Extracellular matrix signaling for early cancer invasion
Extracellular matrix signaling for early cancer invasion
Early lung cancer and the tumor microenvironment
Oncogenic activation of ERK in alveolar epithelium initiates the cells’ transformation into lung adenocarcinoma (LUAD), the most common type of lung cancer. Initiated cells can lie dormant for decades. Once awakened, if the cancer is caught early, before it has invaded throughout the lung and body, patients have a better prognosis. Changes in the extracellular matrix of the early tumor microenvironment can push initiated cells to become invasive and aggressive, causing tumor progression that results in metastasis. We discovered that expression of extracellular matrix Tenascin-C promotes early tumor cell invasion and progression to aggressive cancer, by signaling through integrin avb1 to activate focal adhesion kinase (FAK) in tumor cells. Fibroblasts express Tenascin-C in response to lung injury and FAK inhibition blocks the Tenascin-C expression and injury-induced tumor progression. This work suggests that FAK inhibitors might benefit patients with early tumors driven by injury-activated extracellular matrix.
In addition to FAK, further hyper-activation of ERK is an established driver of progression to metastasis. We have identified how some LUAD’s circumvent ERK pathway negative feedback loops to increase ERK activity to levels that promote progression to metastasis. We found that loss of the transcription factor NKX2-1 removes its induction of the ERK phosphatase DUSP6. This signal allows for increased ERK activity in vivo and promotes lung cancer cell line invasion and lung cancer progression in genetically-engineered mouse models and tumor xenografts.
- Samson, et al. BioRxiv (2024)
- Ingram, et al. Oncogene (2022)
RAS/ERK and microenvironment crosstalk for invasion
Invasion is present in the earliest detectable stages of LUAD and promotes tumor progression to metastasis. Invading cancer cells must overcome the structural restraints of tissue organization to move through the stroma and into the vasculature. The cells crawl along, degrade, and squeeze between the extracellular matrix (ECM) fibrils. The fibers, in turn, signal to the tumor cells to promote invasion.
Current projects: signaling for extracellular matrix and ERK
Current projects focus on identifying signals that induce fibroblast expression of ECM and tumor cell ERK hyperactivation in early LUAD.
Affiliations
- Department of Oncological Sciences
- Department of Biomedical Engineering
- Cancer Biology and Microenvironment Program
- Lung Center of Excellence
- Computational Oncology Research Initiative
- Molecular Biology Graduate Program
Collaborations
Mechanobiology: The Mendoza lab has a funded collaboration with the Weiss lab in the Biomedical Engineering department. This collaboration applies computational modeling and experimental stretching of lung tissue to understand the biomechanical signals involved in lung tumor growth.
Pollution and lung cancer: The Mendoza has lab a funded collaboration with Drs. Judy Ou and Chen Chen in Population Health Sciences to understand and target the cancer-promoting signals in particulate matter pollution.
Pathology: Support is also provided by Dr. Lyska Emerson in the Department of Pathology.