Aaron T Griffin

Aaron T Griffin

Columbia University in the City of New York

H-index: 6

North America-United States

About Aaron T Griffin

Aaron T Griffin, With an exceptional h-index of 6 and a recent h-index of 6 (since 2020), a distinguished researcher at Columbia University in the City of New York, specializes in the field of Systems Biology, Cancer, Genomics, Bioinformatics.

His recent articles reflect a diverse array of research interests and contributions to the field:

Discovery and validation of effective combination therapies targeting cell state-specific master regulator vulnerabilities by network-based protein activity inference in …

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations

Abstract PR01: Identification and pharmacological targeting of treatment-resistant, stem-like breast cancer cells for combination therapy

Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer

Network-based inference identifies cell state-specific drugs targeting master regulator vulnerabilities in diffuse midline glioma

NaRnEA: an information theoretic framework for gene set analysis

Network-based elucidation of colon cancer drug resistance by phosphoproteomic time-series analysis

DIPG-49. A SYSTEMS BIOLOGY APPROACH TO DEFINING AND TARGETING CELL STATE-SPECIFIC MASTER REGULATOR DEPENDENCIES IN DIFFUSE MIDLINE GLIOMA

Aaron T Griffin Information

University

Columbia University in the City of New York

Position

Columbia University College of Physicians and Surgeons

Citations(all)

237

Citations(since 2020)

161

Cited By

118

hIndex(all)

6

hIndex(since 2020)

6

i10Index(all)

6

i10Index(since 2020)

5

Email

University Profile Page

Columbia University in the City of New York

Aaron T Griffin Skills & Research Interests

Systems Biology

Cancer

Genomics

Bioinformatics

Top articles of Aaron T Griffin

Discovery and validation of effective combination therapies targeting cell state-specific master regulator vulnerabilities by network-based protein activity inference in …

Authors

Ester Calvo Fernandez,Lorenzo Tomassoni,Xu Zhang,Aleksandar Obradovic,Pasquale Laise,Aaron T Griffin,Lukas Vlahos,Junqiang Wang,Hanna E Minns,Diana V Morales,Christian Simmons,Matthew Gallito,Hong-Jian Wei,Zhiguo Zhang,Robyn Gartrell,Luca Szalontay,Stergios Zacharoulis,Cheng-Chia Wu,Andrea Califano,Jovana Pavisic

Journal

Cancer Research

Published Date

2024/3/22

Diffuse Midline Glioma (DMG) are fatal pediatric brain tumors with no effective systemic therapies. We leveraged network-based methodologies to dissect tumor heterogeneity, discover Master Regulators (MR) representing pharmacologically accessible vulnerabilities of distinct DMG cell states, and validated candidate MR-reversing drugs predicted by the NYS CLIA-certified OncoTarget and OncoTreat algorithms (Cancer Discov 2023) in vivo. We first interrogated single cell DMG regulatory networks generated by ARACNe (Nat Genet 2005) with publicly available gene expression signatures from 3,039 tumor cells across 6 patients using VIPER (Nat Genet 2016) to infer single cell regulatory protein activity. Clustering of cells by protein activity defined 7 patient-independent cell states with distinct MR profiles reflecting known glial lineage markers (OPC-like-S1, OPC-like-S2, OC-like-S1, OC-like-S2, Cycling, AC-like …

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations

Authors

Ester Calvo Fernandez,Lorenzo Tomassoni,Xu Zhang,Junqiang Wang,Aleksandar Obradovic,Pasquale Laise,Aaron T Griffin,Lukas Vlahos,Hanna E Minns,Diana V Morales,Christian Simmons,Matthew Gallitto,Hong-Jian Wei,Timothy J Martins,Pamela S Becker,John R Crawford,Theophilos Tzaridis,Robert J Wechsler-Reya,James Garvin,Robyn D Gartrell,Luca Szalontay,Stergios Zacharoulis,Cheng-Chia Wu,Zhiguo Zhang,Andrea Califano,Jovana Pavisic

