# Mechanisms of linkage of stem and invasive phenotypes during metastatic colonization

> **NIH NIH P01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $398,713

## Abstract

ABSTRACT
Metastasis, the primary cause of breast cancer-related mortality, is a multistep process culminating with the
formation of tumor foci within distant organs. However, only a subpopulation of cancer cells within the primary
tumor microenvironment is capable of completing the entire metastatic cascade, which includes intravasation,
survival in circulation, extravasation, and tumor growth at distant sites. We identified a population of highly
invasive, non-proliferating, non-apoptotic, chemo-resistant cancer cells capable of intravasation (published) and
extravasation (preliminary results). These cells express high levels of MenaINV, a pro-metastatic isoform of the
actin-regulatory protein Mena required for maturation of invasive protrusions called invadopodia, which enable
cancer cells to cross endothelium and disseminate. MenaINV localization to the cell membrane, which is required
for its function, may be regulated by PI3Kβ through phosphoinositide signaling. We found that MenaINV
expression (published) and a stem cell program (preliminary results) are induced in tumor cells by direct contact
with tumor-associated macrophages. Interestingly, we also found that chemotherapy co-induces MenaINV and
the stem program in a macrophage-dependent manner. The emergence of MenaINV expressing stem cells may
be one of the crucial steps to metastasis because these cells are not only transendothelial migration-competent
but also have tumor-initiating capability. In primary breast tumors, cancer cells expressing high levels of MenaINV
are able to enter blood vessels through Tumor Microenvironments of Metastasis (TMEM) doorways. These tightly
controlled transient openings in capillary walls were first described by our group and are composed of
macrophages, endothelial cells and Mena-expressing tumor cells in direct physical contact. TMEM doorways
and cancer cell re-dissemination from lung metastases are also observed in lung metastases, but it is currently
unknown if stem program is required for cancer cell dissemination from this secondary site. Interestingly, we and
others found that chemotherapy in a macrophage-dependent manner increases the proportion of cancer cells
co-expressing high levels of MenaINV and stem cell transcription factor SOX9. Thus, we hypothesize that
induction of the transendothelial migration-competent phenotype in cancer cells (identified by the expression of
MenaINV) is mechanistically linked to the stem program, and that the induction of this transendothelial migration-
competent stem phenotype is potentiated by chemotherapy. We will use high resolution intravital imaging of the
lungs in combination with stem and Mena biosensors to determine in vivo how the interplay of stemness and
MenaINV regulate extravasation and metastatic colonization of the lungs and determine the mechanism by which
chemotherapy induced hypoxia and macrophage influx affect cancer phenotype in metastatic foci in the lungs.
The successful completion of this...

## Key facts

- **NIH application ID:** 10408967
- **Project number:** 1P01CA257885-01A1
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Maja Hrzenjak Oktay
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $398,713
- **Award type:** 1
- **Project period:** 2022-07-05 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10408967

## Citation

> US National Institutes of Health, RePORTER application 10408967, Mechanisms of linkage of stem and invasive phenotypes during metastatic colonization (1P01CA257885-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10408967. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*