# Regulation of RBP Function during EMT

> **NIH NIH R01** · UNIVERSITY OF NEBRASKA MEDICAL CENTER · 2024 · $433,583

## Abstract

The goal of this research is to characterize Ras-driven and KSR1-dependent mechanisms that modulate
tumor initiation, drug resistance and the epithelial-to-mesenchymal transition (EMT) in colorectal cancer. Tumor
initiating cells (TICs) are a subpopulation of tumor cells defined by their ability to self-renew and regenerate the
entire heterogeneous tumor population and are believed to be a reservoir of drug resistant persister cells. EMT-
like behavior contributes to tumor initiation, invasion, and metastasis. Partial reversal of EMT to a “hybrid” state
is necessary for efficient TIC formation and metastatic colonization. In turn, TICs lose clonogenicity and self-
renewal and acquire the invasive behavior of mesenchymal cells that drives their dissemination. While the
interconversion of tumor cells to migratory and invasive mesenchymal cells from self-renewing TICs is necessary
for metastasis, little is known about the mechanisms that direct tumor cells between these phenotypes. We
combined targeting of genes encoding key effectors of Ras signaling with polysome profiling and computational
analysis to discover that the molecular scaffold KSR1 mediates resistance to clinically approved drugs and regulates
TIC formation and EMT via RNA binding protein SRSF9. Our preliminary data suggest the hypothesis that KSR1-
dependent signaling in KRAS-mutated CRC promotes the splicing and translation of mRNAs critical to CRC
tumor initiation, drug resistance, and EMT. Using genetically modified CRC organoids, mouse models, and cells,
the synergistic expertise of our team will characterize these novel pathways controlling CRC behavior in vitro
and in vivo by 1) Characterizing the KSR1-dependent pathway(s) necessary for tumor initiation and resistance,
2) Defining the KSR1-dependent mechanism(s) driving cells from partial EMT toward invasive mesenchymal
behavior, and 3) Determining how KSR1-dependent splicing promotes translation of proteins critical for EMT.
Completion of this research will reveal novel mechanisms that may be targeted to improve therapeutic response
and inhibit tumor initiation and metastasis.

## Key facts

- **NIH application ID:** 10812607
- **Project number:** 1R01CA277495-01A1
- **Recipient organization:** UNIVERSITY OF NEBRASKA MEDICAL CENTER
- **Principal Investigator:** Robert E. Lewis
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $433,583
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10812607

## Citation

> US National Institutes of Health, RePORTER application 10812607, Regulation of RBP Function during EMT (1R01CA277495-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10812607. Licensed CC0.

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