The Problem

Progression of fibrosis, solid tumors and developmental disorders involve cell proliferation, invasion and epithelial-mesenchymal plasticity - processes that have been linked to therapy resistance and metastatic dissemination in cancers of the liver, breast and pancreas. Importantly, there is a strong correlation between these cellular processes and poor patient outcomes. Many signaling pathways and molecular/cellular mechanisms that control normal tissue homeostasis and repair are reactivated and/or dysregulated during the progression of solid tumors. However, there are fundamental gaps in our knowledge regarding how the complexity of extracellular matrix (ECM) proteins and growth factors (GF) within 3D in vitro and in vivo microenvironments interact to govern cellular processes associated with disease. Our research laboratory aims to identify and elucidate how cell intrinsic and extrinsic factors regulate fibrosis, normal tissue repair and cancer progression.

 The Approach

Our research group has developed and applied pathophysiologically relevant 3D in vitro and in vivo models to make the following scientific contributions...

1. Identified mechanisms by which pseudopodium-enriched atypical kinase 1 (PEAK1) controls fibroblast activation and activin-A secretion in disease contexts (Wang et al. 2010 PNAS, Hamalian et al. 2021 Oncogene),

2. Defined mechanisms by which eukaryotic initiation factor 5A 1/2 (eIF5A1/2) integrates fibronectin and TGFβ signals during EMT/P (Fujimura et al. 2014 Cancer Research, Agajanian et al. 2015 PLoS One, Agajanian et al. 2015 BBRC, Strnadel et al. 2017 Cancer Research, Guth/Adamian et al. 2019 BBRC, Geller et al. 2023 bioRxiv),

3. Determined mechanisms by which integrin alpha 1 (ITGA1) transduces collagen signaling in malignant and non-malignant epithelial cells (Gharibi/Kim et al. 2017 Scientific Reports, Aquino et al. 2024 BBRC),

4. Developed an immune-competent mouse model for studying how soluble/secreted factors affect the lung epithelium and immune cell remodeling (Meade/Sanchez/Aguayo et al. 2019 Oncotarget), and

5. Elucidated mechanisms by wich cell-surface receptors mediate stem cell responses to TGFβ stimulation during tissue regeneration (Zoni et al. 2017 Oncogene and Hoover et al. 2018 BBRC).

These advances together with our use of two- and three-dimensional in vitro/ex vivo cell systems, primary patient samples, molecular biology, live-cell microscopy, multiplexing single-cell spatial biology methods, flow cytometry, RNAseq, bioinformatics and preclinical vertebrate animal models give my laboratory a distinct advantage over others to address central problems in cancer biology and tissue regeneration. Our group has received extramural funding to date of over $5 M, including renewal of our NIH R01-equivalent SC1 award (SC1GM121182) for a second cycle and philanthropic giving from the Sidney Stern Memorial Trust, Sutter Family and the Aylozyan Family Foundation.