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Your search keyword '"Comaills,V"' showing total 2 results
Start Over Author "Comaills,V" Publisher national academy of sciences
2 results on '"Comaills,V"'

1. COX-2 mediates tumor-stromal prolactin signaling to initiate tumorigenesis.

Author

Zheng Y, Comaills V, Burr R, Boulay G, Miyamoto DT, Wittner BS, Emmons E, Sil S, Koulopoulos MW, Broderick KT, Tai E, Rengarajan S, Kulkarni AS, Shioda T, Wu CL, Ramaswamy S, Ting DT, Toner M, Rivera MN, Maheswaran S, and Haber DA

Subjects
Animals, Carcinogenesis drug effects, Celecoxib pharmacology, Cell Transformation, Neoplastic drug effects, Cell Transformation, Neoplastic metabolism, Cell Transformation, Neoplastic pathology, Cyclooxygenase 2 metabolism, Cyclooxygenase 2 Inhibitors pharmacology, Dinoprostone metabolism, Disease Models, Animal, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Male, Mice, Nuclear Receptor Subfamily 4, Group A, Member 1 metabolism, Prostatic Neoplasms drug therapy, Retinoid X Receptors metabolism, Signal Transduction drug effects, Stromal Cells drug effects, Stromal Cells pathology, Up-Regulation drug effects, Up-Regulation physiology, Carcinogenesis metabolism, Prolactin metabolism, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Signal Transduction physiology, Stromal Cells metabolism
Abstract

Tumor-stromal communication within the microenvironment contributes to initiation of metastasis and may present a therapeutic opportunity. Using serial single-cell RNA sequencing in an orthotopic mouse prostate cancer model, we find up-regulation of prolactin receptor as cancer cells that have disseminated to the lungs expand into micrometastases. Secretion of the ligand prolactin by adjacent lung stromal cells is induced by tumor cell production of the COX-2 synthetic product prostaglandin E2 (PGE2). PGE2 treatment of fibroblasts activates the orphan nuclear receptor NR4A (Nur77), with prolactin as a major transcriptional target for the NR4A-retinoid X receptor (RXR) heterodimer. Ectopic expression of prolactin receptor in mouse cancer cells enhances micrometastasis, while treatment with the COX-2 inhibitor celecoxib abrogates prolactin secretion by fibroblasts and reduces tumor initiation. Across multiple human cancers, COX-2, prolactin, and prolactin receptor show consistent differential expression in tumor and stromal compartments. Such paracrine cross-talk may thus contribute to the documented efficacy of COX-2 inhibitors in cancer suppression., Competing Interests: Conflict of interest statement: Massachusetts General Hospital has filed for patent protection for the circulating tumor cell inertial focusing (iChip) technology., (Copyright © 2019 the Author(s). Published by PNAS.)

Published
2019
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2. Homeobox B9 induces epithelial-to-mesenchymal transition-associated radioresistance by accelerating DNA damage responses.

Author

Chiba N, Comaills V, Shiotani B, Takahashi F, Shimada T, Tajima K, Winokur D, Hayashida T, Willers H, Brachtel E, Vivanco MD, Haber DA, Zou L, and Maheswaran S

Subjects
Ataxia Telangiectasia Mutated Proteins, Cell Cycle radiation effects, Cell Cycle Proteins metabolism, Cell Line, Tumor, Cell Nucleus metabolism, Cell Nucleus radiation effects, DNA Repair radiation effects, DNA-Binding Proteins metabolism, Enzyme Activation radiation effects, Female, Histones metabolism, Humans, Intracellular Signaling Peptides and Proteins metabolism, Protein Serine-Threonine Kinases metabolism, Radiation, Ionizing, Signal Transduction radiation effects, Transforming Growth Factor beta metabolism, Tumor Suppressor Proteins metabolism, Tumor Suppressor p53-Binding Protein 1, DNA Damage, Epithelial-Mesenchymal Transition radiation effects, Homeodomain Proteins metabolism, Radiation Tolerance radiation effects
Abstract

Homeobox 9 (HOXB9), a nontransforming transcription factor overexpressed in breast cancer, alters tumor cell fate and promotes tumor progression and metastasis. Here we show that HOXB9 confers resistance to ionizing radiation by promoting DNA damage response. In nonirradiated cells, HOXB9 induces spontaneous DNA damage, phosphorylated histone 2AX and p53 binding protein 1 foci, and increases baseline ataxia telangiectasia mutated (ATM) phosphorylation. Upon ionizing radiation, ATM is hyperactivated in HOXB9-expressing cells during the early stages of the double-stranded DNA break (DSB) response, accelerating accumulation of phosphorylated histone 2AX, mediator of DNA-damage checkpoint 1, and p53 binding protein 1, at DSBs and enhances DSB repair. The effect of HOXB9 on the response to ionizing radiation requires the baseline ATM activity before irradiation and epithelial-to-mesenchymal transition induced by TGF-β, a HOXB9 transcriptional target. Our results reveal the impact of a HOXB9-TGF-β-ATM axis on checkpoint activation and DNA repair, suggesting that TGF-β may be a key factor that links tumor microenvironment, tumor cell fate, DNA damage response, and radioresistance in a subset of HOXB9-overexpressing breast tumors.

Published
2012
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