Journal

bioRxiv

Published Date

2024/3/17

Diffuse Midline Gliomas (DMGs) are universally fatal, primarily pediatric malignancies affecting the midline structures of the central nervous system. Despite decades of clinical trials, treatment remains limited to palliative radiation therapy. A major challenge is the coexistence of molecularly distinct malignant cell states with potentially orthogonal drug sensitivities. To address this challenge, we leveraged established network-based methodologies to elucidate Master Regulator (MR) proteins representing mechanistic, non-oncogene dependencies of seven coexisting subpopulations identified by single-cell analysis—whose enrichment in essential genes was validated by pooled CRISPR/Cas9 screens. Perturbational profiles of 372 clinically relevant drugs helped identify those able to invert the activity of subpopulation-specific MRs for follow-up in vivo validation. While individual drugs predicted to target individual …

Abstract PR01: Identification and pharmacological targeting of treatment-resistant, stem-like breast cancer cells for combination therapy

Authors

Jeremy Worley,Heeju Noh,Daoqi You,Mikko M Turunen,Hongxu Ding,Evan Paull,Aaron T Griffin,Adina Grunn,Kristina Guillan,Erin C Bush,Samantha J Brosius,Prabhjot S Mundi,Peter Sims,Piero Dalerba,Filemon S Dela Cruz,Andrew L Kung,Andrea Califano

Journal

Cancer Research

Published Date

2024/2/1

Marker-based isolation of Cancer Stem-Like Cells (CSLCs), which can display preferential resistance to standard-of-care chemotherapy, has proven challenging, due to their very small frequency in breast cancer tissue, thus impeding their characterization, as well as identification and targeting of mechanistic dependencies. To address this challenge, we leveraged a systems biology framework for the protein-activity based characterization of CSLC biology at the single cell level and for the identification of drugs that could reprogram them to a differentiated, chemotherapy-sensitive state. To enrich for CSLCs we performed flow cytometry-based sorting of cells dissociated from 7 metastatic breast cancer patients, both TNBC and HR+, using the EpCAM and CD49f markers, followed by RNA-seq profiling. Protein activity-based clustering, using the VIPER algorithm (Alvarez et al. Nat Genet 2017), identified …

Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer

Authors

Vivek Naranbhai,Arvind Ravi,Matthew Hellmann,Monica Arniella,Mark Holton,Samuel Freeman,Chip Stewart,Ignaty Leshchiner,Jaegil Kim,Yo Akiyama,Aaron Griffin,Natalie Vokes,Mustafa Sakhi,Vashine Kamesan,Hira Rizvi,Biagio Ricciuti,Patrick Forde,Valsamo Anagnostou,Jonathan Riess,Don Gibbons,Nathan Pennell,Vamsidhar Velcheti,Subba Digumarthy,Mari Mino-Kenudson,Andrea Califano,John Heymach,Roy Herbst,Julie Brahmer,Kurt Schalper,Victor Velculescu,Brian Henick,Naiyer Rizvi,Pasi Janne,Mark Awad,Andrew Chow,Benjamin Greenbaum,Marta Luksza,Alice Shaw,Jedd Wolchok,Nir Hacohen,Gad Getz,Justin Gainor

Journal

Cancer Research

Published Date

2023/4/4

Responders to checkpoint blockade in Non Small Cell Lung Cancer (NSCLC) often feature an inflamed microenvironment prior to therapy. However, the complete set of molecular drivers connecting this histologic observation to enhanced tumor clearance remain enigmatic. In updated analysis of the Stand Up 2 Cancer-Mark Foundation (SU2C-MARK) Cohort - a collection of 393 patients with whole exome and/or RNA sequencing along with matched checkpoint blockade response annotation - we identify a prominent predictive role for inducible components of the immunoproteasome, a non-canonical peptide processing complex upstream of antigen presentation. Notably, these subunits are enriched as predictors relative to interferon-inducible genes as well as proteasome components in general, and are consistently associated with objective response, progression-free survival and overall survival. Expression of …

Network-based inference identifies cell state-specific drugs targeting master regulator vulnerabilities in diffuse midline glioma

Authors

Ester Calvo Fernandez,Junqiang Wang,Xu Zhang,Hong-Jian Wei,Hanna E Minns,Aaron T Griffin,Lukas Vlahos,Timothy J Martins,Pamela S Becker,John Crawford,Robyn D Gartrell,Luca Szalontay,Stergios Zacharoulis,Zhiguo Zhang,Robert Wechsler-Reya,Cheng-Chia Wu,Andrea Califano,Jovana Pavisic

