.1158/1541-7786.MCR-12-0307 (2012).
6 Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 68, 394-424, doi:10.3322/caac.21492 (2018).
7 Keller, E. T. The role of osteoclastic activity in prostate cancer skeletal metastases. Drugs Today (Barc) 38, 91-102, doi:10.1358/dot.2002.38.2.820105 (2002).
8 Gandaglia, G. et al. Impact of the Site of Metastases on Survival in Patients with Metastatic Prostate Cancer. Eur Urol 68, 325-334, doi:10.1016/j.eururo.2014.07.020 (2015).
9 Wong, Y. N., Ferraldeschi, R., Attard, G. & de Bono, J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat Rev Clin Oncol 11, 365-376, doi:10.1038/nrclinonc.2014.72 (2014).
10 Lytton, B. Prostate cancer: a brief history and the discovery of hormonal ablation treatment. J Urol 165, 1859-1862 (2001).
11 Hellerstedt, B. A. & Pienta, K. J. The current state of hormonal therapy for prostate cancer. CA Cancer J Clin 52, 154-179, doi:10.3322/canjclin.52.3.154 (2002).
12 Heinlein, C. A. & Chang, C. Androgen receptor in prostate cancer. Endocr Rev 25, 276-308, doi:10.1210/er.2002-0032 (2004).
13 Berthold, D. R. et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: updated survival in the TAX 327 study. J Clin Oncol 26, 242-245, doi:10.1200/JCO.2007.12.4008 (2008).
14 de Bono, J. S. et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 364, 1995-2005, doi:10.1056/NEJMoa1014618 (2011).
15 Scher, H. I. et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med 367, 1187-1197, doi:10.1056/NEJMoa1207506 (2012).
16 Gilligan, T. & Kantoff, P. W. Chemotherapy for prostate cancer. Urology 60, 94-100; discussion 100, doi:10.1016/s0090-4295(02)01583-2 (2002).
17 Smyth, E. C. et al. Gastric cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 27, v38-v49, doi:10.1093/annonc/mdw350 (2016).
18 Wilke, H. et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial. Lancet Oncol 15, 1224-1235, doi:10.1016/S1470-2045(14)70420-6 (2014).
19 Riihimaki, M., Hemminki, A., Sundquist, K., Sundquist, J. & Hemminki, K. Metastatic spread in patients with gastric cancer. Oncotarget 7, 52307-52316, doi:10.18632/oncotarget.10740 (2016).
20 Mokadem, I. et al. Recurrence after preoperative chemotherapy and surgery for gastric adenocarcinoma: a multicenter study. Gastric Cancer 22, 1263-1273, doi:10.1007/s10120-019-00956-6 (2019).
21 Shiozawa, Y., Nie, B., Pienta, K. J., Morgan, T. M. & Taichman, R. S. Cancer stem cells and their role in metastasis. Pharmacol Ther 138, 285-293, doi:10.1016/j.pharmthera.2013.01.014 (2013).
22 Oskarsson, T., Batlle, E. & Massague, J. Metastatic stem cells: sources, niches, and vital pathways. Cell Stem Cell 14, 306-321, doi:10.1016/j.stem.2014.02.002 (2014).
23 Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8, 755-768, doi:10.1038/nrc2499 (2008).
24 Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res 67, 1030-1037, doi:10.1158/0008-5472.CAN-06-2030 (2007).
25 Pine, S. R., Marshall, B. & Varticovski, L. Lung cancer stem cells. Dis Markers 24, 257-266 (2008).
26 Zhang, D. G., Jiang, A. G., Lu, H. Y., Zhang, L. X. & Gao, X. Y. Isolation, cultivation and identification of human lung adenocarcinoma stem cells. Oncol Lett 9, 47-54, doi:10.3892/ol.2014.2639 (2015).
27 Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313-323, doi:10.1016/j.stem.2007.06.002 (2007).
28 Li, F., Tiede, B., Massague, J. & Kang, Y. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 17, 3-14, doi:10.1038/sj.cr.7310118 (2007).
29 Collins, A. T., Berry, P. A., Hyde, C., Stower, M. J. & Maitland, N. J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65, 10946-10951, doi:10.1158/0008-5472.CAN-05-2018 (2005).
30 Abel, E. V. & Simeone, D. M. Biology and clinical applications of pancreatic cancer stem cells. Gastroenterology 144, 1241-1248, doi:10.1053/j.gastro.2013.01.072 (2013).
31 Liu, S. et al. Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2, 78-91, doi:10.1016/j.stemcr.2013.11.009
S2213-6711(13)00149-5 [pii] (2014).
32 Odoux, C. et al. A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res 68, 6932-6941, doi:10.1158/0008-5472.CAN-07-5779 (2008).
33 Prasetyanti, P. R. & Medema, J. P. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol Cancer 16, 41, doi:10.1186/s12943-017-0600-4 (2017).
34 Rich, J. N. Cancer stem cells: understanding tumor hierarchy and heterogeneity. Medicine (Baltimore) 95, S2-S7, doi:10.1097/MD.0000000000004764 (2016).
35 Tang, D. G. Understanding cancer stem cell heterogeneity and plasticity. Cell Res 22, 457-472, doi:10.1038/cr.2012.13 (2012).
