Role of biomechanics and tumor microenvironment in osteosarcoma progression

Shoaib, Zunaira

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https://hdl.handle.net/2142/132512 Copy

Description

Title

Role of biomechanics and tumor microenvironment in osteosarcoma progression

Author(s)

Shoaib, Zunaira

Issue Date

2025-11-24

Director of Research (if dissertation) or Advisor (if thesis)

• Fan, Timothy M
• Irudayaraj, Joseph

Doctoral Committee Chair(s)

Fan, Timothy M

Committee Member(s)

• Harley, Brendan
• Lau, Gee

Department of Study

Pathobiology

Discipline

VMS - Pathobiology

Degree Granting Institution

University of Illinois Urbana-Champaign

Degree Name

Ph.D.

Degree Level

Dissertation

Keyword(s)

• oncology
• osteosarcoma
• mechanobiology
• tumor microenvironment
• cancer stem cells
• fibroblasts
• cancer research

Abstract

This dissertation presents research conducted under the themes of tumor heterogeneity, mechanobiology and the tissue microenvironment. It aims to understand the different influences, physical and biochemical, present in the osteosarcoma tissue microenvironment and connect them to give a broader understanding of the tumor microenvironment and the interactions between cellular neighborhoods. Chapter 1 is an introduction and a detailed review of existing literature on the mechanobiological pathways relevant to osteosarcoma. It underscores the significance of tumor mechanobiology at both macro and cellular levels by providing information on mechano-structural properties of pathological bone and highlighting cellular mechanotransductors which are subjects of research and discussion in the next chapters. Chapter 2 investigates tumor heterogeneity and osteosarcoma cell plasticity across distinct mechano-structural bone niches to elucidate environments conducive for the maintenance of cancer stem cells (CSCs), which are one of the leading causes of osteosarcoma recurrence, metastasis and therapeutic resistance. Using tunable mineralized 3D collagen scaffolds mimicking different bone niches present across normal and pathological bone, this study discovered that soft, anisotropic niches were favorable homes for CSCs as compared to stiff, isotropic niches. Overall, the findings in chapter 2 show how osteosarcoma subpopulations can exist in different spatial territories and contribute to tumor progression in distinct ways. Chapter 3 investigates the role of fibrosis and host cancer-associated fibroblasts (CAFs) populating the metastatic lung microenvironment in osteosarcoma. Considering the organotropism of metastatic osteosarcoma to the lung, the findings from this chapter present the anti-fibrotic drug Setanaxib as a viable therapeutic option for disrupting the interaction between pulmonary CAFs and osteosarcoma. Under the overarching theme of this dissertation, it provides supporting evidence for modulating the tumor microenvironment and the associated non-cancerous cell populations as a significant approach to understanding and treating osteosarcoma. Chapter 4 provides evidence that the cytoskeletal linker and oncoprotein Ezrin is a potential mechanotransductor in osteosarcoma due to its exclusive nuclear localization and its association with metastatic cells and high-grade tumors. These findings add to the foundation of Ezrin being an attractive biomechanical target in osteosarcoma. Chapter 5 is a pilot study which shows the pro-fibrotic effect of atmospheric pollutant PFAS on the pulmonary microenvironment. Our findings show that PFAS compound “PFOA” induces aggressive fibrosis in the lung only through inhalation in a relatively short time. These findings could be used to create new models of fibrotic lung disease which could be used to study pulmonary biomechanics in osteosarcoma. Chapter 6 details a research proposal for the creation of biomimetic drug-encapsulating nanoparticles for targeted delivery to the pulmonary metastatic microenvironment. The proposal leverages the neutrophil population in the pulmonary metastatic microenvironment of osteosarcoma for chemotaxis-driven targeting of the tumor area with anti-fibrotic drugs. It builds upon the foundation of CAF-osteosarcoma interaction in chapter 3 and complements the overall dissertation theme by connecting diverse influences in the tissue microenvironment. Ultimately the overarching purpose of this dissertation and doctoral research is to contribute to basic understanding for the foundation of building therapeutic approaches based on cellular plasticity and biomechanical signatures, by elucidating the domino effect that happens across the tissue microenvironment when one component of the landscape is modulated.

Graduation Semester

2025-12

Type of Resource

Thesis

Handle URL

https://hdl.handle.net/2142/132512

Copyright and License Information

Copyright 2025 Zunaira Shoaib

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