In this work, we develop a stochastic multiscale model for glioma growth and invasion in the brain, incorporating the effects of therapeutic interventions. The model accounts for tumor cell migration influenced by brain tissue heterogeneity and anti-crowding mechanisms, while explicitly addressing treatment-related uncertainties through stochastic processes. Starting from a microscopic description of individual cell dynamics, we derive the corresponding system of macroscopic random reaction-diffusion-taxis equations governing cell density and tissue evolution. Finally, we conduct several numerical experiments to assess the efficacy of different treatment protocols, evaluated with respect to both established and newly proposed clinical criteria and measurable outcomes.
Mesenchymal cell migration starts with the protrusion of the cell’s leading edge, enabled by the branching growth of the actin network. Two crucial molecular players in protrusion are actin filaments and the Arp2/3 protein complex, the branching agent. Traditionally, protrusion models are intuited from several perturbative experiments. Recent multiplex microscopy imaging data promise to drastically change this paradigm by providing measurements of naturally fluctuating densities of key proteins at the leading edge of unperturbed cells. We report the first attempt to reconstruct the mechanistic protrusion model from such data. We analyze fluctuations of F-actin and Arp2/3 densities and cell edge velocity using phase space and regression analysis to reconstruct linearized stochastic actin-Arp2/3-velocity coupled dynamics. We then build a nonlinear partial differential equation model of these dynamics based on previous knowledge of this system and parsimony. The resulting model recovers the rates of reactions and mechanical and transport processes in the lamellipodium from a single non-perturbative experiment. The model posits that the only essential nonlinearities in the lamellipodial dynamics stem from the retrograde flow of F-actin. The model suggests that the protrusion is dominated by a damped oscillatory cycle resulting from a combination of positive feedback from Arp2/3 to protrusion velocity and negative feedback from F-actin to the velocity. Significance statement Traditionally, models of intracellular mechanochemistry are intuited from perturbative experiments. Multiplex microscopy imaging changes this by providing measurements of naturally fluctuating densities of key proteins in unperturbed cells. We use such data to reconstruct a mechanistic model of cell leading edge. We build equations for actin system and edge velocity using data, previous knowledge and parsimony. The resulting model recovers the rates of reactions and mechanical and transport processes at the leading edge. The model suggests that the protrusion is dominated by a damped oscillatory cycle resulting from a combination of positive feedback from Arp2/3 to protrusion velocity and negative feedback from F-actin to the velocity. ### Competing Interest Statement The authors have declared no competing interest. U.S. National Science Foundation, https://ror.org/021nxhr62, DMS-1953430, DMS-2545859, DMS-2451263 NIH Common Fund, https://ror.org/001d55x84, R35GM136428
High-grade serous ovarian carcinoma (HGSOC) is characterized by high mortality rates and the frequent development of chemotherapy resistance. A hallmark of HGSOC progression is the formation of multicellular spheroids in malignant ascites that facilitate peritoneal dissemination and metastasis. While the CDC42-regulated kinases MRCKα and MRCKβ (MRCK) were previously found to be highly expressed in ovarian tumors and to be essential for cell migration and spheroid growth, the underlying molecular mechanisms were poorly defined. Mass spectrometry identified the RhoA-selective guanine nucleotide exchange factor GEF-H1 as a primary interacting partner of MRCKα. Functional assays revealed that MRCK inhibition or knockdown led to significantly increased levels of active GEF-H1 and subsequent RhoA activation. MRCKα was found to phosphorylate GEF-H1 on Ser174, and pharmacological inhibition of MRCK reduced this phosphorylation and decreased the association of GEF-H1 with α-Tubulin. Live-cell imaging and 3D assays demonstrated that MRCK inhibition disrupted cell-cell contacts and impaired the compaction of multicellular structures, ultimately reducing the viability of patient-derived organoids. These findings delineate a novel signaling crosstalk mechanism in which MRCKα represses GEF-H1-mediated RhoA activation to facilitate the formation of cell-cell contacts that contribute to the survival and growth of HGSOC cells in 3D multicellular structures. This study highlights MRCK as a potential therapeutic target to inhibit the growth and spread of HGSOC. ### Competing Interest Statement The authors have declared no competing interest. National Institutes of Health, CA282766 Canada Research Chairs, https://ror.org/0517h6h17, 950-231665, CRC-2024-00113 Natural Sciences and Engineering Research Council, https://ror.org/01h531d29, RGPIN-2020-05388 Cancer Research Society, 878415 Canadian Cancer Society, 706833 Ontario Institute for Cancer Research, P.CTIP.982 Toronto Metropolitan University, https://ror.org/05g13zd79 University of Toronto, https://ror.org/03dbr7087
Rxiv mechanobio