Journal

Cancer Research

Published Date

2023/4/4

Diffuse Midline Glioma (DMG) are fatal pediatric brain tumors with no therapies. We leveraged network-based methodologies to dissect the heterogeneity of DMG tumors and to discover Master Regulator (MR) proteins representing pharmacologically accessible, mechanistic determinants of molecularly distinct cell states. We produced the first DMG regulatory network from 122 publicly available RNAseq profiles with ARACNe (Basso et al. Nat Genet 2005), and inferred sample-specific MR protein activity with VIPER (Alvarez et al. Nat Genet 2016) based on the differential expression of their targets. 7 of the top 25 most active MRs found comprise a well-characterized MR block (MRB2) (Paull et al.Cell 2021), frequently activated across aggressive tumors, and enriched in DMG patient MR signatures (Fisher’s Exact Test p=4.4 × 10−18). A CRISPR/Cas9 KO screen across 3 DMG patient cell lines identified a set of 73 …

NaRnEA: an information theoretic framework for gene set analysis

Authors

Aaron T Griffin,Lukas J Vlahos,Codruta Chiuzan,Andrea Califano

Journal

Entropy

Published Date

2023/3/21

Gene sets are being increasingly leveraged to make high-level biological inferences from transcriptomic data; however, existing gene set analysis methods rely on overly conservative, heuristic approaches for quantifying the statistical significance of gene set enrichment. We created Nonparametric analytical-Rank-based Enrichment Analysis (NaRnEA) to facilitate accurate and robust gene set analysis with an optimal null model derived using the information theoretic Principle of Maximum Entropy. By measuring the differential activity of ~2500 transcriptional regulatory proteins based on the differential expression of each protein’s transcriptional targets between primary tumors and normal tissue samples in three cohorts from The Cancer Genome Atlas (TCGA), we demonstrate that NaRnEA critically improves in two widely used gene set analysis methods: Gene Set Enrichment Analysis (GSEA) and analytical-Rank-based Enrichment Analysis (aREA). We show that the NaRnEA-inferred differential protein activity is significantly correlated with differential protein abundance inferred from independent, phenotype-matched mass spectrometry data in the Clinical Proteomic Tumor Analysis Consortium (CPTAC), confirming the statistical and biological accuracy of our approach. Additionally, our analysis crucially demonstrates that the sample-shuffling empirical null models leveraged by GSEA and aREA for gene set analysis are overly conservative, a shortcoming that is avoided by the newly developed Maximum Entropy analytical null model employed by NaRnEA.

Network-based elucidation of colon cancer drug resistance by phosphoproteomic time-series analysis

Authors

George Rosenberger,Wenxue Li,Mikko Turunen,Jing He,Prem S Subramaniam,Sergey Pampou,Aaron T Griffin,Charles Karan,Patrick Kerwin,Diana Murray,Barry Honig,Yansheng Liu,Andrea Califano

Journal

bioRxiv

Published Date

2023/2/16

Aberrant signaling pathway activity is a hallmark of tumorigenesis and progression, which has guided targeted inhibitor design for over 30 years. Yet, adaptive resistance mechanisms, induced by rapid, context-specific signaling network rewiring, continue to challenge therapeutic efficacy. By leveraging progress in proteomic technologies and network-based methodologies, over the past decade, we developed VESPA—an algorithm designed to elucidate mechanisms of cell response and adaptation to drug perturbations—and used it to analyze 7-point phosphoproteomic time series from colorectal cancer cells treated with clinically-relevant inhibitors and control media. Interrogation of tumor-specific enzyme/substrate interactions accurately inferred kinase and phosphatase activity, based on their inferred substrate phosphorylation state, effectively accounting for signal cross-talk and sparse phosphoproteome …

DIPG-49. A SYSTEMS BIOLOGY APPROACH TO DEFINING AND TARGETING CELL STATE-SPECIFIC MASTER REGULATOR DEPENDENCIES IN DIFFUSE MIDLINE GLIOMA

