Biology subjects

Sanz-Gomez, N.

Publications and source records attributed to Sanz-Gomez, N..

3 recordsLinked to original sources

bioRxiv2024

Osmotic Stress Influences Microtubule Drug Response Via WNK1 Kinase Signaling

Ion homeostasis is critical for numerous cellular processes, and disturbances in ionic balance underlie diverse pathological conditions, including cancer progression. Targeting ion homeostasis is even considered as a strategy to treat cancer. However, very little is known about how ion homeostasis may influence anticancer drug response. In a genome-wide CRISPR-Cas9 resistance drug screen, we identified and validated the master osmostress regulator WNK1 kinase as a modulator of the response to the mitotic drug rigosertib. Osmotic stress and WNK1 inactivation lead to an altered response not only to rigosertib treatment but also to other microtubule-related drugs, minimizing the prototypical mitotic arrest produced by these drugs. This effect is due to an alteration in microtubule stability and polymerization dynamics, likely maintained by fluctuations in intracellular molecular crowding upon WNK1 inactivation. This promotes resistance to microtubule depolymerizing drugs, and increased sensitivity to microtubule stabilizing drugs. In summary, our data proposes WNK1 osmoregulation activity as a biomarker for microtubule-associated chemotherapy response.

cancer biology↗

bioRxiv2023

Nuclear VANGL2 Inhibits Lactogenic Differentiation

Planar cell polarity (PCP) proteins coordinate tissue morphogenesis by governing cell patterning and polarity. Asymmetrically localized on the plasma membrane of cells, PCP proteins are also trafficked by endocytosis, suggesting they may have intracellular functions that are dependent or independent of their extracellular role, but whether these functions extend to transcriptional control remains unknown. Here, we show the nuclear localization of transmembrane, PCP protein, VANGL2, in undifferentiated, but not differentiated, HC11 cells, which serve as a model for mammary lactogenic differentiation. Loss of Vangl2 function results in upregulation of pathways related to STAT5 signaling. We identify DNA binding sites and a nuclear localization signal in VANGL2, and use CUT&RUN to demonstrate direct binding of VANGL2 to specific DNA binding motifs, including one in the Stat5a promoter. Knockdown (KD) of Vangl2 in HC11 cells and primary mammary organoids results in upregulation of Stat5a, Ccnd1 and Csn2, larger acini and organoids, and precocious differentiation; phenotypes rescued by overexpression of Vangl2, but not Vangl2{Delta}NLS. Together, these results advance a paradigm whereby PCP proteins coordinate tissue morphogenesis by keeping transcriptional programs governing differentiation in check.

cell biology↗

bioRxiv2023

TPX2 expression promotes sensitivity to dasatinib in breast cancer by activating the YAP transcriptional signaling.

Chromosomal instability (CIN) is a hallmark of cancer aggressiveness, providing genetic plasticity and tumor heterogeneity that allows the tumor to evolve and adapt to stress conditions. CIN is considered a cancer therapeutic biomarker because healthy cells do not exhibit CIN. Despite recent efforts to identify therapeutic strategies related to CIN, the results obtained have been very limited. CIN is characterized by a genetic signature where a collection of genes, mostly mitotic regulators, are overexpressed in CIN-positive tumors, providing aggressiveness and poor prognosis. We attempted to identify new therapeutic strategies related to CIN genes by performing a drug screen, using cells that individually express CIN-associated genes in an inducible manner. We find that the overexpression of TPX2 enhances sensitivity to the SRC inhibitor dasatinib due to activation of the YAP pathway. Furthermore, using breast cancer data from the TCGA and a cohort of cancer-derived patient samples, we find that both TPX2 expression and YAP activation are present in a significant percentage of cancer tumor samples, providing poor prognosis, being therefore putative biomarkers for dasatinib therapy.

cancer biology↗