Beyond Bistability: A Multistable Cascade Model of Bioelectric Cancer Normalization

Beyond Bistability: A Multistable Cascade Model of Bioelectric Cancer Normalization | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Beyond Bistability: A Multistable Cascade Model of Bioelectric Cancer Normalization Shuhrat Okilov, Khamidov Ulugbek This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9099969/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Every computational model of bioelectric cancer treats the system as bistable: a healthy attractor near −70 mV and a cancer attractor near −10 mV, separated by a single barrier. This paper argues that the real system is more complex and more therapeutically useful than that. Direct microelectrode measurements of unsynchronized MCF-7 breast cancer cells reveal not two but four discrete membrane potential peaks at −9, −17, −25, and −40 mV (Woodfork, Wonderlin & Strobl, 1995). The standard interpretation attributes these peaks to cell cycle phases. We propose an alternative: these peaks represent four quasi-stable bioelectric states forming a cascade between the cancer and healthy attractors. If correct, this reframes normalization from a single difficult jump across 60 mV to a series of smaller, achievable steps of 8–15 mV each. We present a bistable lattice model (reproducing published critical cloud sizes of 5–8 cells radius) and show that instructor cells increase cloud stability by ≈ 6.3×. We construct a toy multistable effective-current model demonstrating that a four-well voltage landscape is dynamically coherent (Supplementary Fig. S1). We then describe a $600 FACS-sorting experiment that distinguishes our hypothesis from the cell-cycle explanation within two weeks. If the cascade model is correct, partial normalization — moving cells one step rather than all the way — becomes a realistic therapeutic target, achievable with existing FDA-approved drugs at doses far lower than those required for full repolarization. Biophysics Cancer Biology Computational Biology Cell Communication and Signaling Oncology membrane potential cancer normalization multistability bistability gap junctions instructor cells MCF-7 cascade bioelectricity Full Text Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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