Authors

Ester Calvo Fernández,Junqiang Wang,Xu Zhang,Hong-Jian Wei,Hanna Minns,Aaron Griffin,Aleksandar Obradovic,Lukas Vlahos,Timothy Martins,Pamela Becker,John Crawford,Robyn Gartrell,Luca Szalontay,Stergios Zacharoulis,Zhiguo Zhang,Robert Wechsler-Reya,Cheng-Chia Wu,Andrea Califano,Jovana Pavisic

Journal

Neuro-Oncology

Published Date

2023/6/1

Extraneural metastases are extremely rare in diffuse midline glioma (DMG), H3K27-altered, despite a tendency toward aggressive local growth and potential neuroaxis dissemination at progression. Ventriculoperitoneal shunt (VPS) placement for cerebrospinal fluid diversion is commonly performed in patients with thalamic tumors and increasingly considered in brainstem disease with developing hydrocephalus. Herein, we present a case of DMG seeding the abdomen presumably via the VPS. This patient was diagnosed at 22 years of age with a bithalamic tumor with extension into the brainstem and cerebellum as well as non-contiguous periventricular spread to the bilateral frontal lobes, with associated hydrocephalus. The patient underwent VPS insertion and biopsy, with pathology consistent with DMG, H3K27-altered. Whole exome sequencing revealed H3-3A and TP53 alterations as well as PDGFRA …

Identifying and Targeting Master Regulators of Drug Resistance in Lung Adenocarcinoma through Network Analysis of Tumor Transcriptomic Data

Authors

Aaron Timothy Griffin

Published Date

2023

Lung cancer is the leading cause of cancer-related mortality each year in the United States. The majority of patients diagnosed with lung adenocarcinoma (LUAD), the most common histological subtype of lung cancer, present with locally advanced or widely metastatic disease. The American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend that these patients receive systemic antineoplastic treatment tailored to the molecular features of each patient’s disease. LUAD tumors which contain an activating genomic alteration in the gene which encodes the Epidermal Growth Factor Receptor (EGFR) are more likely to respond to treatment with a tyrosine kinase inhibitor (TKI) directed against the EGFR oncoprotein rather than cytotoxic chemotherapy or immune checkpoint inhibitors. However, up to 25% of patients diagnosed with metastatic EGFR-mutated LUAD tumors will not derive clinical benefit from treatment with the current standard-of-care third-generation EGFR TKI osimertinib.The biochemical mechanisms underlying this phenotype of primary TKI-resistance are poorly understood; as a result, alternative treatment strategies for these patients are limited and no FDA-approved method exists for predicting TKI-resistance at the time of diagnosis. To address this unmet need in the field of thoracic oncology, we have implemented a novel systems biology paradigm developed in the Califano Laboratory which focuses on identifying and targeting key transcriptional regulatory proteins responsible for the initiation and maintenance of tumor phenotypes which we refer to as Master Regulators (MRs …

Genomic and transcriptomic analysis of checkpoint blockade response in advanced non-small cell lung cancer

Authors

Arvind Ravi,Matthew D Hellmann,Monica B Arniella,Mark Holton,Samuel S Freeman,Vivek Naranbhai,Chip Stewart,Ignaty Leshchiner,Jaegil Kim,Yo Akiyama,Aaron T Griffin,Natalie I Vokes,Mustafa Sakhi,Vashine Kamesan,Hira Rizvi,Biagio Ricciuti,Patrick M Forde,Valsamo Anagnostou,Jonathan W Riess,Don L Gibbons,Nathan A Pennell,Vamsidhar Velcheti,Subba R Digumarthy,Mari Mino-Kenudson,Andrea Califano,John V Heymach,Roy S Herbst,Julie R Brahmer,Kurt A Schalper,Victor E Velculescu,Brian S Henick,Naiyer Rizvi,Pasi A Jänne,Mark M Awad,Andrew Chow,Benjamin D Greenbaum,Marta Luksza,Alice T Shaw,Jedd Wolchok,Nir Hacohen,Gad Getz,Justin F Gainor

Journal

Nature genetics

Published Date

2023/5

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up To Cancer-Mark Foundation cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including (1) favorable (for example, ATM altered) and unfavorable (for example, TERT amplified) genomic subgroups, (2) a prominent association between expression of inducible components of the immunoproteasome and response and (3) a dedifferentiated tumor-intrinsic subtype with enhanced response to checkpoint blockade. Taken together …

