# Autophagy Heterogeneity and Tumor Metastasis

> **NIH NIH R21** · PENNSYLVANIA STATE UNIV HERSHEY MED CTR · 2021 · $417,005

## Abstract

The goal of this project is to investigate the intratumoral heterogeneity of autophagy activity in breast cancer
metastasis. Autophagy is a highly conserved lysosomal degradation pathway that is induced in response to
environmental or intracellular stress for the recycling of damaged proteins or organelles and the maintenance of
cellular homeostasis. While autophagy serves as a tumor suppressor to limit malignant transformation, it also
enables the growth and survival of cancer cells within the nutrient- and oxygen-deprived tumor microenvironment
(TME). Hypoxia is associated with enhanced metastasis and poor prognosis; however, the role of hypoxia-
induced autophagy in tumor progression is not clear. We have established a novel orthotopic model of breast
cancer in which autophagy is physiologically and reversibly suppressed in hypoxic tumor regions. Notably, the
loss of autophagy in hypoxic tumor regions significantly increases lung metastasis without affecting primary
tumor growth. Moreover, the loss of hypoxia-induced autophagy also enhances lung metastasis compared to
tumors in which autophagy is constitutively suppressed. Collectively, we hypothesize that the loss of hypoxia-
induced autophagy increases tumor stress to promote metastasis via collaboration with nearby autophagy-
competent cells to establish tumor subpopulations with high and low autophagic activity that drive metastasis
through the fibronectin-integrin signaling and metabolic coupling. The hypotheses will be tested in two Specific
Aims: 1) To identify and characterize the tumor subpopulations with increased metastatic potential during the
loss of hypoxia-induced autophagy or induction of autophagy heterogeneity; 2) To investigate the mechanisms
by which heterogeneous autophagy activity mediates intra-tumor cell communication. Completion of these
studies will significantly enhance our understanding of autophagy in tumor metastasis and provide insight into
the appropriate modulation of autophagy for cancer therapy.

## Key facts

- **NIH application ID:** 10212775
- **Project number:** 1R21CA252748-01A1
- **Recipient organization:** PENNSYLVANIA STATE UNIV HERSHEY MED CTR
- **Principal Investigator:** HONG-GANG WANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $417,005
- **Award type:** 1
- **Project period:** 2021-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212775

## Citation

> US National Institutes of Health, RePORTER application 10212775, Autophagy Heterogeneity and Tumor Metastasis (1R21CA252748-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10212775. Licensed CC0.

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