Bradshaw, Andrew
(2021)
Inflammation in the Tumor Microenvironment: Experimental Models of Metastatic Melanoma Therapy.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Melanomas are heterogeneous tumors comprised of distinct cell subtypes that collectively form a single ‘organ’. The failure to effectively target the genetic diversity within this malignant organ underlies stalled tumor regression. This is referred to as resistance, wherein the tumor organ or microenvironment (TME) no long shrinks in response to therapy. Instead, invasive melanomas outgrow and secrete signals to alter the TME thereby promoting progression and dissemination. This inflammatory process shares many features in common with wound healing, and chronic inflammation has become an emergent hallmark of cancer. This dissertation establishes that transforming growth factor-β (TGFβ) release is an essential mediator of the persistent inflammation in the TME. In response to therapeutic stress, melanoma is shown to upregulate expression of pro-inflammatory cytokines and TGFβ. These molecules concomitantly antagonize the stroma leading to the activation of gene networks associated with wound healing and epithelial-to-mesenchymal transition (EMT). Here, TGFβ ligands are shown to transmit signals to fibroblasts to promote transformation into contractile myofibroblasts, referred to as cancer associated fibroblasts (CAF). These α-smooth muscle actin (αSMA+) CAFs transiently accumulate in wounds and sites of chronic inflammation. Within these inflamed sites CAFs secrete and synthesize ‘wound-associated’ extracellular matrix (ECM) which blunt the anti-tumor response to therapies. Dysregulated ECM promotes drug resistance via growth factor binding (e.g. TGFβ) and cell-ECM signaling that promotes invasion of dense tissue melanoma spheroids. Here, matricellular tumor-
v
ECM is shown to contain the matrikine tenascin-C (TNC). Tenascin-C has been experimentally shown to bind epidermal growth factor receptor (EGFR), promote malignant invasion, and promote motility and survival. Cocultures therapy inflamed melanomas are shown to stoke (αSMA+) CAFs. Clinically relevant inhibitors of the TGFβ receptor were used to perturb TGFβ signaling between the tumor-and-stroma. This led to the suppression of CAF transformation and limited in vitro outgrowth of melanoma via drug sensitization to mitogen-activated protein kinase (MEK) inhibitors. In vivo, a combination strategy to inhibit TGFβ activation of mouse CAFs results in MEK suppression of melanoma outgrowth and limits metastasis. Thus, combined targeting of the tumor-and-stroma limits cytotoxic cell stress and CAF remodeling of the inflamed TME and prevents deposition of progression associated ECM molecules.
Share
| Citation/Export: |
|
| Social Networking: |
|
Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
25 May 2021 |
| Date Type: |
Publication |
| Defense Date: |
7 May 2020 |
| Approval Date: |
25 May 2021 |
| Submission Date: |
3 April 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
186 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
Melanoma, Extracellular matrix, Matrisome, Inflammation |
| Date Deposited: |
26 May 2021 02:32 |
| Last Modified: |
26 May 2021 02:32 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/40494 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Actions (login required)
 |
View Item |
![[feed]](/images/feed-icon-32x32.png){kind=icon}