DIPG-57. A systems biology approach to defining and targeting master regulator dependencies from bulk and single-Cell RNA-seq in diffuse midline glioma (DMG)

Authors

Ester Calvo Fernández,Junqiang Wang,Aaron Griffin,Hanna Minns,Hong-Jian Wei,Xu Zhang,Luca Szalontay,Prabhjot Mundi,Cheng-Chia Wu,Robyn Gartrell,Stergios Zacharoulis,Andrea Califano,Jovana Pavisic

Journal

Neuro-Oncology

Published Date

2022/6/1

Diffuse midline glioma (DMG) are fatal pediatric brain tumors with no effective systemic therapies. Molecular profiling demonstrates epigenetic dysregulation and heterogeneity, and novel approaches are needed to identify promising drugs and drug combinations. We used network-based computational analysis of RNA-seq to discover Master Regulator (MR) proteins that represent targetable, mechanistic determinants of distinct DMG cell states. We reverse-engineered the first DMG-specific regulatory network from 122 publicly available DMG RNA-seq profiles with ARACNe. Using this network, we measured sample-specific protein activity based on differential expression of their targets via VIPER. Activity-based clustering identified two clusters showing a trend in survival differences (>1 year, by χ2). The most activated MRs (i.e., TOP2A, CENPF, BUB1B, FOXM1, GTSE1, MKI67, E2F8), relative to normal caudate …

Abstract A007: Pancreatic cancer comprises co-existing transcriptional states regulated by distinct master regulator programs

Authors

Pasquale Laise,Mikko Turunen,Hans Carlo Maurer,Alvaro Curiel Garcia,Ela Elyada,Bernhard Schmierer,Lorenzo Tomassoni,Jeremy Worley,Mariano J Alvarez,Jordan Kesner,Xiangtian Tan,Somnath Tagore,Ester Calvo Fernandez,Kelly Wong,Alexander LE Wang,Sabrina Ge,Alina C Iuga,Aaron T Griffin,Winston Wong,Gulam A Manji,Faiyaz Notta,David A Tuveson,Kenneth PP Olive,Andrea Califano

Journal

Cancer Research

Published Date

2022/11/15

Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of single cell RNA-seq profiles showed that most PDA tumors comprise three coexisting lineages whose aberrant transcriptional state is mechanistically controlled by distinct regulatory programs. These lineages were characterized by the aberrant activation of either gastrointestinal lineage markers (GLS), transcriptional effectors of morphogen pathways (MOS) and acinar to ductal metaplasia markers (ALS). Each lineage was characterized by cells in two different cell states determined by the differential activation of MEK signaling (M+/M-) and high cellular plasticity. These states were confirmed in multiple cohorts, cell lines, PDX models and harmonized with bulk profile analyses. Master regulators (MRs) of GLS and …

A systems biology approach to defining tumor heterogeneity, prognostic and targetable master regulator protein signatures from bulk and single cell RNA-seq in diffuse midline …

Authors

Ester Calvo Fernández,Junqiang Wang,Aaron T Griffin,Luca Szalontay,Stergios Zacharoulis,Jovana Pavisic,Andrea Califano

Journal

Cancer Research

Published Date

2022/6/15

Despite major advances in molecular profiling and numerous clinical trials, diffuse midline glioma (DMG) remains a fatal disease with median survival of only ~9 months and no identified effective drugs. To address this challenge, we leveraged network-based methodologies to dissect the heterogeneity of DMG tumors and to discover Master Regulator (MR) proteins representing pharmacologically accessible, mechanistic determinants of molecularly distinct DMG cell states. The study has produced the first DMG-specific regulatory network, reverse-engineered from 122 publicly available pediatric DMG RNA-seq profiles with ARACNe (Basso et al. Nat Genet 2005). Using this network, we measured protein activity for each sample via VIPER (Alvarez et al., Nat Genet 2016). Activity-based clustering identified 2 clusters, characterized by significant overall survival difference (>1 year, p-val=0.02 by χ2 analysis). Protein …

Integrative analysis of checkpoint blockade response in advanced non-small cell lung cancer