36 Colacino, J. A. et al. Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by Transcriptional Profiling. Stem Cell Reports 10, 1596-1609, doi:10.1016/j.stemcr.2018.03.001 (2018).
37 Pang, R. et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem Cell 6, 603-615, doi:10.1016/j.stem.2010.04.001 (2010).
38 Patrawala, L. et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 25, 1696-1708, doi:10.1038/sj.onc.1209327 (2006).
39 Richardson, G. D. et al. CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117, 3539-3545, doi:10.1242/jcs.01222 (2004).
40 Kanwal, R., Shukla, S., Walker, E. & Gupta, S. Acquisition of tumorigenic potential and therapeutic resistance in CD133+ subpopulation of prostate cancer cells exhibiting stem-cell like characteristics. Cancer Lett 430, 25-33, doi:10.1016/j.canlet.2018.05.014 (2018).
41 Wang, L. et al. Enrichment of prostate cancer stem-like cells from human prostate cancer cell lines by culture in serum-free medium and chemoradiotherapy. Int J Biol Sci 9, 472-479, doi:10.7150/ijbs.5855 (2013).
42 Dubrovska, A. et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci U S A 106, 268-273, doi:10.1073/pnas.0810956106 (2009).
43 Jiang, J. et al. Trastuzumab (herceptin) targets gastric cancer stem cells characterized by CD90 phenotype. Oncogene 31, 671-682, doi:10.1038/onc.2011.282 (2012).
44 Sauzay, C., Voutetakis, K., Chatziioannou, A., Chevet, E. & Avril, T. CD90/Thy-1, a Cancer-Associated Cell Surface Signaling Molecule. Front Cell Dev Biol 7, 66, doi:10.3389/fcell.2019.00066 (2019).
45 Gao, L. et al. CD90 affects the biological behavior and energy metabolism level of gastric cancer cells by targeting the PI3K/AKT/HIF-1alpha signaling pathway. Oncol Lett 21, 191, doi:10.3892/ol.2021.12451 (2021).
46 Hu, Y. et al. Multiple roles of THY1 in gastric cancer based on data mining. Translational Cancer Research 9, 2748-2757 (2020).
47 Shu, X. et al. Distinct biological characterization of the CD44 and CD90 phenotypes of cancer stem cells in gastric cancer cell lines. Mol Cell Biochem 459, 35-47, doi:10.1007/s11010-019-03548-1 (2019).
48 Li, A. et al. The actin-bundling protein fascin stabilizes actin in invadopodia and potentiates protrusive invasion. Curr Biol 20, 339-345, doi:10.1016/j.cub.2009.12.035 (2010).
49 Paz, H., Pathak, N. & Yang, J. Invading one step at a time: the role of invadopodia in tumor metastasis. Oncogene 33, 4193-4202, doi:10.1038/onc.2013.393 (2014).
50 Leong, H. S. et al. Invadopodia are required for cancer cell extravasation and are a therapeutic target for metastasis. Cell Rep 8, 1558-1570, doi:10.1016/j.celrep.2014.07.050 (2014).
51 Baldassarre, M. et al. Dynamin participates in focal extracellular matrix degradation by invasive cells. Mol Biol Cell 14, 1074-1084, doi:10.1091/mbc.e02-05-0308 (2003).
52 Buccione, R., Caldieri, G. & Ayala, I. Invadopodia: specialized tumor cell structures for the focal degradation of the extracellular matrix. Cancer Metastasis Rev 28, 137-149, doi:10.1007/s10555-008-9176-1 (2009).
53 Yamaguchi, H. et al. Lipid rafts and caveolin-1 are required for invadopodia formation and extracellular matrix degradation by human breast cancer cells. Cancer Res 69, 8594-8602, doi:10.1158/0008-5472.CAN-09-2305 (2009).
54 Tolde, O., Rosel, D., Vesely, P., Folk, P. & Brabek, J. The structure of invadopodia in a complex 3D environment. Eur J Cell Biol 89, 674-680, doi:10.1016/j.ejcb.2010.04.003 (2010).
55 Grass, G. D., Bratoeva, M. & Toole, B. P. Regulation of invadopodia formation and activity by CD147. J Cell Sci 125, 777-788, doi:10.1242/jcs.097956 (2012).
56 Antelmi, E. et al. Beta1 integrin binding phosphorylates ezrin at T567 to activate a lipid raft signalsome driving invadopodia activity and invasion. PLoS One 8, e75113, doi:10.1371/journal.pone.0075113 (2013).
57 Revach, O. Y. et al. Mechanical interplay between invadopodia and the nucleus in cultured cancer cells. Sci Rep 5, 9466, doi:10.1038/srep09466 (2015).
58 Murphy, D. A. & Courtneidge, S. A. The 'ins' and 'outs' of podosomes and invadopodia: characteristics, formation and function. Nat Rev Mol Cell Biol 12, 413-426, doi:10.1038/nrm3141 (2011).
59 Seals, D. F. et al. The adaptor protein Tks5/Fish is required for podosome formation and function, and for the protease-driven invasion of cancer cells. Cancer Cell 7, 155-165, doi:10.1016/j.ccr.2005.01.006 (2005).
