# Molecular Dissection of Cytokine Crosstalk in the Tumor Microenvironment

> **NIH NIH P01** · CLEVELAND CLINIC LERNER COM-CWRU · 2022 · $1,916,095

## Abstract

PROJECT SUMMARY
Despite recognition of the broad consequences of inflammation in cancer biology, the mechanistic impact on the
tumor landscape remains incompletely understood. Indeed, innate and adaptive immune functions in cancer can
be beneficial or detrimental and the opposing roles highlight the gap of knowledge in our understanding of how
inflammation sculpts the tumor microenvironment (TME). This Program Project will address this gap of
knowledge by defining and delineating how cytokines modulate the functions of the multiple cell types composing
the tumor microenvironment. Our previous work has revealed the potential for these inflammatory cytokines to
regulate a spectrum of cancer cell phenotypes, including their self-renewal and cellular hierarchy or stemness,
that are associated with the epithelial-mesenchymal transition (EMT). Moreover, these phenotypes are
commonly associated with cancer progression through modulation of differentiation potential, cell-cell
interactions and mobility, fibrosis, and sensitivity to multiple therapeutic modalities. The program is now centered
on two major themes. The first is to define the signaling mechanisms that govern how cytokines (type I IFNs, IL-
17,TGFβ) modulate (both positively and negatively) the EMT process. The cellular targets include stem-like
tumor cells as well as the non-tumor derived populations, including fibroblasts and immune cells. The second
theme relates these cell-specific EMT responses to specific effects on metastasis, fibrosis, and resistance to
multiple therapeutic strategies. Our major goal is to parlay our improved understanding of cytokine effects in the
TME into specific improvements in cancer therapy. Collectively the three projects in the application will test the
following overarching hypothesis: Cytokine signals have distinct and sometimes conflicting mechanistic roles in
cancer progression though alterations in EMT and cancer stem cell development. Such mechanisms lead to
critical phenotypic properties responsible for continuous metastatic spread and resistance to multiple therapeutic
modalities (chemotherapy, immune therapy). This hypothesis will be tested by (1) defining the signaling events
initiated by TGFβ, IL-17, and/or Type I IFNs and the endpoint changes in specific gene expression that are
causally linked with control of TME and cancer cell phenotypes, (2) determination of how these specific signaling
pathways and gene expression events are mechanistically responsible for acquisition of therapeutic resistance
and (3) evaluation of the distinct cell type contributions to tumor phenotypes and therapeutic resistance, with
emphasis on tumor cell intrinsic mechanisms, immune cell infiltrates and activities, and stromal cell control of
tumor access.

## Key facts

- **NIH application ID:** 10493937
- **Project number:** 1P01CA272161-01
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** GEORGE ROBERT STARK
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,916,095
- **Award type:** 1
- **Project period:** 2022-09-13 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10493937

## Citation

> US National Institutes of Health, RePORTER application 10493937, Molecular Dissection of Cytokine Crosstalk in the Tumor Microenvironment (1P01CA272161-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10493937. Licensed CC0.

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