The Problem

Progression of cancers in the breast, pancreas and liver involve tumor cell proliferation, therapy resistance and metastatic dissemination to distant tissues – there is a strong correlation between these events and poor patient survival (Wang et al. 2019 BMC Cancer). Notably, 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. My research laboratory aims to identify and elucidate how cell intrinsic and extrinsic factors regulate cancer metastasis and therapy resistance, and whether these mechanisms may also control normal tissue repair processes. Ultimately, our goal is to develop novel strategies to diagnose cancers earlier and treat disease progression more effectively.

 The Approach

In this regard, our research group has made several seminal scientific contributions. In summary, we have…

1. Identified a SNAI2-PEAK1-INHBA stromal fibroblast signaling axis that supports targeted therapy resistance and metastasis by driving anti-apoptotic signaling in subpopulations of HER2-positive breast cancer cells (Hamalian et al. 2021 Oncogene).

2. Defined eIF5A1/2- and PEAK1-dependent mechanisms in breast and pancreatic tumor cells that facilitate TGFβ-induced EMT and metastasis (Fujimura et al. 2014 Cancer Research, Agajanian et al. 2015 PLoS One, Agajanian et al. 2015 BBRC, Hoover/Adamian et al. 2016 Oncotarget, Strnadel et al. 2017 Cancer Research, and Guth/Adamian et al. 2019 BBRC),

3. Determined that ITGA1-dependent pancreatic cancer cell adhesion to collagen mediates TGFβ-induced EMT, metastasis, and chemotherapy resistance (Gharibi/Kim et al. 2017 Scientific Reports),

4. Developed a tumor cell-free, immune-competent mouse model for studying how soluble/secreted factors affect the premetastatic niche and identified a novel eIF5A1/2-LCN2 axis that reprograms the premetastic lung to support triple-negative breast cancer cell expansion (Meade/Sanchez/Aguayo et al. 2019 Oncotarget), and

5. Elucidated cooperative signaling mechanisms of the cell-surface Cripto/GRP78 complex during cancer metastasis and 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 immunofluorescence, 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 $3 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.