# The Role of the Integrated Stress Response in Cancer

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $1,074,314

## Abstract

ABSTRACT/SUMMARY (Overall)
The overall goal of this Program is to investigate the role of the Integrated Stress Response (ISR)
signaling pathway in tumor cell fate and tumor progression. Rapidly proliferating cancer cells
must thrive in a microenvironment wherein metabolic nutrients such as glucose, oxygen and
growth factors become limiting as tumor volume expands beyond the established vascularity of
the tissue. The ISR integrates signals from sensors (such as the endoplasmic reticulum kinase
PERK and cytoplasmic kinase GCN2) of cellular nutrients to homeostatic processes including
translational control, carbon and oxygen metabolism and receptor signaling. The ISR has also
been shown to facilitate oncogene-mediated tumor progression, suggesting that it may also
respond to bioenergetic challenges triggered by aberrant oncogene-dependent signaling. The
overall hypothesis to be tested in the proposed studies is that the Integrated Stress Response
plays a pivotal role in mediating MYC-dependent and hypoxia-dependent tumor
progression through its capacity to engage and regulate key pathways involved in
circadian, translational, metabolic and immune functions thereby facilitating tumor cell
survival and growth. The above hypothesis will be tested by three highly integrated projects:
Project 1 will define miRNAs subject to ISR control whose function is to fine-tune protein
synthesis during an ISR/UPR response. Two key, microRNAs, miR-211 and miR-217, are the
focus; collectively, they function as regulators of Bmal1 during ER stress and their contribution to
Bmal1 repression to lymphoma progression is critical for tumorigenesis. Project 2 will identify
critical nodes in metabolism and translation control which are coordinately regulated by both ATF4
and c-MYC and delineate the mechanism of co-regulation of common transcriptional targets. It
will also functionally test the role of ATF4 in MYC-dependent transformation and tumorigenesis.
Project 3 will delineate the mechanisms underlying ISR-induced IFNAR1-dependent and
independent inactivation of the IFN1 pathway, its role in the loss of viability of intratumoral
cytotoxic lymphocytes and the generation of the immune privileged niches. It will also determine
whether targeting these mechanisms can augment anti-cancer immunity. All three projects will
make extensive use of Core A (Administrative) and scientific Cores B (Metabolomics/Genomics)
and C (Biostatistics) and have already established a working, highly collaborative relationship.
Collectively, our three integrated and synergistic Projects will provide a molecular framework that
addresses the potential efficacy of targeting the ISR to antagonize malignancy in three highly
prevalent and lethal types of tumors.

## Key facts

- **NIH application ID:** 10247627
- **Project number:** 5P01CA165997-08
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Constantinos Koumenis
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,074,314
- **Award type:** 5
- **Project period:** 2013-09-18 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10247627

## Citation

> US National Institutes of Health, RePORTER application 10247627, The Role of the Integrated Stress Response in Cancer (5P01CA165997-08). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10247627. Licensed CC0.

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