Skip to main content

MSTPublications: March 2021

Posted by on Tuesday, March 30, 2021 in New Publications .

Structure-function analysis of oncogenic EGFR Kinase Domain Duplication reveals insights into activation and a potential approach for therapeutic targeting.
Du Z*, Brown BP*, Kim S, Ferguson D, Pavlick DC, Jayakumaran G, Benayed R, Gallant JN, Zhang YK, Yan Y, Red-Brewer M, Ali SM, Schrock AB, Zehir A, Ladanyi M, Smith AW, Meiler J, Lovly CM.
Nat Commun. 2021 Mar 2;12(1):1382. doi: 10.1038/s41467-021-21613-6.

Mechanistic understanding of oncogenic variants facilitates the development and optimization of treatment strategies. We recently identified in-frame, tandem duplication of EGFR exons 18 – 25, which causes EGFR Kinase Domain Duplication (EGFR-KDD). Here, we characterize the prevalence of ERBB family KDDs across multiple human cancers and evaluate the functional biochemistry of EGFR-KDD as it relates to pathogenesis and potential therapeutic intervention. We provide computational and experimental evidence that EGFR-KDD functions by forming asymmetric EGF-independent intra-molecular and EGF-dependent inter-molecular dimers. Time-resolved fluorescence microscopy and co-immunoprecipitation reveals EGFR-KDD can form ligand-dependent inter-molecular homo- and hetero-dimers/multimers. Furthermore, we show that inhibition of EGFR-KDD activity is maximally achieved by blocking both intra- and inter-molecular dimerization. Collectively, our findings define a previously unrecognized model of EGFR dimerization, providing important insights for the understanding of EGFR activation mechanisms and informing personalized treatment of patients with tumors harboring EGFR-KDD. Finally, we establish ERBB KDDs as recurrent oncogenic events in multiple cancers.

Noradrenergic signaling disengages feedforward transmission in the nucleus accumbens shell.
Manz KM, Coleman BC, Grueter CA, Shields BC, Tadross MR, Grueter BA.
J Neurosci. 2021 Mar 16:JN-RM-2420-20. doi: 10.1523/JNEUROSCI.2420-20.2021. Online ahead of print.

The nucleus accumbens shell (NAcSh) receives extensive monoaminergic input from multiple midbrain structures. However, little is known how norepinephrine (NE) modulates NAc circuit dynamics. Utilizing a dynamic electrophysiological approach with optogenetics, pharmacology, and drugs acutely restricted by tethering (DART), we explored microcircuit-specific neuromodulatory mechanisms recruited by NE signaling in the NAcSh of parvalbumin (PV)-specific reporter mice. Surprisingly, NE had little direct effect on modulation of synaptic input at medium spiny neurons (MSNs). In contrast, we report that NE transmission selectively modulates glutamatergic synapses onto PV-expressing fast-spiking interneurons (PV-INs) by recruiting postsynaptically-localized α2 adrenoreceptors (ARs). The synaptic effects of α2-AR activity decrease PV-IN-dependent feedforward inhibition onto medium spiny projection neurons (MSNs) evoked via optogenetic stimulation of cortical afferents to the NAcSh. These findings provide insight into a new circuit motif in which NE has a privileged line of communication to tune feedforward inhibition in the NAcSh. SIGNIFICANCE STATEMENT: The nucleus accumbens (NAc) directs reward-related motivational output by integrating glutamatergic input with diverse neuromodulatory input from monoamine centers. The present study reveals a synapse-specific regulatory mechanism recruited by norepinephrine (NE) signaling within parvalbumin-expressing interneuron (PV-IN) feedforward inhibitory microcircuits. PV-IN-mediated feedforward inhibition in the NAc is instrumental in coordinating NAc output by synchronizing the activity of medium spiny projection neurons (MSNs). By negatively regulating glutamatergic transmission onto PV-INs via α2 adrenergic receptors, NE diminishes feedforward inhibition onto MSNs to promote NAc output. These findings elucidate previously unknown microcircuit mechanisms recruited by the historically overlooked NE system in the NAc.

