AP-1 and TGFß cooperativity drives non-canonical Hedgehog signaling in resistant basal cell carcinoma.

Animals Carcinoma, Basal Cell / metabolism Cell Line, Tumor Cell Nucleus / metabolism Chromatin / metabolism DNA, Neoplasm / metabolism Drug Resistance, Neoplasm Extracellular Matrix / metabolism Gene Ontology Guanine Nucleotide Exchange Factors / metabolism Hair Follicle / metabolism Hedgehog Proteins / metabolism Humans Mice Mice, Inbred C57BL NIH 3T3 Cells Neoplasm Proteins / metabolism Protein Binding Signal Transduction Skin Neoplasms / metabolism Smad3 Protein / metabolism Trans-Activators / metabolism Transcription Factor AP-1 / metabolism Transforming Growth Factor beta / metabolism Up-Regulation

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 10 2020
Historique:
received: 01 04 2020
accepted: 01 09 2020
entrez: 9 10 2020
pubmed: 10 10 2020
medline: 21 10 2020
Statut: epublish

Résumé

Tumor heterogeneity and lack of knowledge about resistant cell states remain a barrier to targeted cancer therapies. Basal cell carcinomas (BCCs) depend on Hedgehog (Hh)/Gli signaling, but can develop mechanisms of Smoothened (SMO) inhibitor resistance. We previously identified a nuclear myocardin-related transcription factor (nMRTF) resistance pathway that amplifies noncanonical Gli1 activity, but characteristics and drivers of the nMRTF cell state remain unknown. Here, we use single cell RNA-sequencing of patient tumors to identify three prognostic surface markers (LYPD3, TACSTD2, and LY6D) which correlate with nMRTF and resistance to SMO inhibitors. The nMRTF cell state resembles transit-amplifying cells of the hair follicle matrix, with AP-1 and TGFß cooperativity driving nMRTF activation. JNK/AP-1 signaling commissions chromatin accessibility and Smad3 DNA binding leading to a transcriptional program of RhoGEFs that facilitate nMRTF activity. Importantly, small molecule AP-1 inhibitors selectively target LYPD3+/TACSTD2+/LY6D+ nMRTF human BCCs ex vivo, opening an avenue for improving combinatorial therapies.

Identifiants

DOI: 10.1038/s41467-020-18762-5 PMID: 33033234 PMC: PMC7546632
pubmed: 33033234
doi: 10.1038/s41467-020-18762-5
pii: 10.1038/s41467-020-18762-5
pmc: PMC7546632
doi:

Substances chimiques

Chromatin 0
DNA, Neoplasm 0
Guanine Nucleotide Exchange Factors 0
Hedgehog Proteins 0
MRTFA protein, human 0
Neoplasm Proteins 0
Smad3 Protein 0
Trans-Activators 0
Transcription Factor AP-1 0
Transforming Growth Factor beta 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

5079

Subventions

Organisme : NIAMS NIH HHS
ID : R01 AR054780
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA237563
Pays : United States
Organisme : NIH HHS
ID : S10 OD010580
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA217017
Pays : United States
Organisme : NCI NIH HHS
ID : K23 CA211793
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR046786
Pays : United States
Organisme : NIAMS NIH HHS
ID : T32 AR007422
Pays : United States
Organisme : NIH HHS
ID : S10 OD018220
Pays : United States
Organisme : NCI NIH HHS
ID : F32 CA254434
Pays : United States

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Auteurs

Catherine D Yao (CD)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Daniel Haensel (D)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
ORCID: 0000-0001-5168-4068

Sadhana Gaddam (S)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Tiffany Patel (T)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Scott X Atwood (SX)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
Department of Developmental and Cell Biology, University of California, Irvine, USA.
ORCID: 0000-0001-7407-9792

Kavita Y Sarin (KY)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
ORCID: 0000-0001-5363-3053

Ramon J Whitson (RJ)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
Genomics Institute of the Novartis Research Foundation, La Jolla, CA, USA.

Siegen McKellar (S)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
University of Washington School of Medicine, Seattle, WA, 98195, USA.
ORCID: 0000-0002-8325-2910

Gautam Shankar (G)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA.

Sumaira Aasi (S)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.

Kerri Rieger (K)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA.
ORCID: 0000-0002-4436-2471

Anthony E Oro (AE)

Program in Epithelial Biology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CA, 94305, USA. oro@stanford.edu.
ORCID: 0000-0002-6261-138X

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs épithéliales épidermoïdes et glandulaires › Tumeurs basocellulaires › Carcinome basocellulaire › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Organites › Noyau de la cellule › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Structures de chromosome › Chromatine › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › ADN tumoral › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace extracellulaire › Matrice extracellulaire › AP-1 and TGFß cooperativity drives...
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questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Régulateurs des protéines G › Facteurs d'échange de nucléotides guanyliques › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Système tégumentaire › Peau › Épiderme › Follicule pileux › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines Hedgehog › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › AP-1 and TGFß cooperativity drives...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Lignées consanguines de souris › Souris de lignée C57BL › AP-1 and TGFß cooperativity drives...
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