# Targeting the autophagy-lysosome system to block pancreatic cancer

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $364,912

## Abstract

PROJECT SUMMARY
 Cancer cells co-opt autophagy - an evolutionarily conserved cellular recycling pathway - to maintain
metabolic fitness. Prior studies have shown that Pancreatic Ductal Adenocarcinoma (PDA) up-regulates
autophagy and lysosomes – acidic organelles where autophagic cargo is degraded – to dramatically increase
the bulk breakdown and recycling of diverse intracellular substrates. An additional, less well understood
function of autophagy is the selective removal of specific proteins in order to endow PDA cells with
enhanced fitness.
 We now show that the autophagy-lysosome pathway selectively targets major histocompatibility
complex class I (MHC-I) protein for degradation as a mechanism of immune evasion. Through affinity-
based capture of intact lysosomes (LysoIP) from normal and PDA cell lines coupled with proteomics-based
analysis, we identified MHC-I as a significantly enriched lysosomal substrate in PDA cells. Consistent with this
finding, immuno-fluorescence staining demonstrates that, unlike normal cells where MHC-I localizes to the
plasma membrane (PM), in PDA cell lines and primary patient PDA specimens, MHC-I is trapped inside
autophagosomes and lysosomes. Importantly, tumor-specific suppression of autophagy is sufficient to 1)
stabilize and re-localize MHC-I to the PM, 2) increase antigen presentation and 3) boost T cell mediated tumor
killing in vitro and in vivo. Building on these findings the goal of this study is to determine the molecular
mechanisms underlying aberrant MHC-I trafficking, and to identify targetable nodes that can be manipulated to
restore MHC-I on the cell surface of PDA cells. Our revised application will leverage the combined power of
biochemistry, genetics, organelle purification and proteomics, a novel mouse model and patient PDA samples
to address the following specific aims: 1) determine how post-translational modifications of MHC-I cooperate
with the autophagy machinery to facilitate capture by autophagosomes, 2) identify where along its trafficking
route is MHC-I diverted to autophagosomes and 3) determine when during the course of PDA evolution does
MHC-I dysregulation occur and can we exploit this information to establish more effective strategies to enhance
antigen presentation and immune mediated tumor killing.
 In summary, our discovery of autophagy dependent degradation of MHC-I highlights an important new
paradigm for immune evasion in PDA and potentially other cancers. Findings from our proposed studies will
determine key molecular mechanisms underlying MHC-I dysregulation and establish new nodes that can be
targeted to restore antigen presentation in PDA.

## Key facts

- **NIH application ID:** 10358483
- **Project number:** 5R01CA251726-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Rushika Miriam Perera
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $364,912
- **Award type:** 5
- **Project period:** 2021-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10358483

## Citation

> US National Institutes of Health, RePORTER application 10358483, Targeting the autophagy-lysosome system to block pancreatic cancer (5R01CA251726-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10358483. Licensed CC0.

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