Authors

Arvind Ravi,Justin F Gainor,Monica B Arniella,Mark Holton,Samuel S Freeman,Chip Stewart,Ignaty Leshchiner,Jaegil Kim,Yo Akiyama,Aaron T Griffin,Natalie I Vokes,Mustafa Sakhi,Vashine Kamesan,Hira Rizvi,Biagio Ricciuti,Patrick M Forde,Valsamo Anagnostou,Jonathan W Riess,Don L Gibbons,Nathan A Pennell,Vamsidhar Velcheti,Subba R Digumarthy,Mari Mino-Kenudson,Andrea Califano,John V Heymach,Roy S Herbst,Julie R Brahmer,Kurt A Schalper,Victor E Velculescu,Brian S Henick,Naiyer Rizvi,Pasi A Jänne,Mark M Awad,Andrew Chow,Benjamin D Greenbaum,Marta Luksza,Alice T Shaw,Jedd Wolchok,Nir Hacohen,Gad Getz,Matthew D Hellmann

Journal

bioRxiv

Published Date

2022/3/23

Anti-PD-1/PD-L1 agents have transformed the treatment landscape of advanced non-small cell lung cancer (NSCLC). While our understanding of the biology underlying immune checkpoint blockade in NSCLC is still incomplete, studies to date have established predictive roles for PD-L1 tumor expression and tumor mutational burden (TMB). To expand our understanding of the molecular features underlying response to checkpoint inhibitors in NSCLC, we describe here the first joint analysis of the Stand Up 2 Cancer - Mark Foundation (SU2C-MARK) Cohort, a resource of whole exome and/or RNA sequencing from 393 patients with NSCLC treated with anti-PD-(L)1 therapy, along with matched clinical response annotation. We identify a number of associations between molecular features and outcome, including: 1) favorable (e.g., ATM altered), and unfavorable (e.g., TERT amplified) genomic subgroups, 2) distinct immune infiltration signatures associated with wound healing (unfavorable) and immune activation (favorable), and 3) a novel de-differentiated tumor-intrinsic subtype characterized by expression of endodermal lineage genes, immune activation, and enhanced response rate. Taken together, results from this cohort extend our understanding of NSCLC-specific predictors, providing a rich set of molecular and immunologic hypotheses with which to further our understanding of the biology of checkpoint blockade in NSCLC.

Elucidation and pharmacological targeting of master regulator proteins representing mechanistic determinants of breast cancer stem-like tumor initiating cell state

Authors

Jeremy Worley,Hongxu Ding,Heeju Noh,Evan Paull,Aaron T Griffin,Adina Grunn,Daoqi You,Kristina Guillan,Erin Bush,Piero Dalerba,Peter Sims,Filemon S Dela Cruz,Andrew L Kung,Andrea Califano

Journal

Cancer Research

Published Date

2022/6/15

Although breast cancer Stem-Like Tumor Initiating Cells (SLTIC) represent only a minute fraction of the total tumor mass, they are resistant to standard of care treatment and play a key role in tumor initiation, maintenance, and progression. Unequivocal SLTIC isolation, using surface markers, has proven highly elusive, thus impeding characterization and targeting of their mechanistic dependencies. To address this challenge, we applied a systems biology approach to effectively characterize SLTIC biology and to prioritize drugs that can reprogram them to a more differentiated state that is sensitive to chemotherapy. To isolate breast cancer cells enriched for SLTICs, we performed flow cytometry-based sorting of tumor cells from 7 metastatic breast cancer patients, based on the expression of Epcam and CD49F, which are established epithelial and SLTIC-enriched cell markers, respectively. Activity-based clustering of …

Pancreatic cancer comprises co-existing transcriptional states regulated by distinct master regulator programs.

