Evidence map›Paper›PMID 39101793›Full record

ArticleHepatology communications2024

Pan-lysyl oxidase inhibition disrupts fibroinflammatory tumor stroma, rendering cholangiocarcinoma susceptible to chemotherapy.

Paul R Burchard, Luis I Ruffolo, Nicholas A Ullman, Benjamin S Dale, Yatee A Dave, Bailey K Hilty, Jian Ye, Mary Georger, Rachel Jewell, Christine Miller and 11 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Hepatology communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.

0numbers the graph read from it
0cells of the map it votes in
9citing 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

9 citing papers in PubMed.

  1. Trial
  2. Review
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  4. Article
  5. Review
  6. Article
  7. Article
  8. Quantitative Assessment of Collagen Architecture to Determine Role of Tumor Stroma During Vestibular Schwannoma Progression.Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery · 2025
    Article
  9. Review
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

21 authors.

Paul R BurchardDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0001-7370-5608
Luis I RuffoloDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0001-6002-9559
Nicholas A UllmanDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0003-1669-1259
Benjamin S DaleJacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.ORCID 0000-0002-1775-3469
Yatee A DaveDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0003-3765-9063
Bailey K HiltyDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0002-9473-0324
Jian YeDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Mary GeorgerDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Rachel JewellDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Christine MillerDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Luis De Las CasasDepartment of Pathology, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Wolfgang JarolimekDrug Discovery, Syntara Ltd., Sydney, New South Wales, Australia.
Lara PerrymanDrug Discovery, Syntara Ltd., Sydney, New South Wales, Australia.
Matthew M ByrneDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0001-5106-4424
Anthony LoriaDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0003-0877-6500
Chelsea MarinDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Mariana Chávez VillaDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
Jen Jen YehDepartments of Surgery and Pharmacology, Lineberger Comprehensive Cancer Center, University of North Carolina System, Chapel Hill, North Carolina, USA.
Brian A BeltDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.
David C LinehanDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0003-1859-2203
Roberto Hernandez-AlejandroDepartment of Surgery, University of Rochester Medical Center, Rochester, New York, USA.ORCID 0000-0002-2312-3498

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

backgroundCholangiocarcinoma (CCA) features highly desmoplastic stroma that promotes structural and functional resistance to therapy. Lysyl oxidases (LOX, LOXL1-4) catalyze collagen cross-linking, thereby increasing stromal rigidity and facilitating therapeutic resistance. Here, we evaluate the role of lysyl oxidases in stromal desmoplasia and the effects of pan-lysyl oxidase (pan-LOX) inhibition in CCA.

methodsResected CCA and normal liver specimens were analyzed from archival tissues. Spontaneous and orthotopic murine models of intrahepatic CCA (iCCA) were used to assess the impact of the pan-LOX inhibitor PXS-5505 in treatment and correlative studies. The functional role of pan-LOX inhibition was interrogated through in vivo and ex vivo assays.

resultsAll 5 lysyl oxidases are upregulated in CCA and reduced lysyl oxidase expression is correlated with an improved prognosis in resected patients with CCA. Spontaneous and orthotopic murine models of intrahepatic cholangiocarcinoma upregulate all 5 lysyl oxidase isoforms. Pan-LOX inhibition reversed mechanical compression of tumor vasculature, resulting in improved chemotherapeutic penetrance and cytotoxic efficacy. The combination of chemotherapy with pan-LOX inhibition increased damage-associated molecular pattern release, which was associated with improved antitumor T-cell responses. Pan-LOX inhibition downregulated macrophage invasive signatures in vitro, rendering tumor-associated macrophages more susceptible to chemotherapy. Mice bearing orthotopic and spontaneously occurring intrahepatic cholangiocarcinoma tumors exhibited delayed tumor growth and improved survival following a combination of pan-LOX inhibition with chemotherapy.

conclusionsCCA upregulates all 5 lysyl oxidase isoforms, and pan-LOX inhibition reverses tumor-induced mechanical forces associated with chemotherapy resistance to improve chemotherapeutic efficacy and reprogram antitumor immune responses. Thus, combination therapy with pan-LOX inhibition represents an innovative therapeutic strategy in CCA.

Indexed as

Bile Duct NeoplasmsCholangiocarcinomaProtein-Lysine 6-OxidaseAmino Acid OxidoreductasesAnimalsAntineoplastic AgentsCell Line, TumorDisease Models, AnimalDrug Resistance, NeoplasmHumansMaleMiceTumor MicroenvironmentAmino Acid OxidoreductasesAntineoplastic AgentsProtein-Lysine 6-Oxidase

Identifiers

PMID39101793
PMCPMC11299993

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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 OpenQuestion graph.