60 Morton, P. E. & Parsons, M. Dissecting cell adhesion architecture using advanced imaging techniques. Cell Adh Migr 5, 351-359, doi:10.4161/cam.5.4.16915 (2011).
61 Gianni, D., Taulet, N., DerMardirossian, C. & Bokoch, G. M. c-Src-mediated phosphorylation of NoxA1 and Tks4 induces the reactive oxygen species (ROS)-dependent formation of functional invadopodia in human colon cancer cells. Mol Biol Cell 21, 4287-4298, doi:10.1091/mbc.E10-08-0685 (2010).
62 Jacob, A. & Prekeris, R. The regulation of MMP targeting to invadopodia during cancer metastasis. Front Cell Dev Biol 3, 4, doi:10.3389/fcell.2015.00004 (2015).
63 Mader, C. C. et al. An EGFR-Src-Arg-cortactin pathway mediates functional maturation of invadopodia and breast cancer cell invasion. Cancer Res 71, 1730-1741, doi:10.1158/0008-5472.CAN-10-1432 (2011).
64 Beaty, B. T. et al. beta1 integrin regulates Arg to promote invadopodial maturation and matrix degradation. Mol Biol Cell 24, 1661-1675, S1661-1611, doi:10.1091/mbc.E12-12-0908 (2013).
65 Beaty, B. T. et al. Talin regulates moesin-NHE-1 recruitment to invadopodia and promotes mammary tumor metastasis. J Cell Biol 205, 737-751, doi:10.1083/jcb.201312046 (2014).
66 Kikuchi, K. & Takahashi, K. WAVE2- and microtubule-dependent formation of long protrusions and invasion of cancer cells cultured on three-dimensional extracellular matrices. Cancer Sci 99, 2252-2259, doi:10.1111/j.1349-7006.2008.00927.x (2008).
67 Schoumacher, M., Goldman, R. D., Louvard, D. & Vignjevic, D. M. Actin, microtubules, and vimentin intermediate filaments cooperate for elongation of invadopodia. J Cell Biol 189, 541-556, doi:10.1083/jcb.200909113 (2010).
68 Branch, K. M., Hoshino, D. & Weaver, A. M. Adhesion rings surround invadopodia and promote maturation. Biol Open 1, 711-722, doi:10.1242/bio.20121867 (2012).
69 Pignatelli, J., Tumbarello, D. A., Schmidt, R. P. & Turner, C. E. Hic-5 promotes invadopodia formation and invasion during TGF-beta-induced epithelial-mesenchymal transition. J Cell Biol 197, 421-437, doi:10.1083/jcb.201108143 (2012).
70 Balzer, E. M. et al. c-Src differentially regulates the functions of microtentacles and invadopodia. Oncogene 29, 6402-6408, doi:10.1038/onc.2010.360 (2010).
71 Eckert, M. A. & Yang, J. Targeting invadopodia to block breast cancer metastasis. Oncotarget 2, 562-568, doi:10.18632/oncotarget.301 (2011).
72 Buschman, M. D. et al. The novel adaptor protein Tks4 (SH3PXD2B) is required for functional podosome formation. Mol Biol Cell 20, 1302-1311, doi:10.1091/mbc.E08-09-0949 (2009).
73 Martin-Villar, E. et al. Podoplanin binds ERM proteins to activate RhoA and promote epithelial-mesenchymal transition. J Cell Sci 119, 4541-4553, doi:10.1242/jcs.03218 (2006).
74 Martin-Villar, E. et al. Podoplanin mediates ECM degradation by squamous carcinoma cells through control of invadopodia stability. Oncogene 34, 4531-4544, doi:10.1038/onc.2014.388 (2015).
75 Navarro, A., Perez, R. E., Rezaiekhaligh, M. H., Mabry, S. M. & Ekekezie, II. Polarized migration of lymphatic endothelial cells is critically dependent on podoplanin regulation of Cdc42. Am J Physiol Lung Cell Mol Physiol 300, L32-42, doi:10.1152/ajplung.00171.2010 (2011).
76 Gligorijevic, B. et al. N-WASP-mediated invadopodium formation is involved in intravasation and lung metastasis of mammary tumors. J Cell Sci 125, 724-734, doi:10.1242/jcs.092726 (2012).
77 Seiler, C. et al. Smooth muscle tension induces invasive remodeling of the zebrafish intestine. PLoS Biol 10, e1001386, doi:10.1371/journal.pbio.1001386 (2012).
78 Lohmer, L. L., Kelley, L. C., Hagedorn, E. J. & Sherwood, D. R. Invadopodia and basement membrane invasion in vivo. Cell Adh Migr 8, 246-255, doi:10.4161/cam.28406 (2014).
79 Yamaguchi, H. & Oikawa, T. Membrane lipids in invadopodia and podosomes: key structures for cancer invasion and metastasis. Oncotarget 1, 320-328, doi:10.18632/oncotarget.100907 (2010).
80 Williams, K. C. et al. Invadopodia are chemosensing protrusions that guide cancer cell extravasation to promote brain tropism in metastasis. Oncogene 38, 3598-3615, doi:10.1038/s41388-018-0667-4 (2019).
