Biology subjects

Sosa, M. S.

Publications and source records attributed to Sosa, M. S..

3 recordsLinked to original sources

bioRxiv2021

Epigenetic reprogramming of DCCs into dormancy suppresses metastasis via restored TGFβ-SMAD4 signaling.

Disseminated cancer cells (DCCs) identified in secondary organs, sometimes before the primary tumor becomes detectable and treated, can remain dormant for years to decades before manifesting. Microenvironmental and epigenetic mechanisms may control the onset and escape from dormancy, and here we reveal how a combination of the DNA methylation inhibitor 5-azacytidine (AZA) and retinoic acid receptor ligands all-trans retinoic acid (atRA), orchestrate a novel program of stable dormancy. Treatment of HNSCC tumor cells with AZA+atRA induced a SMAD2/3/4 dependent regulation of downstream transcriptional program that restored the anti-proliferative function of TGF{beta} signaling. Significantly, AZA+atRA or AZA+AM80, an RAR specific agonist, strongly suppresses lung metastasis formation. The metastatic suppression occurs via the induction and maintenance of phenotypically homogenous dormant SMAD4+/NR2F1+ non-proliferative DCCs. These findings suggest that strategies that maintain or induce dormancy programs may be a viable alternative strategy to improve patient outcomes by preventing or significantly delaying metastasis development.

cancer biology↗

bioRxiv2021

A specific agonist of the orphan nuclear receptor NR2F1 suppresses metastasis through the induction of cancer cell dormancy

AO_SCPLOWBSTRACTC_SCPLOWDisseminated tumor cells (DTCs) in secondary organs often remain dormant for a long period of time before re-awakening and growing into overt metastases. We have previously identified NR2F1/COUP-TF1, an orphan nuclear receptor, as a master regulator of tumor cell dormancy in head and neck squamous cell carcinoma (HNSCC) and other cancer types. Here we describe the identification and function of a novel NR2F1 agonist herein referred to as compound 26 (C26). C26 was found to specifically activate NR2F1 in HNSCC cells, leading to increased NR2F1 transcription and nuclear protein accumulation. C26-mediated activation of NR2F1 induced growth arrest of HNSCC PDX line and cell lines in 3D cultures in vitro and on chicken embryo chorioallantoic membrane (CAM) in vivo. The effect of C26 on growth arrest was lost when NR2F1 was knocked out by CRISPR/Cas9. C26-induced growth arrest was mediated by activation of an NR2F1-regulated dormancy program, including upregulation of cyclin-dependent kinase (CDK) inhibitor p27 and the transcription factors retinoic acid receptor {beta} (RAR{beta}) and Sox9. In mice bearing HNSCC PDX tumors, combined adjuvant and neo-adjuvant treatment with C26 resulted in complete inhibition of lethal lung metastasis. Mechanistic analysis showed that lung DTCs in C26-treated mice displayed an NR2F1hi/p27hi/Ki-67lo phenotype, which kept them dormant in a single-cell state preventing their outgrowth into overt metastases. Our work reveals a novel NR2F1 agonist and provides a proof of principle strategy supporting that inducing DTC dormancy using NR2F1 agonists could be used as a therapeutic strategy to prevent metastasis.

cancer biology↗

bioRxiv2021

NR2F1 is a barrier to dissemination of early-evolved mammary cancer cells

SO_SCPLOWUMMARYC_SCPLOWCancer cells disseminate during very early and sometimes asymptomatic stages of tumor progression. Granted that biological barriers to tumorigenesis exist, there must also be limiting steps to early dissemination, all of which remain largely unknown. We report that the orphan nuclear receptor NR2F1/COUP-TF1 serves as a barrier to early dissemination. High-resolution intravital imaging revealed that loss of function of NR2F1 in HER2+ early cancer cells increased in vivo dissemination without accelerating mammary tumor formation. NR2F1 expression was positively regulated by the tumor suppressive MMK3/6-p38-MAPK pathway and downregulated by HER2 and Wnt4 oncogenic signaling. NR2F1 downregulation by HER2 in early cancer cells led to decreased E-cadherin expression and {beta}-catenin membrane localization, disorganized laminin 5 deposition, and increased expression of CK14, TWIST1, ZEB1 and PRRX1. Our findings reveal the existence of an inhibitory mechanism of dissemination regulated by NR2F1 downstream of HER2 signaling.

cancer biology↗