Fate or coincidence: Do COPD and major depression share genetic risk factors?
Martucci VL, Richmond B, Davis LK, Blackwell TS, Cox NJ, Samuels D, Edwards DV, Aldrich MC.
Hum Mol Genet. 2021 Mar 10:ddab068. doi: 10.1093/hmg/ddab068. Online ahead of print.

Major depressive disorder (MDD) is a common comorbidity in chronic obstructive pulmonary disease (COPD), affecting up to 57% of patients with COPD. While the comorbidity of COPD and MDD is well established, the causal relationship between these two diseases is unclear. A large-scale electronic health record (EHR) clinical biobank and genome-wide association study (GWAS) summary statistics for MDD and lung function traits were used to investigate potential shared underlying genetic susceptibility between COPD and MDD. Linkage disequilibrium score regression was used to estimate genetic correlation between phenotypes. Polygenic scores (PRS) for MDD and lung function traits were developed and used to perform a phenome-wide association study (PheWAS). Multi-trait-based conditional and joint analysis identified single nucleotide polymorphisms (SNPs) influencing both lung function and MDD. We found genetic correlations between MDD and all lung function traits were small and not statistically significant. A PRS-MDD was significantly associated with an increased risk of COPD in a PheWAS (odds ratio [OR] = 1.12, 95% confidence interval [CI]: 1.09-1.16) when adjusting for age, sex, and genetic ancestry, but this relationship became attenuated when controlling for smoking history (OR = 1.08, 95% CI: 1.04-1.13). No significant associations were found between the lung function PRS and MDD. Multi-trait-based conditional and joint analysis identified three SNPs that may contribute to both traits, two of which were previously associated with mood disorders and COPD. Our findings suggest that the observed relationship between COPD and MDD may not be driven by a strong shared genetic architecture.

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell
Shiuan E, Reddy A, Dudzinski SO, Lim AR, Sugiura A, Hongo R, Young K, Liu X-D, Smith CC, O’Neal J, Dahlman KB, McAlister R, Chen B, Ruma K, Roscoe N, Bender J, Ward J, Kim JY, Vaupel C, Bordeaux J, Ganesan S, Mayer TM, Riedlinger GM, Vincent BG, Davis NB, Haake SM, Rathmell JC, Jonasch E, Rini BI, Rathmell WK, Beckermann KE.
Cancers. 2021; 13(6):1475.

Predicting response to ICI therapy among patients with renal cell carcinoma (RCC) has been uniquely challenging. We analyzed patient characteristics and clinical correlates from a retrospective single-site cohort of advanced RCC patients receiving anti-PD-1/PD-L1 monotherapy (N = 97), as well as molecular parameters in a subset of patients, including multiplexed immunofluorescence (mIF), whole exome sequencing (WES), T cell receptor (TCR) sequencing, and RNA sequencing (RNA-seq). Clinical factors such as the development of immune-related adverse events (odds ratio (OR) = 2.50, 95% confidence interval (CI) = 1.05–5.91) and immunological prognostic parameters, including a higher percentage of circulating lymphocytes (23.4% vs. 17.4%, p = 0.0015) and a lower percentage of circulating neutrophils (61.8% vs. 68.5%, p = 0.0045), correlated with response. Previously identified gene expression signatures representing pathways of angiogenesis, myeloid inflammation, T effector presence, and clear cell signatures also correlated with response. High PD-L1 expression (>10% cells) as well as low TCR diversity (≤644 clonotypes) were associated with improved progression-free survival (PFS). We corroborate previously published findings and provide preliminary evidence of T cell clonality impacting the outcome of RCC patients. To further biomarker development in RCC, future studies will benefit from integrated analysis of multiple molecular platforms and prospective validation.

