Date of Award

Fall 2024

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Program/Concentration

Biomedical Sciences

Committee Director

Robert Bruno

Committee Director

Patrick Sachs

Committee Member

Peter Mollica

Committee Member

Lisa Shollenberger

Committee Member

Harold Riethman

Abstract

The dynamic cellular microenvironment, made up of resident cells and various macromolecules, differs markedly across tissues in the body. The multidirectional signals that cells receive from this microenvironment, along with the signaling they send back, heavily influence their physiology and behavior. Recent important findings have further validated this notion as the mammary microenvironment has been shown to suppress tumor progression by redirecting cancer cells to adopt a normal mammary epithelial progenitor fate in vivo. However, the mechanism(s) driving changes in metabolic reprogramming and cancer fate redirection is understudied. The work presented in this dissertation focuses on exploring the impact of the microenvironment through mitochondrial transfer from various mammary and adipose-derived stem cells to breast cancer cells. We establish the occurrence of mitochondrial transfer in 2D and 3D cellular environments using our unique 3D bioprinting system to successfully produce chimeric organoids and tumoroids. Furthermore, we show mitochondrial transfer occurs between donor and recipient cells primarily through tunneling nanotubes (TNTs) with minimal amounts seen from extracellular transfer of mitochondria likely via extracellular vesicles (EVs). This organelle exchange results in various cellular and metabolic alterations within cancer cells, making them susceptible to microenvironmental exchanges. To the best of our knowledge, this is the first description of a 3D bioprinter-assisted organoid system for studying mitochondrial transfer. These studies are also the first mechanistic insights into the process of mammary microenvironmental redirection and metabolic reprogramming of cancer and provide a framework for new therapeutic strategies to enhance patient survival.

Rights

In Copyright. URI: http://rightsstatements.org/vocab/InC/1.0/ This Item is protected by copyright and/or related rights. You are free to use this Item in any way that is permitted by the copyright and related rights legislation that applies to your use. For other uses you need to obtain permission from the rights-holder(s).

DOI

10.25777/kt8e-yp06

ISBN

9798302855558

Download

Share

COinS