81 Pike, L. J. Lipid rafts: bringing order to chaos. J Lipid Res 44, 655-667, doi:10.1194/jlr.R200021-JLR200 (2003).
82 Lee, J. L., Wang, M. J., Sudhir, P. R. & Chen, J. Y. CD44 engagement promotes matrix-derived survival through the CD44-SRC-integrin axis in lipid rafts. Mol Cell Biol 28, 5710-5723, doi:10.1128/MCB.00186-08 (2008).
83 Destaing, O., Block, M. R., Planus, E. & Albiges-Rizo, C. Invadosome regulation by adhesion signaling. Curr Opin Cell Biol 23, 597-606, doi:10.1016/j.ceb.2011.04.002 (2011).
84 A., C. M. CD44-Src signalling promotes invadopodia formation in prostate cancer (PC3) cells. . OA Cancer 1, 14 (2013).
85 Fernandez-Munoz, B. et al. The transmembrane domain of podoplanin is required for its association with lipid rafts and the induction of epithelial-mesenchymal transition. Int J Biochem Cell Biol 43, 886-896, doi:10.1016/j.biocel.2011.02.010 (2011).
86 Martin-Villar, E. et al. Podoplanin associates with CD44 to promote directional cell migration. Mol Biol Cell 21, 4387-4399, doi:10.1091/mbc.E10-06-0489 (2010).
87 Astarita, J. L., Acton, S. E. & Turley, S. J. Podoplanin: emerging functions in development, the immune system, and cancer. Front Immunol 3, 283, doi:10.3389/fimmu.2012.00283 (2012).
88 de Laurentiis, A., Donovan, L. & Arcaro, A. Lipid rafts and caveolae in signaling by growth factor receptors. Open Biochem J 1, 12-32, doi:10.2174/1874091X00701010012 (2007).
89 Tan, X., Egami, H., Nozawa, F., Abe, M. & Baba, H. Analysis of the invasion-metastasis mechanism in pancreatic cancer: involvement of plasmin(ogen) cascade proteins in the invasion of pancreatic cancer cells. Int J Oncol 28, 369-374 (2006).
90 He, Y. et al. Interaction between cancer cells and stromal fibroblasts is required for activation of the uPAR-uPA-MMP-2 cascade in pancreatic cancer metastasis. Clin Cancer Res 13, 3115-3124, doi:10.1158/1078-0432.CCR-06-2088 (2007).
91 Lester, R. D., Jo, M., Montel, V., Takimoto, S. & Gonias, S. L. uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. J Cell Biol 178, 425-436, doi:10.1083/jcb.200701092 (2007).
92 Jo, M. et al. Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling. J Biol Chem 284, 22825-22833, doi:10.1074/jbc.M109.023960 (2009).
93 Castellanos, J. A., Merchant, N. B. & Nagathihalli, N. S. Emerging targets in pancreatic cancer: epithelial-mesenchymal transition and cancer stem cells. Onco Targets Ther 6, 1261-1267, doi:10.2147/OTT.S34670 (2013).
94 Stankic, M. et al. TGF-beta-Id1 signaling opposes Twist1 and promotes metastatic colonization via a mesenchymal-to-epithelial transition. Cell Rep 5, 1228-1242, doi:10.1016/j.celrep.2013.11.014 (2013).
95 Wistow, G. J., Mulders, J. W. & de Jong, W. W. The enzyme lactate dehydrogenase as a structural protein in avian and crocodilian lenses. Nature 326, 622-624, doi:10.1038/326622a0 (1987).
96 Kumar, S., Sheokand, N., Mhadeshwar, M. A., Raje, C. I. & Raje, M. Characterization of glyceraldehyde-3-phosphate dehydrogenase as a novel transferrin receptor. Int J Biochem Cell Biol 44, 189-199, doi:10.1016/j.biocel.2011.10.016 (2012).
97 Pancholi, V. & Fischetti, V. A. A major surface protein on group A streptococci is a glyceraldehyde-3-phosphate-dehydrogenase with multiple binding activity. J Exp Med 176, 415-426, doi:10.1084/jem.176.2.415 (1992).
98 Chen, C., Zabad, S., Liu, H., Wang, W. & Jeffery, C. MoonProt 2.0: an expansion and update of the moonlighting proteins database. Nucleic Acids Res 46, D640-D644, doi:10.1093/nar/gkx1043 (2018).
99 Mani, M. et al. MoonProt: a database for proteins that are known to moonlight. Nucleic Acids Res 43, D277-282, doi:10.1093/nar/gku954 (2015).
100 Attanasio, F. et al. Novel invadopodia components revealed by differential proteomic analysis. Eur J Cell Biol 90, 115-127, doi:10.1016/j.ejcb.2010.05.004 (2011).
101 Diaz-Ramos, A., Roig-Borrellas, A., Garcia-Melero, A. & Lopez-Alemany, R. alpha-Enolase, a multifunctional protein: its role on pathophysiological situations. J Biomed Biotechnol 2012, 156795, doi:10.1155/2012/156795 (2012).