DDIWAS: High-throughput electronic health record-based screening of drug-drug interactions.
Wu P, Nelson SD, Zhao J, Stone CA Jr, Feng Q, Chen Q, Larson EA, Li B, Cox NJ, Stein CM, Phillips EJ, Roden DM, Denny JC, Wei WQ.
J Am Med Inform Assoc. 2021 Mar 13:ocab019. doi: 10.1093/jamia/ocab019. Online ahead of print.

Objective: We developed and evaluated Drug-Drug Interaction Wide Association Study (DDIWAS). This novel method detects potential drug-drug interactions (DDIs) by leveraging data from the electronic health record (EHR) allergy list.
Materials and methods: To identify potential DDIs, DDIWAS scans for drug pairs that are frequently documented together on the allergy list. Using deidentified medical records, we tested 616 drugs for potential DDIs with simvastatin (a common lipid-lowering drug) and amlodipine (a common blood-pressure lowering drug). We evaluated the performance to rediscover known DDIs using existing knowledge bases and domain expert review. To validate potential novel DDIs, we manually reviewed patient charts and searched the literature.
Results: DDIWAS replicated 34 known DDIs. The positive predictive value to detect known DDIs was 0.85 and 0.86 for simvastatin and amlodipine, respectively. DDIWAS also discovered potential novel interactions between simvastatin-hydrochlorothiazide, amlodipine-omeprazole, and amlodipine-valacyclovir. A software package to conduct DDIWAS is publicly available.
Conclusions: In this proof-of-concept study, we demonstrate the value of incorporating information mined from existing allergy lists to detect DDIs in a real-world clinical setting. Since allergy lists are routinely collected in EHRs, DDIWAS has the potential to detect and validate DDI signals across institutions.

Improving the measurement of alexithymia in autistic adults: a psychometric investigation and refinement of the twenty-item Toronto Alexithymia Scale.
Williams ZJ, Gotham KO.
Mol Autism. 2021 Mar 2;12(1):20. doi: 10.1186/s13229-021-00427-9.

Oncogenic functions and therapeutic targeting of EphA2 in cancer.
Wilson K, Shiuan E, Brantley-Sieders DM.
Oncogene. 2021 Mar 8. doi: 10.1038/s41388-021-01714-8. Online ahead of print.

From Good to Bad: The Opposing Effects of PTHrP on Tumor Growth, Dormancy, and Metastasis Throughout Cancer Progression
Edwards CM, Johnson, RW.Front. Oncol. 2021 Mar 22. 11:644303. doi: 10.3389/fonc.2021.644303. Online ahead of print. 

Targeting Histone Modifications in Bone and Lung Metastatic Cancers.
Edwards CM, Johnson RW.
Curr Osteoporos Rep. 2021 Mar 15. doi: 10.1007/s11914-021-00670-2. Online ahead of print.

Evaluating human autosomal loci for sexually antagonistic viability selection in two large biobanks.
Kasimatis KR, Abraham A, Ralph PL, Kern AD, Capra JA, Phillips PC.
Genetics. 2021 Mar 3;217(1):1-10. doi: 10.1093/genetics/iyaa015.

ConceptWAS: a high-throughput method for early identification of COVID-19 presenting symptoms and characteristics from clinical notes.
Zhao J, Grabowska ME, Eric Kerchberger V, Smith JC, Nur Eken H, Feng Q, Peterson JF, Trent Rosenbloom S, Johnson KB, Wei WQ.
J Biomed Inform. 2021 Mar 24:103748. doi: 10.1016/j.jbi.2021.103748. Online ahead of print.

Single-cell analysis by mass cytometry reveals metabolic states of early-activated CD8+ T cells during the primary immune response.
Levine LS, Hiam-Galvez KJ, Marquez DM, Tenvooren I, Madden MZ, Contreras DC, Dahunsi DO, Irish JM, Oluwole OO, Rathmell JC, Spitzer MH.
Immunity. 2021 Mar 6:S1074-7613(21)00084-4. doi: 10.1016/j.immuni.2021.02.018. Online ahead of print.