Pablo Tamayo

Pablo Tamayo
University of California, San Diego | UCSD · Department of Medicine

Ph.D. Statistical Physics

About

420
Publications
66,326
Reads
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105,612
Citations
Additional affiliations
May 1999 - present
Oracle Corporation
Position
  • Consulting Member of Technical Staff
December 1997 - present
Broad Institute of MIT and Harvard
Position
  • Sr. Computational Biologist
January 1996 - January 1999
Thinking Machines Corporation
Position
  • Principal Investigator
Education
August 1985 - May 1990
Boston University
Field of study
  • Physics
August 1979 - May 1984
Universidad Metropolitana
Field of study
  • Engineering Physics

Publications

Publications (420)
Article
Full-text available
Natural killer (NK) cells are known to mediate killing of various cancer types, but tumor cells can develop resistance mechanisms to escape NK cell-mediated killing. Here, we use a “two cell type” whole genome CRISPR-Cas9 screening system to discover key regulators of tumor sensitivity and resistance to NK cell-mediated cytotoxicity in human gliobl...
Preprint
Background Changes in microenvironment cell-cell interactions (CCI) during the progression from ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC) are poorly understood. Gene expression studies are confounded by cellular heterogeneity and few separate stromal and epithelial contributions, resulting in a lack of reliable prognostic b...
Preprint
Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. Still, inferring biological processes requires additional post hoc statistics and annotation for interpretation of features learned from software packages developed for NMF implementation. Here, we aim to introduce a suite of computati...
Article
In the study of human disease, the use of gene expression data has been crucial to the functional characterization of changes in molecular pathway activity and for identifying targets for novel treatments. However, the interpretation of this data is often complicated by its high dimensionality and the difficulty of identifying biological signals wi...
Article
As the availability of genomic data and analysis tools from large-scale cancer initiatives continues to increase, with single-cell studies adding new dimensions to the potential scientific insights, the need has become more urgent for a software environment that supports the rapid pace of cancer data science. The electronic analysis notebook has re...
Article
e16199 Background: Primary liver cancer is the third most frequent cause of cancer-related death worldwide, with hepatocellular carcinoma (HCC) composing 75% of cases. Recent preclinical models suggest that immunotherapy targeting programmed cell death protein 1 (PD-1) leads to CD8+ T-cell activation but not tumor regression in nonalcoholic fatty l...
Article
e16163 Background: While the incidence and rates of mortality are in decline for the vast majority of cancers, those of hepatocellular carcinoma (HCC) continue to increase. Forecasts from the Surveillance, Epidemiology, and End Results (SEER) database suggest that the Hispanic population will have the highest incidence rate of HCC in the United Sta...
Article
Introduction The homologous recombination repair (HRR) pathway is a frequently mutated pathway in advanced prostate cancer. The clinical course of patients with HRR gene alterations who have metastatic hormone sensitive prostate cancer (mHSPC) has not been fully characterized. Here, we examine the outcomes of men with mHSPC with HRR alterations. M...
Article
Background: The invasion of malignant cells into surrounding stroma is the histological hallmark differentiating invasive ductal carcinoma (IDC) from ductal carcinoma in situ (DCIS). The associated variations in the cellular composition and interactions in the tumor microenvironment, and how those mediate invasion are poorly understood. Systematic...
Article
389 Background: Hepatocellular carcinoma (HCC) is the most rapidly growing cause of cancer-related mortality in the United States. Recent preclinical studies suggest that immunotherapy agents targeted at programmed cell death protein 1 (PD-1) do not lead to tumor regression in HCC with underlying nonalcoholic steatohepatitis (NASH). However, furthe...
Article
Full-text available
Background CDK12 inactivation leading to increased neoantigen burden has been hypothesized to sensitize tumors to immune checkpoint inhibition. Pan-cancer data regarding the frequency of CDK12 alterations are limited. We aimed to characterize CDK12 alterations across all cancer types through real-world clinical-grade sequencing. Methods This was a...
Article
With an increasing number of patients with degenerative hepatic diseases such as liver fibrosis, and a limited supply of donor organs, there is an unmet need for therapies that can repair or regenerate damaged liver tissue. Treatment with macrophages that are capable of phagocytosis and anti-inflammatory activities such as secretion of matrix metal...
