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Fahrmann, J. F.

Publications and source records attributed to Fahrmann, J. F..

2 recordsLinked to original sources
bioRxiv2023

Integrated spatial transcriptomics and lipidomics of precursor lesions of pancreatic cancer identifies enrichment of long chain sulfatide biosynthesis as an early metabolic alteration

BackgroundThe development of diverse spatial profiling technologies has provided an unprecedented insight into molecular mechanisms driving cancer pathogenesis. Here, we conducted the first integrated cross-species assessment of spatial transcriptomics and spatial metabolomics alterations associated with progression of intraductal papillary mucinous neoplasms (IPMN), bona fide cystic precursors of pancreatic ductal adenocarcinoma (PDAC). MethodsMatrix Assisted Laster Desorption/Ionization (MALDI) mass spectrometry (MS)-based spatial imaging and Visium spatial transcriptomics (ST) (10X Genomics) was performed on human resected IPMN tissues (N= 23) as well as pancreata from a mutant Kras;Gnas mouse model of IPMN. Findings were further compared with lipidomic analyses of cystic fluid from 89 patients with histologically confirmed IPMNs, as well as single-cell and bulk transcriptomic data of PDAC and normal tissues. ResultsMALDI-MS analyses of IPMN tissues revealed long-chain hydroxylated sulfatides, particularly the C24:0(OH) and C24:1(OH) species, to be selectively enriched in the IPMN and PDAC neoplastic epithelium. Integrated ST analyses confirmed that the cognate transcripts engaged in sulfatide biosynthesis, including UGT8, Gal3St1, and FA2H, were co-localized with areas of sulfatide enrichment. Lipidomic analyses of cystic fluid identified several sulfatide species, including the C24:0(OH) and C24:1(OH) species, to be significantly elevated in patients with IPMN/PDAC compared to those with low-grade IPMN. Targeting of sulfatide metabolism via the selective galactosylceramide synthase inhibitor, UGT8-IN-1, resulted in ceramide-induced lethal mitophagy and subsequent cancer cell death in vitro, and attenuated tumor growth of mutant Kras;Gnas allografts. Transcript levels of UGT8 and FA2H were also selectively enriched in PDAC transcriptomic datasets compared to non-cancerous areas, and elevated tumoral UGT8 was prognostic for poor overall survival. ConclusionEnhanced sulfatide metabolism is an early metabolic alteration in cystic pre-cancerous lesions of the pancreas that persists through invasive neoplasia. Targeting sulfatide biosynthesis might represent an actionable vulnerability for cancer interception.

cancer biology↗
bioRxiv2023

EGFR inhibition in lung adenocarcinoma upregulates cell surface expression of the placental antigen ALPP and enhances efficacy of ALPP-ADC therapy

Alkaline phosphatase placental type (ALPP) and ALPPL2 are closely related and regulated GPI anchored proteins that are known to be expressed on the cell surface in some cancers, whereas normal tissue expression is largely limited to the placenta. Clinical utility of ALPP is potentially limited by heterogenous expression in tumors. Here, we assessed ALPP and ALPPL2 surfaceome protein levels in 158 cancer cell lines and mRNA expression levels in 10,967 tumors representing 32 cancer types from The Cancer Genome Atlas (TCGA), which revealed ALPP, and to a lesser extent ALPPL2, to be variably expressed in several cancer types including lung adenocarcinoma (LUAD). Surface expression of ALPP was confirmed by tissue microarray analysis of 204 lung tumors. Using LUAD as a model system, we demonstrated that treatment with EGFR inhibitors, or induction of cancer cell quiescence via nutrient deprivation greatly enhanced ALPP surface expression. Mechanistic studies revealed that enhancement of surface ALPP expression in LUAD following gefitinib treatment was mediated through repression of EGFR signaling and activation of the transcription factor FoxO3a, which was identified as an upstream transcriptional regulator of ALPP. Using xenograft models of LUAD, we further demonstrated that gefitinib treatment upregulates surface expression of ALPP in LUAD cells but not in normal tissues. Combination therapy with gefitinib and an ALPP antibody conjugated with Monomethylauristatin F (ALPP-ADC-MAF) resulted in superior anti-cancer efficacy compared with gefitinib or ALPP-ADC-MAF alone. Our findings support a novel combination treatment modality that boosts the efficacy of ALPP-ADC directed therapy.

cancer biology↗