102 Subramanian, A. & Miller, D. M. Structural analysis of alpha-enolase. Mapping the functional domains involved in down-regulation of the c-myc protooncogene. J Biol Chem 275, 5958-5965, doi:10.1074/jbc.275.8.5958 (2000).
103 Luo, Q. et al. Constitutive heat shock protein 70 interacts with alpha-enolase and protects cardiomyocytes against oxidative stress. Free Radic Res 45, 1355-1365, doi:10.3109/10715762.2011.627330 (2011).
104 Gao, S. et al. Mitochondrial binding of alpha-enolase stabilizes mitochondrial membrane: its role in doxorubicin-induced cardiomyocyte apoptosis. Arch Biochem Biophys 542, 46-55, doi:10.1016/j.abb.2013.12.008 (2014).
105 Miles, L. A. et al. Role of cell-surface lysines in plasminogen binding to cells: identification of alpha-enolase as a candidate plasminogen receptor. Biochemistry 30, 1682-1691 (1991).
106 Redlitz, A., Fowler, B. J., Plow, E. F. & Miles, L. A. The role of an enolase-related molecule in plasminogen binding to cells. Eur J Biochem 227, 407-415, doi:10.1111/j.1432-1033.1995.tb20403.x (1995).
107 Li, C. et al. Proteome analysis of human lung squamous carcinoma. Proteomics 6, 547-558, doi:10.1002/pmic.200500256 (2006).
108 Jankowska, R. et al. Serum antibodies to retinal antigens in lung cancer and sarcoidosis. Pathobiology 71, 323-328, doi:10.1159/000081728 (2004).
109 Sato, N. et al. Human CD8 and CD4 T cell epitopes of epithelial cancer antigens. Cancer Chemother Pharmacol 46 Suppl, S86-90, doi:10.1007/pl00014057 (2000).
110 Chang, G. C. et al. Identification of alpha-enolase as an autoantigen in lung cancer: its overexpression is associated with clinical outcomes. Clin Cancer Res 12, 5746-5754, doi:10.1158/1078-0432.CCR-06-0324 (2006).
111 Cappello, P. et al. An integrated humoral and cellular response is elicited in pancreatic cancer by alpha-enolase, a novel pancreatic ductal adenocarcinoma-associated antigen. Int J Cancer 125, 639-648, doi:10.1002/ijc.24355 (2009).
112 He, P. et al. Proteomics-based identification of alpha-enolase as a tumor antigen in non-small lung cancer. Cancer Sci 98, 1234-1240, doi:10.1111/j.1349-7006.2007.00509.x (2007).
113 Dowling, P. et al. Proteomic analysis of isolated membrane fractions from superinvasive cancer cells. Biochim Biophys Acta 1774, 93-101, doi:10.1016/j.bbapap.2006.09.014 (2007).
114 Wygrecka, M. et al. Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood 113, 5588-5598, doi:10.1182/blood-2008-08-170837 (2009).
115 Zhou, W. et al. Mass spectrometry analysis of the post-translational modifications of alpha-enolase from pancreatic ductal adenocarcinoma cells. J Proteome Res 9, 2929-2936, doi:10.1021/pr901109w (2010).
116 Tomaino, B. et al. Circulating autoantibodies to phosphorylated alpha-enolase are a hallmark of pancreatic cancer. J Proteome Res 10, 105-112, doi:10.1021/pr100213b (2011).
117 Tsai, S. T. et al. ENO1, a potential prognostic head and neck cancer marker, promotes transformation partly via chemokine CCL20 induction. Eur J Cancer 46, 1712-1723, doi:10.1016/j.ejca.2010.03.018 (2010).
118 Song, Y. et al. Alpha-enolase as a potential cancer prognostic marker promotes cell growth, migration, and invasion in glioma. Mol Cancer 13, 65, doi:10.1186/1476-4598-13-65 (2014).
119 Liu, Y. Q. et al. Effects of alpha-enolase (ENO1) over-expression on malignant biological behaviors of AGS cells. Int J Clin Exp Med 8, 231-239 (2015).
120 Bae, S. et al. alpha-Enolase expressed on the surfaces of monocytes and macrophages induces robust synovial inflammation in rheumatoid arthritis. J Immunol 189, 365-372, doi:10.4049/jimmunol.1102073 (2012).
121 Capello, M., Ferri-Borgogno, S., Cappello, P. & Novelli, F. alpha-Enolase: a promising therapeutic and diagnostic tumor target. FEBS J 278, 1064-1074, doi:10.1111/j.1742-4658.2011.08025.x (2011).
122 Nickel, W. Unconventional secretory routes: direct protein export across the plasma membrane of mammalian cells. Traffic 6, 607-614, doi:10.1111/j.1600-0854.2005.00302.x (2005).
123 Zakrzewicz, D. et al. The interaction of enolase-1 with caveolae-associated proteins regulates its subcellular localization. Biochem J 460, 295-307, doi:10.1042/BJ20130945 (2014).
124 Perconti, G. et al. Pro-invasive stimuli and the interacting protein Hsp70 favour the route of alpha-enolase to the cell surface. Sci Rep 7, 3841, doi:10.1038/s41598-017-04185-8 (2017).
