Evidence map›Paper›PMID 40640948›Full record

ArticleJournal of experimental & clinical cancer research : CR2025

PHGDH drives 5-FU chemoresistance in colorectal cancer through the Hedgehog signaling.

Caterina Mancini, Giulia Lori, Gianluca Mattei, Marta Iozzo, Dayana Desideri, Fabio Cianchi, Laura Fortuna, Federico Passagnoli, Daniela Massi, Filippo Ugolini and 15 more

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In one paragraph

Article in Journal of experimental & clinical cancer research : CR, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing 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

7 citing papers in PubMed.

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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

25 authors.

Caterina Mancini *Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Giulia Lori *Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Gianluca MatteiDepartment of Health Sciences Clinical Pharmacology and Oncology Unit, University of Florence, Florence, Italy.
Marta IozzoDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Dayana DesideriDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Fabio CianchiDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Laura FortunaDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Federico PassagnoliDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Daniela MassiDepartment of Health Sciences, University of Florence, Florence, Italy.
Filippo UgoliniDepartment of Health Sciences, University of Florence, Florence, Italy.
Luca MesseriniDepartment of Health Sciences, University of Florence, Florence, Italy.
Salvatore PiscuoglioIRCCS Humanitas Research Hospital, Rozzano, Milano, Italy.
Antonio PezoneDepartment of Biology, University of Naples "Federico II", Naples, Italy.
Francesca MagheriniDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Alessio BiagioniDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Tiziano LottiniDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Demetra ZambardinoDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
Giuseppina Ivana TruglioDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
Elena PetricciDepartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
Alberto MagiDepartment of Information Engineering, University of Florence, Florence, Italy.
Annarosa ArcangeliDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
Luisa MarescaDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy.
Barbara SteccaCore Research Laboratory, ISPRO, Florence, Italy.
Erica PranziniDepartment of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy. erica.pranzini@unifi.it.
Maria Letizia TaddeiDepartment of Experimental and Clinical Medicine, University of Florence, Florence, Italy. marialetizia.taddei@unifi.it.

Funding

Associazione Italiana per la Ricerca sul Cancro IG27094Tuscany Health Ecosystem ECS00000017-CUP B83C22003920001
6 · The paper itself

Abstract

backgroundPhosphoglycerate dehydrogenase (PHGDH) is the rate-limiting enzyme in the de novo Serine synthesis pathway (SSP), a highly regulated pathway overexpressed in several tumors. Specifically, PHGDH expression is dynamically regulated during different stages of tumor progression, promoting cancer aggressiveness. Previously, we demonstrated that high Serine (Ser) availability, obtained by increased exogenous uptake or increased PHGDH expression, supports 5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC). Beyond its metabolic role in sustaining Ser biosynthesis, different "non-enzymatic roles" for PHGDH have recently been identified. The present study aims to investigate non-enzymatic mechanisms through which PHGDH regulates 5-FU response in CRC.

methodsOverexpression and gene silencing approaches have been used to modulate PHGDH expression in human CRC cell lines to investigate the role of this enzyme in 5-FU cellular response. Identified mechanisms have been validated in selected 5-FU resistant cell lines, CRC patients-derived tumor tissue samples, and patients-derived 3D organoids. Transcriptomic analysis was performed on wild-type and PHGDH-silenced cell lines, allowing the identification of pathways responsible for PHGDH-mediated 5-FU resistance. The relevance of identified genes was validated in vitro and in vivo in a CRC xenograft model.

resultsPHGDH expression is highly variable among CRC tissues and patient-derived 3D organoids. A retrospective analysis of CRC patients highlighted a correlation between PHGDH expression and therapy response. Coherently, the modulation of PHGDH expression by gene silencing/overexpression affects 5-FU sensitivity in CRC cell lines. Transcriptomic analysis on CRC cell lines stably silenced for PHGDH evidenced down regulation in Hedgehog (HH) pathway. Accordingly, in vitro and in vivo studies demonstrated that the combined treatment of 5-FU and HH pathway inhibitors strongly hinders CRC cell survival and tumor growth in CRC xenograft models.

conclusionsPHGDH sustains 5-FU resistance in CRC by mediating the upregulation of the HH signaling; targeting the here identified PHGDH-HH axis increases 5-FU susceptibility in different CRC models suggesting the 5-FU/HH-inhibitors combinatorial therapeutic strategy as a valid approach to counteract drug resistance in CRC.

Indexed as

Colorectal NeoplasmsDrug Resistance, NeoplasmFluorouracilHedgehog ProteinsPhosphoglycerate DehydrogenaseAnimalsAntimetabolites, AntineoplasticCell Line, TumorGene Expression Regulation, NeoplasticHumansMiceSignal TransductionXenograft Model Antitumor AssaysAntimetabolites, AntineoplasticFluorouracilHedgehog ProteinsPhosphoglycerate Dehydrogenase5-FluorouracilChemo-resistanceColorectal cancerHedgehog signalingPhosphoglycerate dehydrogenaseSerineStemness

Identifiers

PMID40640948
PMCPMC12243184

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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.