MS06 - ONCO-06

Data-driven integration and modeling of cellular processes in cell motility and cancer progression: Experiments and mathematical models (Part 2)

Thursday, July 17 at 10:20am

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Note: this minisymposia has multiple sessions. The other session is: and Part-1.

Yangjin Kim (Brown University and Konkuk University), Magdalena Stolarska at University of St. Thomas

Description:

Cell motility is a crucial step in metastasis and other detrimental processes in cancer such as cell infiltration in glioblastoma. Cancer is a complex, multiscale process, in which genetic mutations occurring at a sub-cellular level manifest themselves as functional changes at the cellular and tissue scale. Because cell motility plays a large role in cancer regulation, understanding the interactions of individual cells with the tumor 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 recent advances and challenges in modelling cell motility, tumor growth, and the development of new therapeutic strategies. Specific goals of the session include: (i) analyzing both computational and analytical solutions to mathematical models of tumor growth and its interaction with the microenvironment, (ii) improving our biochemical/biomechanical understanding of fundamental mechanism of cell motility in the context of cancer progression, and (iii) comparing experimental data and projecting new experimental ideas that allow us to better understand cellular processes that lead to the design of data-driven platforms for clinical diagnosis.

Donggu Lee

Konkuk University

"Asthma-mediated control of optic glioma growth via T cell-microglia interactions: Mathematical model"

Optic glioma, a slow-growing tumor, is associated with Neurofibromatosis type 1 (NF1) mutations and increased midkine (MDK) production. To elucidate the role of asthma in regulation of glioma formation, we investigated the role of T cells and the subsequent pathways in regulation of microglia, a key player in tumor microenvironment (TME). While asthma is often linked to chronic inflammation, our mathematical analysis and experimental evidence suggest that it can play a significant role in suppressing proliferation of optic glioma cells via immune reprogramming of T cells and delicate control of signaling network in microglia. The mathematical model unveil the complex interaction between brain tumor and immune cells in the brain. Our results indicate that asthma-induced T cell reprogramming inhibit tumor growth by promoting the release of Decorin, which leads to a chain of suppression of CCR8 and NFkB in microglia and CCL5 production. These findings highlight the potential of leveraging asthma-induced immune regulation as a novel mechanism for glioma suppression and demonstrate the power of mathematical modeling in uncovering complex tumor-immune interactions.

Ji Young Yoo

University of Texas Health Science Center at Houston

"Reshaping the Tumor Microenvironment by targeting IGF2-IGF1R signaling: Enhancing Viro-Immunotherapy"

The FDA approval of oncolytic herpes simplex-1 virus (oHSV) therapy for melanoma patients underscores its therapeutic promise as a cancer immunotherapy. However, despite this promise only a small subset of patients respond favorably in the clinic. Oncolytic virotherapies work both through direct oncolysis of infected cancer cells and by inducing of inflammatory response and concurrent activation of anti-tumor immunity through the release of tumor antigens from the lysed cancer cells, a phenomenon referred to as viro-immunotherapy. However, the induction of an immunosuppressive tumor microenvironment (TME) by the tumor both before and shortly after therapy poses the greatest hurdle to lasting efficacy and viro-immunotherapy. Our work centers on understanding the oHSV therapy resistance mechanism and characterizing the impact of viro-immunotherapy to design a better viro-immunotherapy to broaden their applications in the clinic. RNA-Seq analysis of oHSV-infected glioblastoma (GBM) and breast cancer (BC) cells identified Insulin-like growth factor 2 (IGF2) as one of the top 10 secreted proteins following infection. Moreover, IGF2 expression was significantly upregulated in 10 out of 14 recurrent GBM patients treated with oHSV, rQNestin34.5v.2 (71.4%) (p=0.0020) (ClinicalTrials.gov, NCT03152318), highlighting its clinical relevance. IGF2 is upregulated in tumor malignancies and its overexpression is associated with resistance to chemotherapy and radiation therapy, worse prognosis, anti-tumor immune suppression in the TME, and cancer metastasis. In order to mitigate oHSV therapy-induced IGF2 and improve the therapeutic efficacy of oHSV, we designed a novel oHSV construct, oHSV-D11mt, which integrates a secretable modified IGF2R domain 11 into the parental oHSV genome that serves as an IGF2 decoy receptor. The secreted IGF2RD11mt selectively binds to IGF2, effectively blocking oHSV-induced IGF2-IGF1R signaling, which lead to enhanced tumor cell cytotoxicity, reduced oHSV-induced neutrophils/PMN-MDSCs infiltration, reduced secretion of immunosuppressive/proangiogenic cytokines, and increased Cytotoxic T lymphocytes (CTLs) infiltration. These effects resulted in enhanced survival of both GBM and BC brain metastasis (BCBM) tumor-bearing mice, abrogating the resistance conferred by IGF2 secretion. Collectively, our findings suggest that oHSV-induced secreted IGF2 exerts a critical role in resistance to oHSV therapy and our novel viral construct represents a promising therapeutic for enhanced viro-immunotherapy.

Alexandra Shyntar

University of Alberta

"Mathematical Modelling of Microtube-Driven Regrowth of Glioma After Local Resection"

In this talk, I will first summarize the results from the paper Weil et al. (2017) “Tumor microtubes convey resistance to surgical lesions and chemotherapy in gliomas.” In this paper, they perform a series of experiments on glioblastoma tumors motivated by the discovery of tumor microtubes (TMs). TMs are thin long protrusions extending from the glioblastoma cell body which help the cancer grow, spread, and facilitate communication between glioma cells. Weil et al. (2017) implanted glioblastoma tumors into mice and tested various treatments (surgery, surgery with targeted therapy, surgery with anti-inflammation treatment, and chemotherapy). They find that TMs help with the faster and denser tumor repopulation in the lesion area. Furthermore, inhibiting the TMs slows down tumor growth significantly. In the second part of the talk, I will show how the experiments outlined in the paper can be modelled with partial differential equations. The effects from the wound healing response and TMs are simplified but are accounted for in the model. The numerical simulations reveal good agreement with the experimental observations and can capture the experimental trends after treatment application. Based on these results, the wound healing mechanisms as well as TM dynamics are key in explaining the experimental observations.

Sean Lawler

The Warren Alpert Medical School, Brown University

"Remodeling the Tumor Microenvironment to Facilitate Glioblastoma Therapy"

Glioblastoma(GBM) is the most common malignant brain tumor and is extremely challenging to treat effectively. Standard of care therapy involves surgical resection followed by radiation and alkylating chemotherapy. This results in a median survival of only 15 months, with resistance to therapy rapidly emerging. Immune checkpoint blockade has not yet shown efficacy in GBM. The GBM tumor microenvironment (TME)is complex and is thought to make a major contribution to resistance to both standard of care and immunotherapies. The GBM TME is characterized by infiltration of suppressive myeloid cells, and microglia, the presence of Tregs and lack of CD8+ T cells. In addition, tumor cells interact with neurons, astrocytes and with one another, subverting neurological signaling mechanisms to drive tumor progression and therapeutic resistance mechanisms. Understanding how to effectively modulate the GBM TME by targeting cellular interactions is essential to provide new therapeutic approaches. In this work, I will discuss approaches being developed in my lab to model these interactions, and the effects of immunomodulatory drugs on the TME that may facilitate responses to immune checkpoint blockade and other therapies, for improved outcomes in this devastating tumor type.

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Annual Meeting for the Society for Mathematical Biology, 2025.