Authors

Pasquale Laise,Mikko Turunen,Hans Carlo Maurer,Alvaro Curiel Garcia,Ela Elyada,Bernhard Schmierer,Lorenzo Tomassoni,Jeremy Worley,Mariano J Alvarez,Jordan Kesner,Xiangtian Tan,Somnath Tagore,Ester Calvo Fernandez,Kelly Wong,Alexander LE Wang,Sabrina Ge,Alina C Iuga,Aaron T Griffin,Winston Wong,Gulam A Manji,Faiyaz Notta,David A Tuveson,Kenneth PP Olive,Andrea Califano

Journal

Cancer Research

Published Date

2022

Despite extensive efforts, reproducible assessment of pancreatic ductal adenocarcinoma (PDA) heterogeneity and plasticity at the single cell level remains elusive. Systematic, network-based analysis of single cell RNA-seq profiles showed that most PDA tumors comprise three coexisting lineages whose aberrant transcriptional state is mechanistically controlled by distinct regulatory programs. These lineages were characterized by the aberrant activation of either gastrointestinal lineage markers (GLS), transcriptional effectors of morphogen pathways (MOS) and acinar to ductal metaplasia markers (ALS). Each lineage was characterized by cells in two different cell states determined by the differential activation of MEK signaling (M+/M-) and high cellular plasticity. These states were confirmed in multiple cohorts, cell lines, PDX models and harmonized with bulk profile analyses. Master regulators (MRs) of GLS and MOS state were predictive of patient’s survival in bulk profiles. Cross-state plasticity was confirmed by lineage tracing assays, while pooled CRISPR/Cas9 assays confirmed the essentiality of identified MR proteins. Finally, mechanistic MR-mediated cell state control was confirmed by MR expression-mediated reprogramming of MOS cells to a GLS state. Our work provided a mechanistic model of pancreatic cancer heterogeneity and testable hypothesis to target cell state-specific pancreatic cancer dependencies.

Identifying synergistic master regulators of pancreatic ductal adenocarcinoma tumorigenesis through CRISPR/Cas9 combinatorial genetic screens

Authors

Aaron T Griffin,Mikko Turunen,Lorenzo Tomassoni,Kenneth P Olive,Pasquale Laise,Andrea Califano

Journal

Cancer Research

Published Date

2022/6/15

Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related mortality and is highly resistant to cytotoxic, targeted, and immune therapies. Compared to other cancers, PDAC is remarkable for its relatively uniform set of DNA alterations; unfortunately, these hallmark events are not currently targetable and other mutations known to confer sensitivity to specific drugs are uncommon. Consequently, cytotoxic combinations remain the standard of care, with most patients quickly exhibiting primary or secondary chemoresistance. Previous studies have shown that transcriptional regulatory proteins can form small, highly interconnected and autoregulated modules that can initiate and maintain malignant tumor cell state, and that the Master Regulator (MR) protein they comprise represent a novel class of non-oncogene dependencies. We used the VIPER algorithm to identify MR proteins representing …

Clinical characteristics and molecular features of non-small cell lung cancers (NSCLCs) following disease progression on immune checkpoint inhibitors (ICIs).

Authors

Justin F Gainor,Arvind Ravi,Mark M Awad,Mark Holton,Monica Arniella,Chip Stewart,Samuel Freeman,Ignaty Leshchiner,Andrew Chow,Brian S Henick,Vamsidhar Velcheti,Aaron Timothy Griffin,Biagio Ricciuti,Jonathan W Riess,Pasi A Janne,Nir Hacohen,Jedd D Wolchok,Matthew David Hellmann,Gad Getz

Published Date

2022/6/1

e21178Background: ICIs are cornerstones of therapy for advanced NSCLC. Despite dramatic and sometimes durable responses to therapy, most patients (pts) either (i) do not respond to therapy (intrinsic resistance), or (ii) subsequently progress after initial clinical benefit (acquired resistance). Currently, insights into the molecular mechanisms of resistance to ICIs in NSCLC are lacking. Methods: To investigate clinical and molecular features of pts progressing on ICIs, we identified pts who underwent repeat tumor biopsies on and/or after disease progression on ICIs and were included in the Stand Up 2 Cancer (SU2C)/Mark Foundation multi-institutional cohort. Biopsy specimens underwent whole-exome sequencing (WES) and/or whole transcriptome sequencing (RNAseq). Results: We identified 37 pts who underwent a total of 47 repeat biopsies on or after ICIs. Six pts underwent multiple post-ICI biopsies (range 2 …

Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses

Authors

Joshua Broyde,David R Simpson,Diana Murray,Evan O Paull,Brennan W Chu,Somnath Tagore,Sunny J Jones,Aaron T Griffin,Federico M Giorgi,Alexander Lachmann,Peter Jackson,E Alejandro Sweet-Cordero,Barry Honig,Andrea Califano

