# Discerning the role of semaphorin 7a in mammary tumor growth and anti-tumor immunity

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2022 · $34,792

## Abstract

Project
Early
the
years
childbirth,
These
vessels.
are
7a —a signaling molecule that activates integrin-β1 signaling in cancer—is upregulated in PPBC and
is associated with increased LVD, TAMs, and metastasis. Additionally, SEMA7A+ tumors recapitulate the
accelerated tumorigenesis and metastatic profiles observed in PPBC and high SEMA7A expression correlates
with decreased overall survival. As such, PPBCs likely only represent a subset of SEMA7A+ cancers; there are
Summary/Abstract
detection and reatment of breast cancer (BC) has reduced the number of BC-related deaths but remains
leading cause of cancer-related death in women ages 15-54. Over half of all BCs diagnosed i n women <40
 of age fit the definition of postpartum breast cancer (PPBC), BCs diagnosed within 10 years of last
which are 2-3 times more likely to metastasize compared to BCs diagnosed in nulliparous patients.
deaths are generally attributed to dissemination of tumor cells to distant tissues via blood and lymphatic
Increased lymphatic vessel density (LVD), ymphovascular invasion, and lymph node positivity (LN+)
frequently observed in PPBC and are associated with worse prognosis. We have identified that semaphorin
(SEMA7A)
t
l
currently no therapies targeting SEMA7A.
to
Tumor-associated
(TME).
prognosis
SEMA7A+ BCs exemplify four key hallmarks of cancer: 1) resistance
 cell death, 2) angiogenesis and lymphangiogenesis, 3) immune evasion, and 4) invasion and metastasis.
macrophages (TAMs) are i mplicated in each and in creating a pro-tumor microenvironment
 As TAMs and LVD are amplified in SEMA7A+ BC, it is probable that they contribute to the worse
 of PPBC. SEMA7A can also polarize macrophages into a subset of TAMs (termed “PoEMs”) that
express lymphatic-associated proteins. These PoEMs intercalate into lymphatic vessels to form PoEM-LEC
chimeric vessels and tumor cells associate with these vessels at PoEM-LEC junctions, which may mediate tumor
cell escape. Moreover, SEMA7A can promote expression of PD-L1-expression on BC cells, LECs, TAMs, and
PoEMs to suppress anti-tumor immunity; however, additional effects of SEMA7A on immune cells of the TME
have not been investigated. Altogether, this led us to the hypothesis that SEMA7A activates pro-survival
signaling in immunosuppressive PoEMs to promote tumor cell dissemination.
Thegoals of thisproposal are to: 1) determine the mechanisms by which SEMA7A induces cell survival
and alters the immune TME to a pro-tumor state, and 2) investigate the chemoattractants produced by PoEMs
that recruit tumor cells to PoEM-LEC junctions and promote metastasis. In aim 1, we will define the mechanisms
of SEMA7A-induced cell survival and effects on immune cells of the TME. We will also establish whether
monoclonal antibody-induced inhibition of SEMA7A impedes tumor growth and immune suppression. In aim 2,
we will define chemoattractants that recruit tumor cells to PoEM-LEC junctions. The results of these studies will
identify how SEMA7A promotes tum...

## Key facts

- **NIH application ID:** 10537926
- **Project number:** 1F31CA268825-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Alan Michael Elder
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $34,792
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537926

## Citation

> US National Institutes of Health, RePORTER application 10537926, Discerning the role of semaphorin 7a in mammary tumor growth and anti-tumor immunity (1F31CA268825-01A1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10537926. Licensed CC0.

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