125 Principe, M. et al. Targeting of surface alpha-enolase inhibits the invasiveness of pancreatic cancer cells. Oncotarget 6, 11098-11113, doi:10.18632/oncotarget.3572 (2015).
126 Hsiao, K. C. et al. Surface alpha-enolase promotes extracellular matrix degradation and tumor metastasis and represents a new therapeutic target. PLoS One 8, e69354, doi:10.1371/journal.pone.0069354 (2013).
127 Li, S., Goncalves, K. A., Lyu, B., Yuan, L. & Hu, G. F. Chemosensitization of prostate cancer stem cells in mice by angiogenin and plexin-B2 inhibitors. Commun Biol 3, 26, doi:10.1038/s42003-020-0750-6 (2020).
128 Mogal, A. & Abdulkadir, S. A. Effects of Histone Deacetylase Inhibitor (HDACi); Trichostatin-A (TSA) on the expression of housekeeping genes. Mol Cell Probes 20, 81-86, doi:10.1016/j.mcp.2005.09.008 (2006).
129 Arensman, M. D. et al. WNT7B mediates autocrine Wnt/beta-catenin signaling and anchorage-independent growth in pancreatic adenocarcinoma. Oncogene 33, 899-908, doi:10.1038/onc.2013.23 (2014).
130 Pai, V. C. et al. ASPM promotes prostate cancer stemness and progression by augmenting Wnt-Dvl-3-beta-catenin signaling. Oncogene, doi:10.1038/s41388-018-0497-4 (2018).
131 Martin, K. H. et al. Quantitative measurement of invadopodia-mediated extracellular matrix proteolysis in single and multicellular contexts. J Vis Exp, e4119, doi:10.3791/4119 (2012).
132 Taylor, B. S. et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 18, 11-22, doi:10.1016/j.ccr.2010.05.026 (2010).
133 Sboner, A. et al. Molecular sampling of prostate cancer: a dilemma for predicting disease progression. BMC Med Genomics 3, 8, doi:10.1186/1755-8794-3-8 (2010).
134 Hu, Y. & Smyth, G. K. ELDA: extreme limiting dilution analysis for comparing depleted and enriched populations in stem cell and other assays. J Immunol Methods 347, 70-78, doi:10.1016/j.jim.2009.06.008 (2009).
135 Kang, H. J., Jung, S. K., Kim, S. J. & Chung, S. J. Structure of human alpha-enolase (hENO1), a multifunctional glycolytic enzyme. Acta Crystallogr D Biol Crystallogr 64, 651-657, doi:10.1107/S0907444908008561 (2008).
136 Lopez-Alemany, R., Correc, P., Camoin, L. & Burtin, P. Purification of the plasmin receptor from human carcinoma cells and comparison to alpha-enolase. Thromb Res 75, 371-381, doi:10.1016/0049-3848(94)90252-6 (1994).
137 Wei, Y., Yang, X., Liu, Q., Wilkins, J. A. & Chapman, H. A. A role for caveolin and the urokinase receptor in integrin-mediated adhesion and signaling. J Cell Biol 144, 1285-1294, doi:10.1083/jcb.144.6.1285 (1999).
138 Didiasova, M. et al. STIM1/ORAI1-mediated Ca2+ Influx Regulates Enolase-1 Exteriorization. J Biol Chem 290, 11983-11999, doi:10.1074/jbc.M114.598425 (2015).
139 Hermann, P. C., Huber, S. L. & Heeschen, C. Metastatic cancer stem cells: a new target for anti-cancer therapy? Cell Cycle 7, 188-193, doi:10.4161/cc.7.2.5326 (2008).
140 Santamaria-Martinez, A. & Huelsken, J. The niche under siege: novel targets for metastasis therapy. J Intern Med 274, 127-136, doi:10.1111/joim.12024 (2013).
141 Pal, B. et al. Integration of microRNA signatures of distinct mammary epithelial cell types with their gene expression and epigenetic portraits. Breast Cancer Res 17, 85, doi:10.1186/s13058-015-0585-0 (2015).
142 Brooks, M. D., Burness, M. L. & Wicha, M. S. Therapeutic Implications of Cellular Heterogeneity and Plasticity in Breast Cancer. Cell Stem Cell 17, 260-271, doi:10.1016/j.stem.2015.08.014 (2015).
143 Yao, D., Dai, C. & Peng, S. Mechanism of the mesenchymal-epithelial transition and its relationship with metastatic tumor formation. Mol Cancer Res 9, 1608-1620, doi:10.1158/1541-7786.MCR-10-0568 (2011).
144 Liu, B. et al. miR-200c/141 Regulates Breast Cancer Stem Cell Heterogeneity via Targeting HIPK1/beta-Catenin Axis. Theranostics 8, 5801-5813, doi:10.7150/thno.29380 (2018).
145 Siemens, H. et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10, 4256-4271, doi:10.4161/cc.10.24.18552 (2011).
146 Bao, B. et al. Curcumin analogue CDF inhibits pancreatic tumor growth by switching on suppressor microRNAs and attenuating EZH2 expression. Cancer Res 72, 335-345, doi:10.1158/0008-5472.CAN-11-2182 (2012).
147 Cao, Q. et al. Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene 27, 7274-7284, doi:10.1038/onc.2008.333 (2008).
