# Schwann Cell Reprogramming and Cancer Perineural Invasion

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2021 · $640,689

## Abstract

The ability of some cancers to invade in, around, and along nerves is a process termed perineural invasion
(PNI). PNI is an indicator of aggressive disease that is associated with morbidity from nerve dysfunction,
increased recurrence, and worse survival. Cancer cells (CC) may be stimulated by a variety of neurotrophic
factors released by nerves to facilitate PNI. This finding highlights the participatory role of the nerve
microenvironment in enabling this adverse process.
Schwann cells (SC) are key mediators of PNI; they intercalate between CC, facilitate CC dispersion, recruit CC
to nerves, enhance CC invasion, and ultimately promote PNI. Interestingly, SC activity in PNI recapitulates the
normal SC response following nerve injury. After nerve trauma, quiescent, myelinating SC are reprogrammed
to an active subtype that shares characteristics with progenitor, dedifferentiated, stem-like SC. These “repair”
SC release neurotrophic factors, recruit macrophages, and promote nerve repair. SC reprogramming following
nerve injury may be controlled by c-Jun or Raf-ERK signaling.
We hypothesize that the SC supporting nerves undergoing cancer invasion experience a transition similar to
SC response following nerve injury. SC affected by cancer invasion are reprogrammed to acquire a phenotype
that enables PNI. This SC phenotype includes: a transformation to a dynamic and motile cell able to interact
with other cell types, the release of neurotrophic ligands, the expression of new cell adhesion molecules, and
the ability to recruit macrophages to sites of PNI. Each of these acquired capabilities recapitulates similar SC
reprogramming as a normal response to trauma, but may paradoxically promote PNI. We will explore how the
interactions between SC and cancer are derived from a conserved nerve-repair program that is exploited by
various cancers to facilitate their progression. This cross-disciplinary proposal combines expertise from
oncology, neurodevelopment, cell biology, macrophage trafficking, pathology, and biostatistics to:
1. Characterize SC reprogramming in PNI and elucidate the drivers of this process. We will explore parallels
 in SC plasticity between nerve injury and PNI.
2. Determine how reprogrammed SC directly promote PNI. We will determine how SC c-Jun and Raf-ERK
 signaling impact PNI, and assess how reprogrammed SC mechanistically support PNI.
3. Assess how reprogrammed SC recruit inflammatory monocytes to indirectly promote PNI. We will
 determine mechanisms of SC-mediated monocyte recruitment and define how macrophages promote PNI.
Our overall objective is to elucidate the relationships between cancer PNI and SC nerve-repair mechanisms to
identify novel targets for therapy. Understanding how normal nerve response to injury paradoxically supports
cancer invasion may reveal novel opportunities and strategies to interrupt this highly adverse process.

## Key facts

- **NIH application ID:** 10227704
- **Project number:** 5R01CA219534-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Richard J Wong
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $640,689
- **Award type:** 5
- **Project period:** 2017-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10227704

## Citation

> US National Institutes of Health, RePORTER application 10227704, Schwann Cell Reprogramming and Cancer Perineural Invasion (5R01CA219534-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10227704. Licensed CC0.

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