Biology subjects

Burkel, B. M.

Publications and source records attributed to Burkel, B. M..

3 recordsLinked to original sources

bioRxiv2025

Inhibiting fibronectin assembly in the breast tumor microenvironment increases cell death and improves response to doxorubicin

PurposeEffective therapies for solid tumors, including breast cancers, are hindered by several roadblocks that can be largely attributed to the fibrotic extracellular matrix (ECM). Fibronectin (FN) is a highly upregulated ECM component in the fibrotic tumor stroma and is associated with poor patient prognosis. This study aimed to investigate the therapeutic potential of an anti-fibrotic peptide that specifically targets FN and blocks the fibrillar assembly of FN. MethodsTo target FN, we used PEGylated Functional Upstream Domain (PEG-FUD), which binds to the 70 kDa N-terminal region of FN with high affinity, localizes to mammary tumors, and potently inhibits FN assembly in vitro and in vivo. Here, we used the 4T1 tumor model to investigate the efficacy and mechanisms of PEG-FUD to inhibit tumor growth. ResultsOur data demonstrates that PEG-FUD monotherapy reduces tumor growth without systemic toxicity. Analysis of the tumor microenvironment revealed that PEG-FUD effectively inhibited FN matrix assembly within tumors and reduced adhesion-mediated signaling through 5 integrin and FAK leading to enhanced tumor cell death. Notably, signaling through FAK has been associated with resistance mechanisms to doxorubicin (DOX). Therefore, we tested the combination of PEG-FUD and Dox, which significantly reduced tumor growth by 60% compared to vehicle control and 30% compared to Dox monotherapy. ConclusionsOur findings demonstrate that PEG-FUD significantly modifies the peritumoral ECM of breast cancer, leading to increased tumor cell death, and potentiates the efficacy of conventional breast cancer therapy.

cancer biology↗

bioRxiv2021

Conversion of cancer-associated fibroblasts from pro- to antitumor improves the sensitivity of pancreatic cancer to chemotherapeutics

Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we show that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, non-natural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

cancer biology↗

bioRxiv2020

Cell-Scale Biophysical Cues from Collagen Fiber Architecture Instruct Cell Behavior and the Propagation of Mechanosensory Signals

Mechanosensory cues from the extracellular matrix underpin numerous cellular behaviors including tumor cell migration yet are influenced by the local structure and organization of the matrix in unknown ways. To investigate mechanical cues with respect to local collagen organization, we used a combination of intravital imaging of the mammary tumor microenvironment and 3D collagen gel systems with both migratory MDA-MB-231 cells and acellular pNIPAAm beads. We identified that fiber organization directs a bias in cell response along the axis of alignment. Using innovative methodology, we determined that local collagen alignment resulted in a 30-fold difference in directional cell-scale stiffness and also dramatically altered the rate at which cell-induced fiber displacements decayed over distance. Our results reveal differential mechanical properties across orthogonal directions in aligned matrices that provide sizeable cues to the cell and have important implications for cellular mechanosensing and cell-cell communication within the tissue microenvironment.

biophysics↗