Evidence map›Paper›PMID 40914989›Full record

ArticleThe Journal of pharmacology and experimental therapeutics2025

Remodeling the sarcoma microenvironment by simultaneous targeting of urokinase-type plasminogen activator receptors and epidermal growth factor receptors to promote antitumor activity.

Ashley J Schulte, Mitzi Lewellen, Willa Durose, Erin Nolan, Leyla Taghizadeh, Deborah Todhunter, Courtney Bush, Haeree P Lang, Mary E Brown, Taylor A DePauw and 13 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Journal of pharmacology and experimental therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

0numbers the graph read from it
0cells of the map it votes in
0citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

0 citing papers in PubMed.

No citing paper in PubMed yet.

4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

23 authors.

Ashley J SchulteAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Mitzi LewellenAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Willa DuroseMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota.
Erin NolanMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota.
Leyla TaghizadehMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota.
Deborah TodhunterMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
Courtney BushAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Haeree P LangDepartment of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Comparative Molecular Biosciences Graduate Program, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Center for Immunology, University of Minnesota, Minneapolis, Minnesota.
Mary E BrownUniversity Imaging Center, University of Minnesota, Minneapolis, Minnesota.
Taylor A DePauwAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Microbiology, Immunology, and Cancer Biology Graduate Program, University of Minnesota, Minneapolis, Minnesota.
Kelly M MakielskiAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Jong Hyuk KimAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Lauren E BurtAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Paula OvernMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
Colleen L ForsterThe University of Minnesota Biological Materials Procurement Network (BioNet), University of Minnesota, Minneapolis, Minnesota.
Davis M SeeligAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
M Gerard O'SullivanAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Veterinary Population Medicine, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota.
Brenda J WeigelAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota.
Paari MuruganAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; The University of Minnesota Biological Materials Procurement Network (BioNet), University of Minnesota, Minneapolis, Minnesota; Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota.
Gary R CutterDepartment of Biostatistics, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama.
Troy C LundMasonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Division of Pediatric, Blood and Masrrow Transplantation, Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota; Center for Immunology, University of Minnesota, Minneapolis, Minnesota; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota.
Daniel A ValleraAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Department of Therapeutic Radiology, Medical School, University of Minnesota, Minneapolis, Minnesota.
Jaime F ModianoAnimal Cancer Care and Research Program, University of Minnesota, St Paul, Minnesota; Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota; Center for Immunology, University of Minnesota, Minneapolis, Minnesota; Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, Minnesota; Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota; Institute for Engineering in Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address: modiano@umn.edu.

Funding

Women's CancerP30CA077598 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Timothy C. Hallstrom · 1998 to 2026
$100.4M
TRAINING GRANT IN MICROBIOLOGY/CANCER RESEARCHT32CA009138 · NCI · UNIVERSITY OF MINNESOTA TWIN CITIES · PI Scott M. Dehm · 1985 to 2026
$11.3M
Veterinary Summer Scholars in Comparative MedicineT35OD011118 · OD · UNIVERSITY OF MINNESOTA · PI EDWARD E PATTERSON · 2012 to 2026
$601k
Molecular Signatures of Biologic Behavior in Pediatric OsteosarcomaK01OD031810 · OD · UNIVERSITY OF MINNESOTA · PI Kelly M Makielski · 2023 to 2026
$498k
NCI NIH HHS P30 CA077598NCI NIH HHS T32 CA009138NIH HHS K01 OD031810NIH HHS T35 OD011118
6 · The paper itself

Abstract

We evaluated the antitumor effects of remodeling the MC17 mouse sarcoma microenvironment (SME) by targeting urokinase-type plasminogen activator receptor (uPAR)- and epidermal growth factor receptor (EGFR)-expressing cells. Specifically, we used eBAT (a bispecific ligand-targeted toxin directed to EGFR and uPAR), and its mouse counterpart, meBAT, to ablate uPAR- and/or EGFR-expressing cells. We chose the MC17 model because the cells are resistant to eBAT, allowing us to exclusively evaluate the role of uPAR- and EGFR-expressing cells in the SME. Our results show that uPAR expression, both by the tumor cells and by the SME, was dispensable for tumor formation. However, uPAR-deficient tumors grew considerably slower than uPAR-expressing tumors. To specifically address mechanisms responsible for antitumor effects of remodeling the SME, we used uPAR-knockout bone marrow chimeras. In uPAR-replete chimeras, systemic administration of eBAT or meBAT depleted tumor-associated macrophages, increased the proportion of phagocytic myeloid cells, and promoted T cell infiltration into the SME, which was associated with delayed tumor growth. All of these effects were reduced or abrogated in uPAR-deficient bone marrow chimeras. We conclude that targeting uPAR- and EGFR-expressing stromal cells led to remodeling of the inflammatory SME, diminished tumor-associated immunosuppression, and improved survival of mice with transplantable sarcomas. SIGNIFICANCE STATEMENT: This study demonstrated that targeting urokinase-type plasminogen activator receptor- and/or epidermal growth factor receptor-expressing cells in the sarcoma microenvironment reprograms tumor-associated inflammation, leading to delayed progression in an aggressive, therapy-resistant mouse model of fibrosarcoma. The results indicate that the therapeutic benefit of remodeling the inflammatory microenvironment is achieved by making the tumors more visible to the immune system, highlighting the potential to incorporate this novel strategy into the management of advanced, treatment-refractory sarcomas.

Indexed as

Antineoplastic AgentsErbB ReceptorsReceptors, Urokinase Plasminogen ActivatorSarcomaTumor MicroenvironmentAnimalsCell Line, TumorMiceMice, Inbred C57BLMice, KnockoutAntineoplastic AgentsErbB ReceptorsReceptors, Urokinase Plasminogen ActivatorAnimal modelsMacrophagesSarcomaTargeted toxinsTumor microenvironmentUrokinase-type plasminogen activator receptor

Identifiers

PMID40914989
PMCPMC12597637

What Socratic holds

Textmetadata
LicenceCC BY-NC-ND
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.