Biology subjects

Santana-Codina, N.

Publications and source records attributed to Santana-Codina, N..

4 recordsLinked to original sources

bioRxiv2026

GALE-dependent glycoproteome remodelling is a determinant of oncogenic RAS transformation

Oncogenic transformation is accompanied by extensive remodelling of the cellular glycosylation landscape, yet the mechanisms linking oncogenic signalling to glycoproteome reprogramming remain poorly defined. We used site-resolved intact glycoproteomics to systematically map oncogenic RAS-dependent changes across the N- and O-linked glycoproteome. Integrating multiomics profiling with functional approaches, we identify UDP-glucose 4-epimerase (GALE) as a transcriptional target of oncogenic RAS that is induced through MAPK signalling and MYC-dependent transcription. GALE depletion selectively disrupted RAS-dependent glycoproteome remodelling, preferentially impairing sialylation of N-linked glycans and O-linked GalNAc-type glycosylation. Functionally, these glycosylation defects were accompanied by suppressed anchorage-independent growth and reduced in vivo tumorigenicity of KRAS-mutant cells, establishing GALE-dependent nucleotide-sugar interconversion as a requirement for malignant growth. Clinically, GALE expression was elevated in pancreatic ductal adenocarcinoma, wherein KRAS mutations are highly prevalent, and across a broad spectrum of human cancers. Collectively, our findings define a regulatory axis that connects oncogenic signalling to nucleotide-sugar precursor availability and diversification of the cellular glycan repertoire, revealing GALE as a metabolic dependency in RAS-driven cancer.

Cancer Biology↗

bioRxiv2024

De novo pyrimidine biosynthesis inhibition synergizes with BCL-XL targeting in pancreatic cancer

Oncogenic KRAS, the genetic driver of 90% of pancreatic adenocarcinoma (PDAC), induces a metabolic rewiring characterized, in part, by dependency on de novo pyrimidine biosynthesis. Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH), an enzyme in the de novo pyrimidine synthesis pathway, delays pancreatic tumor growth in vivo; however, limited monotherapy efficacy suggests compensatory pathways and that combinatorial strategies are required for enhanced efficacy. Here, we use an integrated metabolomic, quantitative temporal proteomic and in vitro and in vivo DHODH inhibitor anchored CRISPR/Cas9 genetic screening approach to identify compensatory pathways to DHODH inhibition (DHODHi) and targets for combination strategies. We demonstrate that DHODHi alters the apoptotic regulatory proteome thereby enhancing sensitivity to inhibitors of the anti-apoptotic BCL2L1 (BCL-XL) protein. Combinatorial regimens with DHODH and BCL-XL inhibition synergistically induce apoptosis in PDAC cell lines and patient-derived PDAC organoids. In vivo DHODH inhibition with Brequinar and BCL-XL degradation with DT2216, a proteolysis targeting chimera (PROTAC), significantly inhibits the growth of PDAC tumors. Our data defines mechanisms of adaptation to DHODH inhibition and identifies a combination therapy strategy in PDAC.

cancer biology↗

bioRxiv2020

Intestinal ferritinophagy is regulated by HIF-2 and is essential for systemic iron homeostasis

Iron is critical for many processes including oxygen transport and erythropoiesis. Transcriptomic analysis demonstrates that HIF-2 regulates over 90% of all transcripts induced following iron deficiency in the intestine. However, beyond divalent metal transporter 1 (DMT1), ferroportin 1 (Fpn1) and duodenal cytochrome b (Dcytb), no other genes/pathways have been critically assessed with respects to their importance in intestinal iron absorption. Ferritinophagy is associated with cargo specific autophagic breakdown of ferritin and subsequent release of iron. We show here that nuclear receptor co-activator 4 (NCOA4)-mediated intestinal ferritinophagy is integrated to systemic iron demand via HIF-2. Duodenal NCOA4 expression is regulated by HIF-2 during high systemic iron demands. Moreover, overexpression of intestinal HIF-2 is sufficient to activate NCOA4 and promote lysosomal degradation of ferritin. Promoter analysis revealed NCOA4 as a direct HIF-2 target. To demonstrate the importance of intestinal HIF-2/ferritinophagy axis in systemic iron homeostasis, whole body and intestine-specific NCOA4-null mouse lines were assessed. These analyses demonstrate an iron sequestration in the enterocytes, and significantly high tissue ferritin levels in the dietary iron deficiency and acute hemolytic anemia models. Together, our data suggests efficient ferritinophagy is critical for intestinal iron absorption and systemic iron homeostasis.

physiology↗

bioRxiv2019

Defining and targeting adaptations to oncogenic KRASG12C inhibition using quantitative temporal proteomics

Covalent inhibitors of the KRASG12C oncoprotein have recently been developed and are being evaluated in clinical trials. Resistance to targeted therapies is common and likely to limit long-term efficacy of KRAS inhibitors (KRASi). To identify pathways of adaptation to KRASi and to predict drug combinations that circumvent resistance, we used a mass spectrometry-based quantitative temporal proteomics and bioinformatics workflow to profile the temporal proteomic response to KRASG12C inhibition in pancreatic and lung cancer 2D and 3D cellular models. We quantified 10,805 proteins across our datasets, representing the most comprehensive KRASi proteomics effort to date. Our data reveal common mechanisms of acute and long-term response between KRASG12C-driven tumors. To facilitate discovery in the cancer biology community, we generated an interactive KRASi proteome website (https://manciaslab.shinyapps.io/KRASi/). Based on these proteomic data, we identified potent combinations of KRASi with PI3K, HSP90, CDK4/6, and SHP2 inhibitors, in some instances converting a cytostatic response to KRASi monotherapy to a cytotoxic response to combination treatment. Overall, using our quantitative temporal proteomics-bioinformatics platform, we have comprehensively characterized the proteomic adaptations to KRASi and identified combinatorial regimens to induce cytotoxicity with potential therapeutic utility.

cancer biology↗