# Molecular mechanisms regulating LMO2+ metastasis initiating cells

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA SANTA CRUZ · 2023 · $344,427

## Abstract

Metastasis remains the primary cause of death in women with breast cancer. While it is well established
that tumor cells are heterogeneous and minority populations within the tumor have tumor-initiating and metastatic
capabilities, the identity of metastasis initiating cells (MICs) in human breast cancer remains controversial. Until
we can identify these cells and study the molecular pathways regulating them, the development of new
therapeutic strategies will be hindered. The long-term goal of this proposal is to understand the intrinsic and
extrinsic molecular signaling regulating MICs. Recently, using single-cell RNA sequencing data from breast
cancer patient samples and sophisticated computational approaches we identified an immature population of
cells in breast cancer that express hematopoietic stem cell transcriptional adaptor and the T-cell oncogene,
LMO2. The objective of this proposal is to determine the molecular mechanism of LMO2 in promoting metastasis.
We hypothesize that LMO2+ cells are a population of MICs in breast cancer that are activated in response to
inflammation and LMO2 is a key adaptor that regulates this process. Our hypothesis is based on our preliminary
results that demonstrate that Lmo2+ cells are metastatic, predict poor distant recurrence-free survival in patients,
LMO2 knockdown reduces metastasis in multiple human tumor models, and LMO2 is required for STAT3
activation in response to IL6 and TNFα. The rationale underlying this proposal is that αidentifying the signaling of
LMO2 in metastasis will elucidate targets in MICs that are open to therapeutic intervention. Guided by strong
preliminary data, our proposal will 1. Determine whether LMO2 is required for inflammation-induced metastasis.
2. Determine the detailed molecular signaling regulated by LMO2-STAT3 axis. 3. Determine whether LMO2+
cells utilize vascular mimicry to metastasize. The proposed research is significant because it will enable the
design of therapeutic strategies targeting MICs in breast cancer. Previous research studies on the identification
of MICs have relied on established lineage markers. The proposed research is innovative because we are
focusing on a population of LMO2+ MICs that were agnostically identified from single-cell RNA sequencing in
breast cancer patient samples. The proposed research will substantially enhance our understanding of MICs
and lay the foundation for novel strategies to treat metastatic breast cancer.

## Key facts

- **NIH application ID:** 10659840
- **Project number:** 1R37CA269754-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA SANTA CRUZ
- **Principal Investigator:** Shaheen Sikandar
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $344,427
- **Award type:** 1
- **Project period:** 2023-05-17 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10659840

## Citation

> US National Institutes of Health, RePORTER application 10659840, Molecular mechanisms regulating LMO2+ metastasis initiating cells (1R37CA269754-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10659840. Licensed CC0.

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