# Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $398,408

## Abstract

Cancer cell invasion is the major cause of lung cancer morbidity. Invasion remain untargeted, in part due
to an incomplete understanding of the molecular underpinnings of the cellular process. The long-term
goal is to identify the mechanisms that drive lung adenocarcinoma invasion. The overall objective here is
to elucidate the Tenascin-C and ERK signaling mechanisms that drive LUAD invasion. The central
hypothesis is that ERK and Tenascin-C work together to induce LUAD invasion. This is based on our
preliminary data. We show that Tenascin-C is expressed early after tumor initiation by activating
upstream mutations in the ERK pathway. We also show that Tenascin-C and ERK are both expressed at
the invasive edge of tumors, and that Tenascin-C induces ERK activity and ERK-dependent tumor cell
invasion in vitro. The central hypothesis will be tested by pursuing three specific aims: 1) Determine the
cell source and stimulus for Tenascin-C production in early LUAD, 2) Determine the mechanism by which
Tenascin-C signals to LUAD tumor cells, and 3) Identify mechanisms of ERK-mediated LUAD invasion.
Under the first aim, we will test if fibroblasts produce Tenascin-C in response to increased strain. In aim
2, we will determine if Tenascin-C signals to induce tumor cell invasion by activating tumor cell integrins
and ERK. In aim 3, we will test if LOK/Ezrin are critical ERK effectors that drive the mesenchymal-mode
invasion observed in LUAD. This will determine the mechanisms by which the lung cancer extracellular
matrix interacts with oncogenic RAS/ERK signaling to drive invasion. The research proposed in this
application is innovative, because it tests a new model of Tenascin-C induction, develops a computation
model of tumor growth within the lung and under stretch, uses organotypic cultures, and tests a new,
druggable ERK effector in the invasion process. The proposed research is significant because it is
expected to advance our understanding of lung cancer with new knowledge of how mechanochemical
signaling between the stroma and cancer confers cancer invasion. Ultimately, such knowledge has the
potential to provide strong scientific justification for the development of new therapies to target invasion
and reduce lung cancer morbidity and mortality.

## Key facts

- **NIH application ID:** 10367122
- **Project number:** 1R01CA255790-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Michelle Christine Mendoza
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,408
- **Award type:** 1
- **Project period:** 2022-05-16 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10367122

## Citation

> US National Institutes of Health, RePORTER application 10367122, Cancer invasion: reciprocity between the extracellular matrix and intrinsic ERK signaling (1R01CA255790-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10367122. Licensed CC0.

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