# Regulation of lung cancer metastasis through transcriptional control of the Golgi apparatus

> **NIH NIH R01** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2021 · $366,000

## Abstract

Our goal is to better understand the biologic basis for metastasis of KRAS-mutant lung cancer (KMLC) and to
develop novel therapeutic approaches on the basis of that improved understanding. Progress in this area could
potentially have a tremendous public health impact because metastasis is the primary cause of death from
lung cancer, and there are currently few effective therapeutic options for KMLC. Towards that goal, we
generated KP mice, which develop metastatic lung adenocarcinoma owing to the co-expression of K-rasG12D
and p53R172H. Our preliminary results show that Zeb1, a transcriptional driver of metastasis in KP mice and
predictor of poor clinical outcome in multiple epithelial tumor types, caused the Golgi organelle to become
more compact and centralized, form ribbon-linked cisternal stacks, and stimulate vesicle trafficking in the
anterograde direction. ZEB1 increased the expression of PAQR11, a Golgi scaffolding protein that was
required for ZEB1-induced Golgi organelle integrity and tumor cell metastatic properties. In pull-down assays,
the scaffolding domain of PAQR11 bound to vesicle coatomer proteins, GTPases that regulate vesicle budding
and tethering, and dynein motor proteins that transport cargo along microtubules towards the cell's center.
PAQR11 depletion reduced the migratory, invasive, and metastatic activities of lung adenocarcinoma cells
derived from KP mice and human KMLC cells. High intra-tumoral PAQR11 levels predicted shorter survival in a
compendium of 11 independent human lung cancer cohorts and a pan-cancer analysis of over 30 tumor types.
On the basis of our preliminary results, we hypothesize that KMLCs gain metastatic potential through
transcriptional control of the Golgi apparatus.
To test this hypothesis, we propose two Specific Aims. In the first Aim, we will determine whether PAQR11
facilitates the dynein-mediated transport of Golgi mini-stacks and ribbon-linking and stacking of cisternae to
create a centralized Golgi complex that drives anterograde vesicle trafficking and promotes tumor cell motility.
In the second Aim, we will determine the extent to which ectopic PAQR11 expression promotes the metastasis
of spontaneously occurring KMLCs.
If our hypothesis is correct, these findings will advance our understanding of the mechanisms by which KMLC
cells gain metastatic propensity and provide researchers in the field with new tools to investigate Golgi
dynamics in tumor cells in the native microenvironment of the lung, an improved understanding of the
underlying causes of lung adenocarcinoma metastasis, and a basis for investigating agents that target
mediators of Zeb1 in clinical trials to prevent KMLC metastasis.

## Key facts

- **NIH application ID:** 10062880
- **Project number:** 5R01CA211125-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jonathan M Kurie
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2016-12-01 → 2022-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10062880

## Citation

> US National Institutes of Health, RePORTER application 10062880, Regulation of lung cancer metastasis through transcriptional control of the Golgi apparatus (5R01CA211125-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10062880. Licensed CC0.

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