MS07 - ONCO-1
Ohio Staters Traditions Room (#2120) in The Ohio Union

Integration of cellular processes in cell motility and cancer progression

Thursday, July 20 at 04:00pm

SMB2023 Follow Thursday during the "MS07" time block.
Room assignment: Ohio Staters Traditions Room (#2120) in The Ohio Union.

Note: this minisymposia has multiple sessions. The other session is MS06-ONCO-1 (click here).

Yangjin Kim, Magdalena Stolarska

Description:

Cancer is a complex, multi-scale process, in which genetic mutations occurring at a sub-cellular level manifest themselves as functional changes at the cellular and tissue scale. Both the immediate microenvironment (cell-cell or cell-matrix interactions) and the extended microenvironment (e.g. vascular bed, stromal cells) are considered major players in tumour progression as well as suppression. The microenvironment is known to control tumour growth and cancer cell invasion to surrounding stromal tissue. Therefore, a thorough understanding of the interaction of individual cells with the microenvironment would provide a foundation to generate new strategies in cancer treatments. In particular, understanding the effect of the microenvironment on the signal transduction pathways of individual cells can improve cancer therapies by allowing one to target the specific biochemical pathways that are associated with the disease. Therefore, the main aim of this session is to discuss current stages and challenges in modelling tumour growth and the development of therapeutic strategies. Specific goals of the session include: (i) analyzing both computational and analytical solutions to mathematical models of tumor growth and its mechanical and biochemical interaction with the microenvironment, (ii) improving our biochemical/biomechanical understanding of fundamental mechanism of cellular movement in the context of cancer progression, and (iii) suggesting possible laboratory experiments that allow us to better understand cellular processes and lead to the design of platforms for clinical diagnosis. The development of mathematical models and their analysis and simulation allows us to shed light on our understanding of tumour growth in the host tissue environment and on the biochemical and biomechanical interactions between players in cancer progression.

Magdalena Stolarska

Univeristy of St. Thomas (Mathematics)

"On the significance of membrane unfolding and cortical stress generation in cell movement"

Cell motility play a critical role in cancer metastasis. Active deformation of the lipid bilayer and underlying actin cortex are important aspects of cell motility but have generally been overlooked in mathematical models. Membrane dynamics, including unfolding and exocytosis from intracellular reservoirs to the lipid bilayer, is necessary for large changes in cell shape, which occur during cell spreading and motility (Figard & Sokac, BioArchitecture, 2014) and for the release of membrane tension that occurs during these shape changes (Pontes et al., J Cell Bio, 2017). Actomyosin contraction of the underlying cortical layer also locally controls variations in cell shape and modes of motility (Salbreux et al., Cell, 2012). The aim of this work is to understand how active deformation of the membrane allows for large deformations of the cell and to understand how local active deformation of the actin cortex leads to amoeboid cell movement. To do this, two related mathematical models are presented. In both models the cell is treated as a viscous fluid that is surrounded by a viscoelastic membrane-cortex pair. Active deformation of the membrane or cell cortex is incorporated into the model via an additive decomposition of the rate of deformation tensor, the active part of which can depend on mechanical or biochemical components of the model, such as membrane tension or local myosin concentration. Using finite element simulations of the model we show that active membrane deformations, such as unfolding, and myosin-based contractility of the cortical layer are required for controlling various modes of cell motility.

Jay Stotsky

University of Minnesota (School of Mathematics)

"Cell Cortex Mechanics and Cell Swimming"

The cell-cortex is a dense layer of cytoskeletal proteins lying underneath the cell-membrane of many types of cells. Because of its proximity to the cell-membrane, it exerts forces on the membrane precipitating movement and shape-change in cells. In turn, coordinated movement and shape-change are pivotal in cancer metastasis and in biological development. Thus, understanding the mechanical behavior of the cortex is an important area of study that can yield insights into a broad array of challenging questions in biology and medicine. However, the cortex also exhibits complicated behaviors that cannot be fully explained by present models. It is an active material, meaning that it converts chemical (or other forms of) energy into mechanical stress, and it is continually remodeled as the proteins that make up the cytoskeleton turn over and are recycled. In this talk, I will discuss recent work towards developing more realistic models, and computational tools to study the cell cortex. This area of research is exciting because of the many applications to biology and medicine and because it lies at the intersection of a diverse array of topics including differential geometry, thermodynamics, numerical analysis, and biomechanics.

Donggu Lee

Konkuk University (Mathematics / Seoul, Republic of Korea)

"Optimal strategies of oncolytic virus-bortezomib therapy"

Proteasome inhibition and oncolytic virotherapy are two emerging targeted cancer therapies. Bortezomib, a proteasome inhibitor, disrupts the degradation of proteins in the cell leading to accumulation of unfolded proteins inducing apoptosis. Oncolytic virotherapy uses genetically modified oncolytic viruses (OV) to infect cancer cells, induce cell lysis, and activate an antitumor response. In this work, optimal control theory is utilized to minimize the cancer cell population by identifying strategic injection protocols of bortezomib and OV. Two different therapeutic protocols are explored: (i) Periodic bortezomib and single administrations of OV therapy; (ii) Alternating sequential combination therapy. These strategies support timely bortezomib and OV injection. Relative doses and administrative costs of the two anti-cancer agents for each approach are qualitatively presented. This study provides potential combination therapeutic strategies in cancer treatment.
Additional authors: Yangjin Kim, Konkuk University; Aurelio A. de los Reyes V, University of Philippines and Institute for Basic Science

Yangjin Kim

Konkuk University (Department of Mathematics)

"Activated NOTCH induced monocyte recruitment suppresses anti-tumor immunity with virotherapy"

The impact of NOTCH signaling on immune therapy is understudied. We found that activation of NOTCH signaling promotes an MDSC enriched immune suppressive environment in brain tumors that limits the benefit from oncolytic immunotherapy. We developed a mathematical model, based on a system of partial differential equations, for the role of NOTCH signaling and macrophages in regulation of tumor growth dynamics and in control of anti-tumor efficacy in onvolytic virus therapy. Experimental data from RNA sequencing and CHIP-PCR indicated that infected tumor cells induced ADAMTS1 expression via RBP-j mediated canonical NOTCH signaling, which then enhanced macrophage recruitment in tumors. We found that Jag1 (NOTCH ligand) expressing macrophages created a feed forward loop in TME that amplified NOTCH signaling in tumor cells distant from sites of viral infection. Then, we investigated how macrophages are recruited to oHSV treated tumors and how these immune cells induce CCL2 production via TLR activation. The critical phenotypic switch towards an M2 phenotype that were immunosuppressive and induced tumor growth, played a significant role in regulation of the immune-tumor dynamics. We tested several hypotheses on the pharmacologic blockade of NOTCH signaling and possible rescue of a CD8 dependent anti-tumor memory response that enhanced therapeutic efficacy of oHSV therapy.
Additional authors: Avner Friedman, Ohio State University Yoshihiro Otani, University of Texas Health Science Center at Houston Junho Lee, Konkuk Univerrsity Balveen Kaur, University of Texas Health Science Center at Houston

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Annual Meeting for the Society for Mathematical Biology, 2023.