Biology subjects

Clemente, V.

Publications and source records attributed to Clemente, V..

3 recordsLinked to original sources

bioRxiv2021

GLS1 is a Protective Factor Rather than a Molecular Target in ARID1A-Mutated Ovarian Clear Cell Carcinoma

Targeting glutamine metabolism has emerged as a novel therapeutic strategy for several human cancers, including ovarian cancer. The primary target of this approach is the kidney isoform of glutaminase, glutaminase 1 (GLS1), a key enzyme in glutamine metabolism that is overexpressed in several human cancers. A first-in-class inhibitor of GLS1, called CB839 (Telaglenastat), has been investigated in several clinical trials, with promising results. The first clinical trial of CB839 in platinum-resistant ovarian cancer patients is forthcoming. ARID1A-mutated ovarian clear cell carcinoma (OCCC) is a relatively indolent and chemoresistant ovarian cancer histotype. In OCCC-derived cells in vitro and mouse models, loss of ARID1A leads to upregulation of GLS1. Thus, targeting of GLS1 with CB839 has been suggested as a targeted approach for OCCC patients with tumors harboring ARID1A-mutations. Here, we investigated whether GLS1 is differentially expressed between OCCC patients whose tumors are ARID1A positive and patients whose tumors are ARID1A negative. In clinical specimens of OCCC, we found that GLS1 overexpression was not correlated with ARID1A loss. In addition, GLS1 overexpression was associated with better clinical outcomes. Our findings suggest that GLS1 expression in OCCC may be a protective factor and that caution should be taken when considering the use of CB839 to treat OCCC patients.

cancer biology↗

bioRxiv2021

UNC-45A is Highly Expressed in the Proliferative Cells of the Mouse Genital Tract and in the Microtubule-Rich Areas of the Mouse Nervous System

UNC-45A is a cytoskeletal-associated protein with a dual and non-mutually exclusive role as a regulator of the acto-myosin system and as a Microtubule (MT)-destabilizing protein. UNC-45A is overexpressed in human cancers including in ovarian cancer patients resistant to the MT-stabilizing drug Paclitaxel. Mapping of UNC-45A in the mouse upper genital tract and central nervous system reveals its enrichment in highly proliferating and prone to remodeling cells and in microtubule-rich areas of in the ovaries and in neurons respectively. In both apparatuses UNC-45A is also abundantly expressed in the ciliated epithelium. Because regulators of acto-myosin contractility and MT stability are essential for the physiopathology of the female reproductive tract and of neuronal development our findings suggest that UNC-45A may have a role in ovarian cancer initiation and development and in neurodegeneration.

neuroscience↗

bioRxiv2021

Targeting Mitochondrial Metabolism in Clear Cell Carcinoma of the Ovaries

Ovarian clear cell carcinoma (OCCC) is a rare but chemorefractory tumor. About 50% of all OCCC patients have inactivating mutations of ARID1A a member of the SWI/SNF chromatin remodeling complex. Members of the SWI/SNF remodeling have emerged as regulators of the energetic metabolism of mammalian cells, however the role of ARID1A as a modulator of the mitochondrial metabolism in OCCCs is yet to be defined. Here we show that ARID1A-loss results in increased mitochondrial metabolism and renders ARID1A-mutated cells increasingly and selectively dependent on it. The increase in mitochondrial activity following ARID1A loss is associated to increase of C-myc and to increased mitochondrial number and reduction of their size consistent with a higher mitochondrial cristae/outer membrane ratio. Significantly, preclinical testing of the complex I mitochondrial inhibitor IACS-010759 extends overall survival in a preclinical model of ARID1A-mutated OCCC. These findings provide the for targeting mitochondrial activity in ARID1A-mutanted OCCCs.

cancer biology↗