# Uncovering the Molecular Determinants of Metastatic Recurrence and Impaired NK Cell Function

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $619,279

## Abstract

PROJECT SUMMARY
Our proposed research employs innovative, unbiased approaches and novel preclinical models to elucidate how
disseminated HER2+ breast cancer cells cells survive in the brain microenvironment and initiate metachronous
metastasis.
Through functional characterization of phenotypically stable preclinical models of HER2+ breast cancer brain
metastasis, we discovered latent/dormant (Lat) HER2+ cells display stem cell-like characteristics, downregulate
immune activating sensors and survive in equilibrium with innate immune surveillance, while brain metastatic
cells escape and metastasize. Moreover, metabolically distinct HER2+ brain-tropic Lat cells and metachronous
brain metastatic (M-BM) cells are resistant to radiation and systemic HER2 targeted therapies. AXL, a
member of the TAM (TYRO3, AXL, MERTK) receptor tyrosine kinase family is enriched in Lat and M-BMs. AXL
expression is enriched in metachronous brain metastatic lesions compared to matched primary tumors from
HER2+ breast cancer patients. Of note, AXL is predominantly nuclear in these brain metastatic lesions and
in our preclinical brain metastatic model systems. CRISPR affinity purification of in situ regulatory elements
revealed enrichment of TEAD transcription factor at the AXL promoter region in Lat and M-BMs. AXL
immunoprecipitation-mass spectrometry analysis identified WRN Helicase Interacting Protein 1 (WRNIP1)
among other nuclear proteins that interact with AXL. WRNIP1 aids maintenance of genomic stability under
replicative stress and promotes survival of Lat and M-BM cells. Depletion of AXL in Lat and M-BM cells or
administration of small molecule AXL inhibitor (BGB324) results in attenuated metastasis initiating
capacity. Noticeably, increased AXL expression and reduced cytotoxicity was also observed in tumor
trained/exposed NK cells, while administration of BGB324 to augmented cytotoxicity.
Thus, our central hypothesis is therapy resistant brain-tropic HER2+ breast cancer cells are dependent
on nuclear AXL signaling response for survival and membranous AXL expression in NK cell results in
dysfunction. The proposed aims will delineate how TEAD signaling response promotes brain metastasis and
assess the impact of AXL inhibitors in limiting tumor cell survival and reactivating NK mediated innate immune
surveillance.

## Key facts

- **NIH application ID:** 10941882
- **Project number:** 1R01CA292390-01
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Srinivas Malladi
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $619,279
- **Award type:** 1
- **Project period:** 2024-07-01 → 2029-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10941882

## Citation

> US National Institutes of Health, RePORTER application 10941882, Uncovering the Molecular Determinants of Metastatic Recurrence and Impaired NK Cell Function (1R01CA292390-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10941882. Licensed CC0.

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