Biology subjects

Nussbaum, D. P.

Publications and source records attributed to Nussbaum, D. P..

4 recordsLinked to original sources

bioRxiv2024

Spatial Transcriptomics of IPMN Reveals Divergent Indolent and Malignant Lineages

PurposeIntraductal papillary mucinous neoplasms (IPMN) occur in 5-10% of the population, but only a small minority progress to pancreatic ductal adenocarcinoma (PDAC). The lack of accurate predictors of high-risk disease leads both to unnecessary operations for indolent neoplasms as well as missed diagnoses of PDAC. Digital spatial RNA profiling (DSP-RNA) provides an opportunity to define and associate transcriptomic states with cancer risk. Experimental DesignWhole-transcriptome DSP-RNA profiling was performed on 10 IPMN specimens encompassing the spectrum of dysplastic changes from normal duct to cancer. Ductal epithelial regions within each tissue were annotated as normal duct (NL), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive carcinoma (INV). Gene expression count data was generated by Illumina sequencing and analyzed with R/Bioconductor. ResultsDimension reduction analysis exposed three clusters reflecting IPMN transcriptomic states denoted "normal-like" (cNL), "low-risk" (cLR) and "high-risk" (cHR). In addition to specific marker genes, the three states exhibited significant enrichment for the exocrine, classical, and basal-like programs in PDAC. Specifically, exocrine function diminished in cHR, classical activation distinguished neoplasia from cNL, and basal-like genes were specifically upregulated in cHR. Intriguingly, markers of cHR were detected in NL and LGD regions from specimens with PDAC but not low-grade IPMN. ConclusionsDSP-RNA of IPMN revealed low-risk (indolent) and high-risk (malignant) expression programs that correlated with the activity of exocrine and basal-like PDAC signatures, respectively, and distinguished pathologically low-grade from malignant specimens. These findings contextualize IPMN pathogenesis and have the potential to transform existing risk stratification models. Statement of translational relevanceCurrent consensus guidelines for management of intraductal papillary mucinous neoplasms (IPMN) of the pancreas utilize clinical and radiographic criteria for risk stratification. Unfortunately, the estimated positive predictive value of these criteria for IPMN-associated pancreatic ductal adenocarcinoma (PDAC) is under 50%, indicating that over half of pancreatectomies are performed for benign disease. Moreover, nearly 15% of patients who were deemed "low risk" by the same criteria harbored PDAC. Surgical resection of IPMN has maximal benefit when performed prior to the development of PDAC, as evidence of carcinoma has been associated with a high rate of recurrence and poor overall survival. Thus, the development of molecular diagnostics that improve the accuracy of IPMN risk classification would have immediate relevance for patient care, both in terms of better selecting patients for potentially curative operations, as well as sparing patients with low-risk lesions from invasive procedures.

cancer biology↗

bioRxiv2023

Comprehensive Assessment of the Intrinsic Pancreatic Microbiome

BackgroundSmall studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation. We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome. MethodsPancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institutes Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings. ResultsSequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology. ConclusionsOur analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation. Significance of this studyO_ST_ABSWhat is already known on this subject?C_ST_ABSO_LIMicrobial colonization, infection, and dysbiosis have been implicated in the oncogenesis of various gastrointestinal tumors (e.g.: Helicobacter pylori in gastric cancer, hepatitis B and C in hepatocellular carcinoma, colon dysbiosis in colon cancer progression). C_LIO_LIFew studies have analyzed the intrinsic pancreatic microbiome, and these have produced conflicting results regarding microbial presence and alterations associated with malignant disease. C_LIO_LIIPMN is a precursor lesion to pancreatic cancer that represents a whole gland defect without an established driver event, and microbiome changes have been implicated as a possible etiology of cyst formation and dysplastic progression. C_LI What are the new findings?O_LIA low-biomass, low-diversity intrinsic pancreatic microbiome is present in both pancreatic tissue and cyst fluid. C_LIO_LIThis intrinsic pancreatic microbiome does not differ in terms of abundance, composition, or diversity between patients with PDAC, IPMN, or other benign conditions of the pancreas. C_LI How might it impact clinical practice in the foreseeable future?O_LIMicrobiome dysbiosis does not appear to be a driver of malignant degeneration of IPMN, and further research is needed to identify drivers of oncogenesis in order for possible chemoprevention strategies to be developed. C_LI

microbiology↗

bioRxiv2022

Mediator Kinase Inhibition Impedes Transcriptional Plasticity and Prevents Resistance to ERK/MAPK-Targeted Therapy in KRAS-Mutant Cancers

Acquired resistance remains a major challenge for therapies targeting oncogene activated pathways. KRAS is the most frequently mutated oncogene in human cancers, yet strategies targeting its downstream signaling kinases have failed to produce durable treatment responses. Here, we developed multiple models of acquired resistance to dual-mechanism ERK/MAPK inhibitors across KRAS-mutant pancreatic, colorectal, and lung cancers, and then probed the long-term events enabling survival against this novel class of drugs. These studies revealed that resistance emerges secondary to large-scale transcriptional adaptations that are diverse and tumor-specific. Transcriptional reprogramming extends beyond the well-established early response, and instead represents a dynamic, evolved population-level process that is refined to attain a stably resistant phenotype. Mechanistic and translational studies reveal that resistance to dual-mechanism ERK/MAPK inhibition is broadly susceptible to manipulation of the epigenetic machinery, and that Mediator kinase, in particular, can be co-targeted at a bottleneck point to prevent diverse, tumor-specific resistance programs.

cancer biology↗

bioRxiv2022

Spatial Transcriptome Profiling of Intraductal Papillary Mucinous Neoplasms Establishes a Molecular Framework for Risk Stratification

The histopathologic heterogeneity of intraductal papillary mucinous neoplasms (IPMN) complicates the prediction of pancreatic ductal adenocarcinoma (PDAC) risk. Intratumoral regions of pancreaticobiliary (PB), intestinal (INT), and gastric foveolar (GF) epithelium may occur with either low-grade dysplasia (LGD) or high-grade dysplasia (HGD). We used digital spatial RNA profiling of dysplastic epithelium (83 regions) from surgically resected IPMN tissues (12 patients) to differentiate subtypes and predict genes associated with malignancy. The expression patterns of PB and GF lesions diverged from INT, suggesting that PB and GF arise from a common lineage. Transcriptional dysregulation within PB lesions mirrored that of PDAC, whereas INT and GF foci did not. Tumor necrosis factor/nuclear factor {kappa}B (TNF-NF{kappa}B) and cell cycle (cycling-S, cycling-G2/M) programs occurred with relative prominence in PB and INT subtypes, respectively. Taken together, this study delineates markers of high-risk IPMN and insights into malignant progression. One Sentence SummarySpatial profiling of the intratumoral heterogeneity of IPMN yields markers of high-risk disease and insights into malignant progression.

cancer biology↗