148 Kent, O. A. et al. A resource for analysis of microRNA expression and function in pancreatic ductal adenocarcinoma cells. Cancer Biol Ther 8, 2013-2024, doi:10.4161/cbt.8.21.9685 (2009).
149 Li, Y. et al. Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 69, 6704-6712, doi:10.1158/0008-5472.CAN-09-1298 (2009).
150 Lu, Y. et al. MiR-200a inhibits epithelial-mesenchymal transition of pancreatic cancer stem cell. BMC Cancer 14, 85, doi:10.1186/1471-2407-14-85 (2014).
151 Tellez, C. S. et al. EMT and stem cell-like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial cells. Cancer Res 71, 3087-3097, doi:10.1158/0008-5472.CAN-10-3035 (2011).
152 Li, Y. et al. Cancer-associated fibroblasts promote the stemness of CD24(+) liver cells via paracrine signaling. J Mol Med (Berl) 97, 243-255, doi:10.1007/s00109-018-1731-9 (2019).
153 Begum, A. et al. Direct Interactions With Cancer-Associated Fibroblasts Lead to Enhanced Pancreatic Cancer Stem Cell Function. Pancreas 48, 329-334, doi:10.1097/MPA.0000000000001249 (2019).
154 Nair, N. et al. A cancer stem cell model as the point of origin of cancer-associated fibroblasts in tumor microenvironment. Sci Rep 7, 6838, doi:10.1038/s41598-017-07144-5 (2017).
155 Bayik, D. & Lathia, J. D. Cancer stem cell-immune cell crosstalk in tumour progression. Nat Rev Cancer, doi:10.1038/s41568-021-00366-w (2021).
156 Muller, L. et al. Bidirectional Crosstalk Between Cancer Stem Cells and Immune Cell Subsets. Front Immunol 11, 140, doi:10.3389/fimmu.2020.00140 (2020).
157 Markopoulos, G. S., Roupakia, E., Marcu, K. B. & Kolettas, E. Epigenetic Regulation of Inflammatory Cytokine-Induced Epithelial-To-Mesenchymal Cell Transition and Cancer Stem Cell Generation. Cells 8, doi:10.3390/cells8101143 (2019).
158 Chen, Y., Tan, W. & Wang, C. Tumor-associated macrophage-derived cytokines enhance cancer stem-like characteristics through epithelial-mesenchymal transition. Onco Targets Ther 11, 3817-3826, doi:10.2147/OTT.S168317 (2018).
159 Korkaya, H., Liu, S. & Wicha, M. S. Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res 17, 6125-6129, doi:10.1158/1078-0432.CCR-10-2743 (2011).
160 Lobo, N. A., Shimono, Y., Qian, D. & Clarke, M. F. The biology of cancer stem cells. Annu Rev Cell Dev Biol 23, 675-699, doi:10.1146/annurev.cellbio.22.010305.104154 (2007).
161 Vermeulen, L., Sprick, M. R., Kemper, K., Stassi, G. & Medema, J. P. Cancer stem cells--old concepts, new insights. Cell Death Differ 15, 947-958, doi:10.1038/cdd.2008.20 (2008).
162 Furlan, F. et al. Urokinase plasminogen activator receptor affects bone homeostasis by regulating osteoblast and osteoclast function. J Bone Miner Res 22, 1387-1396, doi:10.1359/jbmr.070516 (2007).
163 Weaver, A. M. Invadopodia. Curr Biol 18, R362-364, doi:10.1016/j.cub.2008.02.028 (2008).
164 Cervero, P., Himmel, M., Kruger, M. & Linder, S. Proteomic analysis of podosome fractions from macrophages reveals similarities to spreading initiation centres. Eur J Cell Biol 91, 908-922, doi:10.1016/j.ejcb.2012.05.005 (2012).
165 Cmoch, A., Groves, P. & Pikula, S. Biogenesis of invadopodia and their cellular functions. Postepy Biochem 60, 62-68 (2014).
166 Flynn, D. C., Cho, Y., Vincent, D. & Cunnick, J. M. Podosomes and Invadopodia: Related structures with Common Protein Components that May Promote Breast Cancer Cellular Invasion. Breast Cancer (Auckl) 2, 17-29, doi:10.4137/bcbcr.s789 (2008).
167 Linder, S. The matrix corroded: podosomes and invadopodia in extracellular matrix degradation. Trends Cell Biol 17, 107-117, doi:10.1016/j.tcb.2007.01.002 (2007).
168 Bergmann, S., Rohde, M., Chhatwal, G. S. & Hammerschmidt, S. Characterization of plasmin(ogen) binding to Streptococcus pneumoniae. Indian J Med Res 119 Suppl, 29-32 (2004).
169 Zakrzewicz, D. et al. Host-derived extracellular RNA promotes adhesion of Streptococcus pneumoniae to endothelial and epithelial cells. Sci Rep 6, 37758, doi:10.1038/srep37758 (2016).
170 Seweryn, E. et al. Distribution of beta-enolase in normal and tumor rat cells. Folia Histochem Cytobiol 46, 519-524, doi:10.2478/v10042-008-0075-7 (2008).
