?(Fig.4c).4c). (4.1M) GUID:?2D055589-5843-44A0-9838-90E003BF3AE6 Video S6. Inhibition of MIF by antibody abolishes the retrograde migration of MDA-MB-231 upon facing L929 41420_2019_176_MOESM7_ESM.mp4 (17M) GUID:?65AD01F3-72FA-4F29-9C1F-BBC512A7BADE Video S7. Inhibition of MEK/ERK by U0126 abolishes the retrograde migration of MDA-MB-231 upon facing L929 41420_2019_176_MOESM8_ESM.mp4 (15M) GUID:?E44E5696-8FC9-4B31-849A-904DCBEAC5E2 Video S8. Inhibition of Ctsk MEK/ERK by U0126 abolishes the retrograde migration of MDA-MB-231 upon facing L929 (treatment of MDA-MB-231 only) 41420_2019_176_MOESM9_ESM.mp4 (12M) GUID:?61C706C9-961E-4615-8487-42A1FC14FEF8 Video S9. Knockout Wwox-/- MEF cells dramatically upregulate the redox activity in wild type MEF cells from a remote distance (merged channels) 41420_2019_176_MOESM10_ESM.mp4 (23M) GUID:?DA707118-9FFE-4F3F-9CCF-81506BCAEFD0 Video S10. Knockout Wwox-/- MEF cells dramatically upregulate the redox activity in wild type MEF cells from a remote distance (red channel) 41420_2019_176_MOESM11_ESM.mp4 (14M) GUID:?B0FB1ECE-9007-425A-B133-649E8F0C7E98 Video S11. Wild type versus wild type MEF cells (merged channels): Redox activity in red 41420_2019_176_MOESM12_ESM.mp4 (21M) GUID:?0FF64014-851A-4C38-9810-0D6582C40FED Video S12. Wild type versus wild type MEF cells (red channel): Redox activity in red 41420_2019_176_MOESM13_ESM.mp4 (11M) GUID:?657C91CA-7541-4B6D-A190-2B3AFC8F5238 Video S13. MDA-MB-435s versus wild type MEF cells 41420_2019_176_MOESM14_ESM.mp4 (143M) GUID:?EA880B93-00B5-48AC-8796-8BE875E51A89 Video S14. MDA-MB-231 cells induce a greater extent of L929 apoptosis under serum-free conditions 41420_2019_176_MOESM15_ESM.mp4 (5.9M) GUID:?E979FDE0-8B38-467E-A185-61343FABB85D Video S15. Restoration of WWOX in MDA-MB-231 allows them to fend off WWOX-negative parental cells 41420_2019_176_MOESM16_ESM.mp4 (3.1M) GUID:?2991402F-8C1A-4636-84B0-5EEF2B44B975 Video S16. Ectopic expression of the N-terminus of WWOX allows MDA-MB-231 to merge with L929 41420_2019_176_MOESM17_ESM.mp4 (2.9M) GUID:?A5224704-C681-45C5-BF17-FC57928A2E95 Supplemental Video Legends 41420_2019_176_MOESM18_ESM.pdf (243K) GUID:?B67DF10B-21B9-47FE-9827-0EA5C43225E9 Abstract Proapoptotic tumor suppressor WWOX is upregulated in the early stage of cancer initiation, which probably provides limitation to cancer growth and progression. Later, WWOX protein is reduced to enhance cancer cell growth, migration, invasiveness KT185 and metastasis. To understand how WWOX works in controlling cancer progression, here we demonstrate that apoptotic stress mediated by ectopic WWOX stimulated cancer cells to secrete basic fibroblast growth factor (bFGF) in order to KT185 support capillary microtubule formation. This event may occur in the cancer initiation stage. Later, when WWOX loss occurs in KT185 cancer cells, hyaluronidase production is then increased in the cancer cells to facilitate metastasis. We determined that inhibition of membrane hyaluronidase Tyr216-phosphorylated Hyal-2 by antibody suppresses cancer growth in vivo. WWOX-negative (WWOX-) cells dodged WWOX+cells in the microenvironment by migrating individually backward to avoid physical contacts and yet significantly upregulating the redox activity of WWOX+parental cells or other WWOX+cell types for causing apoptosis. Upon detecting the presence of WWOX+cells from a distance, WWOX- cells exhibit activation of MIF, Hyal-2, Eph, and Wnt pathways, which converges to MEK/ERK signaling and enables WWOX- cells to evade WWOX+cells. Inhibition of each pathway by antibody or specific chemicals enables WWOX- cells to merge with WWOX+cells. In addition, exogenous TGF- assists WWOX- cells to migrate collectively forward and merge with WWOX+cells. Metastatic WWOX- cancer cells frequently secrete high levels of TGF-, which conceivably assists them to merge with WWOX+cells in target organs and secure a new home base in the WWOX+microenvironment. Together, loss of WWOX allows cancer cells to develop strategies to dodge, compromise and even kill WWOX-positive cells in microenvironment. Introduction Proapoptotic tumor suppressor WW domain-containing oxidoreductase, designated WWOX, FOR or WOX1, is known to limit cancer growth and metastasis1C5. However, WWOX is even crucial in maintaining physiological settings, rather than functioning in tumor suppression. Null mutations of gene cause severe neural diseases (e.g., epileptic encephalopathy, microcephaly, and spinocerebellar ataxia), metabolic disorders (including lipid, cholesterol, and glucose metabolism), disorder of sex differentiation, and early death in the newborns2,6,7. Spontaneous tumor formation is rarely found in the WWOX-deficient newborns. Importantly, gene is one of the 5 recently discovered risk factors in Alzheimers disease8. WWOX interacts with specific cytosolic proteins, mainly functioning in normal cell physiology and death1C5 and metabolism such as glycolysis, fatty KT185 acid degradation and acetyl-CoA generation9. WWOX localizes, in part, in the mitochondria via its mRNA than cells expressing siWWOX or a scrambled sequence. The mRNA levels of Hyal-1 and Hyal-2 of high WWOX-expressing cells were significantly lower.