Article
Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by imatinib, a tyrosine kinase inhibitor (TKI). However, IM does not cure GIST and adjuvant therapy only delays recurrence in high-risk tumors. We hypothesized that GIST contains cells with primary imatinib resistance that may represent...
Article
The characterization of cancer genomes has provided insight into somatically altered genes across tumors, transformed our understanding of cancer biology, and enabled tailoring of therapeutic strategies. However, the function of most cancer alleles remains mysterious, and many cancer features transcend their genomes. Consequently, tumor genomic cha...
Article
Full-text available
MDSCs are immune cells of myeloid lineage that plays a key role in promoting tumor growth. The expansion of MDSCs in tumor-bearing hosts reduces the efficacy of checkpoint inhibitors and CAR-T therapies, and hence strategies that deplete or block the recruitment of MDSCs have shown benefit in improving responses to immunotherapy in various cancers,...
Article
Full-text available
In adult tissue, stem and progenitor cells must tightly regulate the balance between proliferation and differentiation to sustain homeostasis. How this exquisite balance is achieved is an area of active investigation. Here, we show that epidermal genes, including ~30% of induced differentiation genes already contain stalled Pol II at the promoters...
Article
Full-text available
Medulloblastoma is the most common malignant pediatric brain tumor. Tumors having high levels of c-MYC have the worst clinical prognosis, with only a minority of patients surviving. To address this unmet clinical need, we generated a human neural stem cell model of medulloblastoma that recapitulated the most aggressive subtype phenotypically and by...
Article
Background/aim: R-spondins control WNT signaling and RSPO1 and LGR6, two of its receptors, are uniquely expressed at high levels in high-grade serous ovarian cancer (HGSOC). The aim of this study was to assess the interrelations between the expression of the RSPOs and LGRs in HGSOC and in the ovarian surface (OSE) and fallopian tube surface epithe...
Article
Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensi...
Article
Full-text available
The dominant paradigm for HPV carcinogenesis includes integration into the host genome followed by expression of E6 and E7 (E6/E7). We explored an alternative carcinogenic pathway characterized by episomal E2, E4, and E5 (E2/E4/E5) expression. Half of HPV positive cervical and pharyngeal cancers comprised a subtype with increase in expression of E2...
Conference Paper
As the availability of genetic and genomic data and analysis tools from large-scale cancer initiatives continues to increase, with single-cell studies adding new dimensions to the potential scientific insights, the need has become more urgent for a software environment that supports the rapid pace of cancer data science. The electronic analysis not...
Conference Paper
Background: In all organisms, the ribosome performs the unique and essential function of translating mRNA into protein. Since deletion of any ribosomal protein (RP) is embryonic lethal in complex eukaryotes, the ribosome is believed to be structurally uniform throughout the organism, with all RPs essential for cell viability. Results: We tested the...
Conference Paper
YAP overactivation is an essential molecular event for cancer initiation and growth of most solid tumors, but pharmacologic targeting of the YAP or Hippo pathway has been proven to be challenging. In this regard, YAP activity is also required for stem and progenitor cell maintenance and function in multiple tissues, and as such, YAP is necessary fo...
Conference Paper
Background: Medulloblastoma is a heterogenous group of tumors that collectively are the most common malignant brain tumor of childhood. Advances in treatment are required as one third of patients die from the disease, and those who survive suffer severe long-term side effects from therapy. The ability to sequence entire genome, methylome, and trans...
Article
Full-text available
Hydrophobic neo‐antigens are more immunogenic because they are better presented by the major histocompatibility complex (MHC) and better recognized by T cells. Tumor cells can evade the immune response by expressing checkpoints such as PD‐L1. Checkpoint blockade reactivates immune recognition and can be effective in diseases such as melanoma, which...
Article
Full-text available
We give results from a detailed analysis of human Ribosomal Protein (RP) levels in normal and cancer samples and cell lines from large mRNA, copy number variation and ribosome profiling datasets. After normalizing total RP mRNA levels per sample, we find highly consistent tissue specific RP mRNA signatures in normal and tumor samples. Multiple RP m...
Article
