# The Aging Cutaneous Microenvironment and Cancer Initiation

> **NIH NIH U01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2021 · $455,335

## Abstract

ABSTRACT
Cancer is clearly a disease of aging. This connection between aging and cancer incidence is especially
true in the case of skin cancer, which is the most common form of human cancer, accounting for more
than all other cancers combined in USA. The major objective of this application is to gain understanding
of cellular and molecular mechanisms that link age-related skin changes to the initiation of skin cancer.
This application is based on our findings that fibroblasts in aged human skin express elevated levels of a
matricellular protein named CCN1, and that elevated CCN1 acts to deleteriously alter the dermal
compartment of skin to create a microenvironment that enhances cancer initiation. Based on these
observations, we have created genetically modified mice that express elevated levels of CCN1 selectively
in dermal fibroblasts (source of elevated CCN1 in aged human skin). These mice exhibit strikingly
accelerated dermal aging and display multiple hallmarks of aging that are seen in human skin. Importantly,
mice that express elevated levels of CCN1 in the dermis also have a high propensity for skin tumor
initiation. These results provide direct support for the overarching hypothesis of this application; that age-
related changes in the dermal microenvironment, driven by fibroblast expression of CCN1, create a dermal
microenvironment that enhances initiation of keratinocyte cancer. We propose to test this hypothesis with
the following specific aims. Aim 1: define the impact of CCN1-induced accelerated dermal aging on
keratinocyte cancer initiation. Aim 2: test the hypothesis that activation of the hepatocyte growth factor
pathway by the CCN1-induced dermal aging microenvironment drives keratinocyte cancer initiation. Aim
3: using targeted gene deletion, test the requirement for CCN1 expression in dermal fibroblasts for the
development of an aging-related dermal microenvironment and initiation of keratinocyte cancer. The aims
of this proposal directly address the objectives of the National Cancer Institute/National Aging Institute
Funding Opportunity Announcement to understand mechanisms by which age-related alterations in the
cellular niche/microenvironment contribute to cancer initiation.

## Key facts

- **NIH application ID:** 10292761
- **Project number:** 1U01AG077924-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** ANDRZEJ A. DLUGOSZ
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $455,335
- **Award type:** 1
- **Project period:** 2021-09-30 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10292761

## Citation

> US National Institutes of Health, RePORTER application 10292761, The Aging Cutaneous Microenvironment and Cancer Initiation (1U01AG077924-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10292761. Licensed CC0.

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