Biology subjects

Fahrmann, J. F.

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

5 recordsLinked to original sources

bioRxiv2024

Aberrant expression of CD14 in breast tumor cells is associated with poor outcome

Emerging evidence suggests that cancer cells can mimic features of immune cells during oncogenic transformation to drive disease progression. We assessed the occurrence of immunological markers in breast cancer cells to determine their expression pattern. We initially analyzed 18 immune protein markers (CCR4, CCR6, CCR7, CD11, CD123, CD14, CD16, CD19, CD24, CD25, CD27, CD3, CD38, CD4, CD45, CD56, CD8 and CXCR3) expressed on the surface of 28 breast cancer cell lines using mass spectrometry. CD14 protein expression in tumor cells and its association with clinical outcomes was subsequently evaluated by tissue microarray (TMA) analysis of 346 breast tumors. Single-cell RNA sequencing data from breast cancer tumors and bulk transcriptomic data of breast cancer cell lines were interrogated for molecular signatures associated with CD14 tumor cell expression. Among the markers interrogated, CD14 protein was aberrantly expressed on the surface of 13 out of 15 triple-negative breast cancer (TNBC), one of six hormone receptor positive (HR+), one of five hormone receptors negative (HR-)/Her2+ cell lines. Likewise, RNA expression revealed higher levels of CD14 in TNBC cell lines compared to other subtypes. Tumor tissue microarray analysis revealed elevated levels of CD14 membrane expression predominantly in TNBC and was associated with higher tumor grade and increased incidence of disease recurrence compared to CD14-negative tumors. The CD14-positive subgroup exhibited Nuclear Factor Kappa Beta (NFkB) and TGF-{beta} centric networks at both the protein and Single-cell RNA levels. We have uncovered a novel subset of breast cancers characterized by aberrant surface expression of CD14 associated with aggressive disease. CD14 identifies a subset of breast cancers with poor outcome and is a potential therapeutic target.

cancer biology↗

bioRxiv2024

A Rigorous Multi-Laboratory Study of Known PDAC Biomarkers Identifies Increased Sensitivity and Specificity Over CA19-9 Alone

A blood test that enables surveillance for early-stage pancreatic ductal adenocarcinoma (PDAC) is an urgent need. Independent laboratories have reported PDAC biomarkers that could improve biomarker performance over CA19-9 alone, but the performance of the previously reported biomarkers in combination is not known. Therefore, we conducted a coordinated case/control study across multiple laboratories using common sets of blinded training and validation samples (132 and 295 plasma samples, respectively) from PDAC patients and non-PDAC control subjects representing conditions under which surveillance occurs. We analyzed the training set to identify candidate biomarker combination panels using biomarkers across laboratories, and we applied the fixed panels to the validation set. The panels identified in the training set, CA19-9 with CA199.STRA, LRG1, TIMP-1, TGM2, THSP2, ANG, and MUC16.STRA, achieved consistent performance in the validation set. The panel of CA19-9 with the glycan biomarker CA199.STRA improved sensitivity from 0.44 with 0.98 specificity for CA19-9 alone to 0.71 with 0.98 specificity (p < 0.001, 1000-fold bootstrap). Similarly, CA19-9 combined with the protein biomarker LRG1 and CA199.STRA improved specificity from 0.16 with 0.94 sensitivity for CA19-9 to 0.65 with 0.89 sensitivity (p < 0.001, 1000-fold bootstrap). We further validated significantly improved performance using biomarker panels that did not include CA19-9. This study establishes the effectiveness of a coordinated study of previously discovered biomarkers and identified panels of those biomarkers that significantly increased the sensitivity and specificity of early-stage PDAC detection in a rigorous validation trial.

cancer biology↗

bioRxiv2024

Vesicle-mediated mitochondrial clearance underlies an actionable metabolic vulnerability in triple-negative breast cancer

Selective autophagy of mitochondria is known to promote survival and progression of cancer cells in various malignancies including triple-negative breast cancer (TNBC). Here, we aimed to identify the essential metabolic adaptations that support mitochondrial quality control with the goal to uncover actionable metabolic vulnerabilities with therapeutic potential. Using an integrated approach of proteomics and untargeted and stable-isotope resolved metabolomics, coupled with functional experimental analyses, we define an alternative mechanism to mitophagy enabled by an onco-metabolic program of heightened extracellular sphingomyelin salvaging in TNBC that facilitates extracellular vesicle (EV)-mediated intracellular clearance of mitochondrial damage. Targeting of the cancer cell sphingolipid onco-metabolic pathway via repurposing of eliglustat, a selective small molecule inhibitor of glucosylceramide synthase (UGCG), resulted in ceramide-induced lethal mitophagy and attenuated tumor growth and prolonged overall survival at clinically achievable doses in an orthotopic syngeneic mouse model of TNBC. Our study defines a mechanism of aberrant sphingolipid metabolism that underlies an actionable metabolic vulnerability for anti-cancer treatment.

cancer biology↗

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↗