171 Seweryn, E. et al. Localization of enolase in the subfractions of a breast cancer cell line. Z Naturforsch C J Biosci 64, 754-758, doi:10.1515/znc-2009-9-1023 (2009).
172 Wang, C. et al. Secreted Pyruvate Kinase M2 Promotes Lung Cancer Metastasis through Activating the Integrin Beta1/FAK Signaling Pathway. Cell Rep 30, 1780-1797 e1786, doi:10.1016/j.celrep.2020.01.037 (2020).
173 Wyatt, E. et al. Regulation and cytoprotective role of hexokinase III. PLoS One 5, e13823, doi:10.1371/journal.pone.0013823 (2010).
174 Vallejo, J. & Hardin, C. D. Expression of caveolin-1 in lymphocytes induces caveolae formation and recruitment of phosphofructokinase to the plasma membrane. FASEB J 19, 586-587, doi:10.1096/fj.04-2380fje (2005).
175 Hertz, L. & Dienel, G. A. Lactate transport and transporters: general principles and functional roles in brain cells. J Neurosci Res 79, 11-18, doi:10.1002/jnr.20294 (2005).
176 Brooks, G. A. The Science and Translation of Lactate Shuttle Theory. Cell Metab 27, 757-785, doi:10.1016/j.cmet.2018.03.008 (2018).
177 Brown, M. A. & Brooks, G. A. Trans-stimulation of lactate transport from rat sarcolemmal membrane vesicles. Arch Biochem Biophys 313, 22-28, doi:10.1006/abbi.1994.1353 (1994).
178 Kong, S. C. et al. Monocarboxylate Transporters MCT1 and MCT4 Regulate Migration and Invasion of Pancreatic Ductal Adenocarcinoma Cells. Pancreas 45, 1036-1047, doi:10.1097/MPA.0000000000000571 (2016).
179 Ganapathy-Kanniappan, S. Molecular intricacies of aerobic glycolysis in cancer: current insights into the classic metabolic phenotype. Crit Rev Biochem Mol Biol 53, 667-682, doi:10.1080/10409238.2018.1556578 (2018).
180 Dai, L. et al. Serological proteome analysis approach-based identification of ENO1 as a tumor-associated antigen and its autoantibody could enhance the sensitivity of CEA and CYFRA 21-1 in the detection of non-small cell lung cancer. Oncotarget 8, 36664-36673, doi:10.18632/oncotarget.17067 (2017).
181 Schiliro, C. & Firestein, B. L. Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation. Cells 10, doi:10.3390/cells10051056 (2021).
182 Liberti, M. V. & Locasale, J. W. The Warburg Effect: How Does it Benefit Cancer Cells? Trends Biochem Sci 41, 211-218, doi:10.1016/j.tibs.2015.12.001 (2016).
183 Ma, L. & Zong, X. Metabolic Symbiosis in Chemoresistance: Refocusing the Role of Aerobic Glycolysis. Front Oncol 10, 5, doi:10.3389/fonc.2020.00005 (2020).
184 Zhao, H. et al. Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells. J Cell Mol Med 21, 2055-2067, doi:10.1111/jcmm.13126 (2017).
185 Georgakopoulos-Soares, I., Chartoumpekis, D. V., Kyriazopoulou, V. & Zaravinos, A. EMT Factors and Metabolic Pathways in Cancer. Front Oncol 10, 499, doi:10.3389/fonc.2020.00499 (2020).
186 Qian, X. et al. Enolase 1 stimulates glycolysis to promote chemoresistance in gastric cancer. Oncotarget 8, 47691-47708, doi:10.18632/oncotarget.17868 (2017).
187 Chen, J. M. et al. Enolase 1 differentially contributes to cell transformation in lung cancer but not in esophageal cancer. Oncol Lett 19, 3189-3196, doi:10.3892/ol.2020.11427 (2020).
188 Yang, T. et al. Enolase 1 regulates stem cell-like properties in gastric cancer cells by stimulating glycolysis. Cell Death Dis 11, 870, doi:10.1038/s41419-020-03087-4 (2020).
189 Sun, L. et al. Alpha-enolase promotes gastric cancer cell proliferation and metastasis via regulating AKT signaling pathway. Eur J Pharmacol 845, 8-15, doi:10.1016/j.ejphar.2018.12.035 (2019).
190 Zhou, J. et al. CircRNA-ENO1 promoted glycolysis and tumor progression in lung adenocarcinoma through upregulating its host gene ENO1. Cell Death Dis 10, 885, doi:10.1038/s41419-019-2127-7 (2019).
191 Hong, J. et al. F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer. Gut, doi:10.1136/gutjnl-2020-322780 (2020).
192 Jung, D. W. et al. A unique small molecule inhibitor of enolase clarifies its role in fundamental biological processes. ACS Chem Biol 8, 1271-1282, doi:10.1021/cb300687k (2013).
193 Cho, H. et al. ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes. Sci Rep 7, 44186, doi:10.1038/srep44186 (2017).
194 Lin, Y. H. et al. An enolase inhibitor for the targeted treatment of ENO1-deleted cancers. Nat Metab 2, 1413-1426, doi:10.1038/s42255-020-00313-3 (2020).