# Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis

> **NIH NIH R01** · MEDICAL UNIVERSITY OF SOUTH CAROLINA · 2021 · $341,981

## Abstract

SUMMARY
Transforming growth factor beta receptor type I/II (TßRI/II) signaling is activated on the plasma membrane
(PM) by ligand binding, inducing Smad3/4-dependent (canonical) or independent cell migration, invasion
and/or metastasis. While Smad3/4 activates, Smad7 binds and inhibits TßRI/II signaling. Primary cilia are
protrusions of PM that mediate cell-to-cell communication and migration/invasion without affecting cell motility
by activating various signaling pathways such as sonic hedgehog (Shh). Ceramide is a bioactive sphingolipid
with tumor suppressive signaling functions, and ceramide synthase 4 (CerS4) generates long chain C18/20-
ceramide. However, any mechanistic link between ceramide metabolism, Smad7 recruitment and TßRI/II
signaling at the primary cilium membrane for the regulation of tumor metastasis remains unknown. Based on
our novel and unpublished preliminary data, we designed this application to test a novel hypothesis that
CerS4/ceramide inhibits TßRI/II trafficking and signaling selectively at the primary cilia membrane via Smad7
to modulate cell migration, invasion and/or metastasis. The following Specific Aims are proposed: Aim 1)
Define the mechanisms by which ceramide regulates TßRI/II signaling by Smad7; Aim 2) Determine the
mechanisms by which ceramide/Smad7 inhibitory complex regulates TßRI/II trafficking to the primary cilia; and
Aim 3) Dissect the downstream mechanism by which TßRI/II signaling at primary cilia induces tumor
metastasis in response to alterations of the CerS4/ceramide/Smad7 axis. Overall, based on our expertise in
cancer signaling and lipid metabolism, we are uniquely positioned to develop novel mechanism-based
strategies for targeting/inhibiting TßRI/II signaling selectively in primary cilium, which then will help attenuate
tumor metastasis without affecting canonical functions of TGF-ß signaling (reducing general toxicity), using
innovative molecular/pharmacologic tools, genetic models, and clinical specimens.

## Key facts

- **NIH application ID:** 10222592
- **Project number:** 5R01CA214461-04
- **Recipient organization:** MEDICAL UNIVERSITY OF SOUTH CAROLINA
- **Principal Investigator:** Besim Ogretmen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $341,981
- **Award type:** 5
- **Project period:** 2018-08-31 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222592

## Citation

> US National Institutes of Health, RePORTER application 10222592, Ceramide metabolism and the regulation of TGF-beta receptor signaling to control metastasis (5R01CA214461-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10222592. Licensed CC0.

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