# Interferon regulation by NBR1-driven chaperone-mediated autophagy in stellate cells in liver cancer

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2022 · $503,559

## Abstract

PROJECT SUMMARY
The long-term goal of this proposal is to understand the molecular and cellular mechanisms in the tumor
microenvironment that govern hepatocellular carcinoma (HCC) development, with a special focus on the role of
hepatic stellate cells (HSCs) as central players in this process. While it is clear that activation of non-parenchymal
cells is a key contributor to liver tumorigenesis, unfortunately, our knowledge of the molecular mechanisms
whereby key stromal and immune cell populations regulated HCC initiation and progression still is fragmentary.
Activated HSCs are key contributors to liver fibrosis and inflammation. The present proposal is based on our
previously published results demonstrating that the autophagy and signaling adaptor p62 is reduced in HSCs
from HCC patients and that its inactivation in mice, either globally or HSC-specific, promoted HCC due to the
hyperactivation of the inflammatory and fibrotic activities of HSCs. Our new unpublished preliminary results
demonstrate that the genetic ablation of NBR1, either globally or selectively in HSCs, completely reverts the pro-
tumorigenic role of p62 deficiency in HSCs. However, this unexpected effect of NBR1 deficiency does not revert
the pro-fibrotic, TGFb-driven effect of p62 loss and did not affect autophagy but resulted in the hyperactivation
of the interferon (IFN) cascade that renders CD8+ T cells more active, increasing anti-tumor immunosurveillance.
Our preliminary data also suggest that this hyperactivation of the IFN pathways is due to impaired chaperone-
mediated autophagy (CMA). Therefore, in this proposal we intend to unravel the mechanisms whereby NBR1
promotes CMA to restrain IFN activation. We will also establish how reduced CMA due to the inactivation of
NBR1 in HSCs results in the reprograming of the tumor microenvironment to repress tumorigenesis. To that end,
we will build on our preliminary data to address the following critical questions: (Aim 1) Establish the molecular
mechanisms whereby NBR1 regulates the IFN response in HSCs by (Aim 1.1) determining the effect of NBR1
and p62 inactivation on CMA activity in HSCs; (Aim 1.2) determining the functional contribution of CMA to NBR1-
mediated IFN regulation in HSCs; and (Aim 1.3) determining the molecular mechanisms whereby NBR1
regulates CMA. We will also (Aim 2) establish the contribution of NBR1 to HSC activation and the creation of a
tumor-suppressive microenvironment by (Aim 2.1) determining the impact that NBR1 deletion in HSCs has in
the tumor microenvironment of HCC; (Aim 2.2) determining the functional contribution of the CMA-STING-IFN
axis in NBR1-deficient HSCs to HCC progression in vivo; and (Aim 2.3) determining the impact of NBR1 loss in
HSCs in therapy response and its relevance in human HCC. Results from these studies will serve to identify new
biomarkers as well as non-parenchymal new therapeutic targets for the prevention and treatment of HCC.

## Key facts

- **NIH application ID:** 10336109
- **Project number:** 1R01CA265892-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Jorge Moscat
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $503,559
- **Award type:** 1
- **Project period:** 2021-12-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10336109

## Citation

> US National Institutes of Health, RePORTER application 10336109, Interferon regulation by NBR1-driven chaperone-mediated autophagy in stellate cells in liver cancer (1R01CA265892-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10336109. Licensed CC0.

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