Journal

Nature biotechnology

Published Date

2021/2

Tumor-specific elucidation of physical and functional oncoprotein interactions could improve tumorigenic mechanism characterization and therapeutic response prediction. Current interaction models and pathways, however, lack context specificity and are not oncoprotein specific. We introduce SigMaps as context-specific networks, comprising modulators, effectors and cognate binding-partners of a specific oncoprotein. SigMaps are reconstructed de novo by integrating diverse evidence sources—including protein structure, gene expression and mutational profiles—via the OncoSig machine learning framework. We first generated a KRAS-specific SigMap for lung adenocarcinoma, which recapitulated published KRAS biology, identified novel synthetic lethal proteins that were experimentally validated in three-dimensional spheroid models and established uncharacterized crosstalk with RAB/RHO. To show that …

A genome-wide copper-sensitized screen identifies novel regulators of mitochondrial cytochrome c oxidase activity

Authors

Natalie M Garza,Aaron T Griffin,Mohammad Zulkifli,Chenxi Qiu,Craig D Kaplan,Vishal M Gohil

Journal

Journal of Biological Chemistry

Published Date

2021/1/1

Copper is essential for the activity and stability of cytochrome c oxidase (CcO), the terminal enzyme of the mitochondrial respiratory chain. Loss-of-function mutations in genes required for copper transport to CcO result in fatal human disorders. Despite the fundamental importance of copper in mitochondrial and organismal physiology, systematic identification of genes that regulate mitochondrial copper homeostasis is lacking. To discover these genes, we performed a genome-wide screen using a library of DNA-barcoded yeast deletion mutants grown in copper-supplemented media. Our screen recovered a number of genes known to be involved in cellular copper homeostasis as well as genes previously not linked to mitochondrial copper biology. These newly identified genes include the subunits of the adaptor protein 3 complex (AP-3) and components of the cellular pH-sensing pathway Rim20 and Rim21, both of …

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Aaron T Griffin FAQs

What is Aaron T Griffin's h-index at Columbia University in the City of New York?

The h-index of Aaron T Griffin has been 6 since 2020 and 6 in total.

What are Aaron T Griffin's top articles?

The articles with the titles of

Discovery and validation of effective combination therapies targeting cell state-specific master regulator vulnerabilities by network-based protein activity inference in …

Elucidation and Pharmacologic Targeting of Master Regulator Dependencies in Coexisting Diffuse Midline Glioma Subpopulations

Abstract PR01: Identification and pharmacological targeting of treatment-resistant, stem-like breast cancer cells for combination therapy

Immunoproteasome expression and checkpoint blockade response in advanced non-small cell lung cancer

Network-based inference identifies cell state-specific drugs targeting master regulator vulnerabilities in diffuse midline glioma

NaRnEA: an information theoretic framework for gene set analysis

Network-based elucidation of colon cancer drug resistance by phosphoproteomic time-series analysis

DIPG-49. A SYSTEMS BIOLOGY APPROACH TO DEFINING AND TARGETING CELL STATE-SPECIFIC MASTER REGULATOR DEPENDENCIES IN DIFFUSE MIDLINE GLIOMA

...

are the top articles of Aaron T Griffin at Columbia University in the City of New York.

What are Aaron T Griffin's research interests?

The research interests of Aaron T Griffin are: Systems Biology, Cancer, Genomics, Bioinformatics

What is Aaron T Griffin's total number of citations?

Aaron T Griffin has 237 citations in total.

What are the co-authors of Aaron T Griffin?

The co-authors of Aaron T Griffin are Barry Honig, Andrea Califano, Kenneth P. Olive, Faiyaz Notta, Alina Iuga, Sherine Chan.

    Co-Authors

    H-index: 132
    Barry Honig

    Barry Honig

    Columbia University in the City of New York

    H-index: 91
    Andrea Califano

    Andrea Califano

    Columbia University in the City of New York

    H-index: 35
    Kenneth P. Olive

    Kenneth P. Olive

    Columbia University in the City of New York

    H-index: 34
    Faiyaz Notta

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