e16617 Background: Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and has significant cancer-related mortality worldwide. Molecularly matched therapy has an emerging role in HCC treatment; however, HCC poses a unique challenge as patients are frequently diagnosed radiographically rather than by tissue biopsy, limi...
Article
In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition (EMT) and MAPK signaling. The...
Article
110 Background: Given the technical limitations of obtaining tissue next-generation sequencing, there has been interest in blood ctDNA to assess genomic alterations in mCRPC. We examined the genomic landscape and prognostic significance of ctDNA in mCRPC. Methods: Single center retrospective analysis of mCRPC patients who underwent ctDNA genomic pr...
Article
Full-text available
Macrophages (MΦ) play a critical role in tumor growth, immunosuppression and inhibition of adaptive immune responses in cancer. Hence, targeting signaling pathways in MΦs that promote tumor immunosuppression will provide therapeutic benefit. PI3Kγ has been recently established by our group and others as a novel immuno-oncology target. Herein, we re...
Article
Purpose: Human papilloma virus (HPV) related head and neck squamous cell carcinoma (HNSCC) is associated with daily marijuana use and is also increasing in parallel with increased marijuana use in the United States. Our study is designed to define the interaction between cannabinoids and HPV positive HNSCC. Experimental design: The expression of...
Article
Full-text available
Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to tr...
Preprint
Full-text available
Alterations involving serine-threonine phosphatase PP2A subunits occur in a range of human cancers and partial loss of PP2A function contributes to cell transformation. Displacement of regulatory B subunits by the SV40 Small T antigen (ST) or mutation/deletion of PP2A subunits alters the abundance and types of PP2A complexes in cells, leading to tr...
Article
Neuroblastoma is the most common extracranial solid tumor of childhood and accounts for 15% of all pediatric cancer-related deaths. New therapies are needed to improve outcomes for children with high-risk and relapsed tumors. Inhibitors of the RET kinase and the RAS-MAPK pathway have previously been shown to be effective against neuroblastoma, sugg...
Article
Recurrent mutations implicate several epigenetic regulators in the early molecular pathobiology of myelodysplastic syndromes (MDS). We hypothesized that MDS subtypes defined by DNA methylation (DNAm) patterns could enhance our understanding of MDS disease biology and identify patients with convergent epigenetic profiles. Bisulfite padlock probe seq...
Article
Full-text available
Cyclin E, a key cell cycle regulatory protein, has been linked to oncogenesis when dysregulated. We have previously shown that overexpression of cyclin E causes replication stress, leading to failure to complete replication at specific chromosomal loci during S phase of the cell cycle. This in turn promotes chromosomal damage during anaphase. Here...
Article
Full-text available
Metformin may reduce the progression of head and neck squamous cell carcinoma (HNSCC); however, whether metformin acts by altering the host metabolism or targets cancer-initiating cells remains poorly understood. This gap in knowledge has prevented the stratification of patient populations who are most likely to benefit from metformin treatment. He...
Conference Paper
INTRODUCTION: Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by Imatinib (IM). However, IM does not cure GIST; adjuvant therapy only delays recurrence in high-risk tumors. Therefore, we hypothesized that GIST contains cells with primary IM resistance, representing a critical target...
Conference Paper
INTRODUCTION: Gastrointestinal stromal tumor (GIST) is commonly driven by oncogenic KIT mutations that are effectively targeted by Imatinib (IM). However, IM does not cure GIST; adjuvant therapy only delays recurrence in high-risk tumors. Therefore, we hypothesized that GIST contains cells with primary IM resistance, representing a critical target...
Conference Paper
The molecular bases underlying neoadjuvant chemotherapy (NAC) response are poorly understood. To elucidate the effects of NAC on breast tumor biology and its association with clinical outcome, we have conducted WES and RNA-Seq profiling of a longitudinal breast cancer (BC) cohort consisting of 146 cases (281 tumors, 109 pairs), including 55 (38%) t...
Article
Full-text available
G protein–coupled receptors (GPCRs) are the largest gene family of cell membrane–associated molecules mediating signal transmission, and their involvement in key physiological functions is well established. The ability of GPCRs to regulate a vast array of fundamental biological processes, such as cardiovascular functions, immune responses, hormone...
Article
Full-text available
The original version of this Article contained an error in the author affiliations. Trey Ideker was incorrectly associated with ‘Department of Medicine (Oncology), Stanford University School of Medicine, 875 Blake Wilbur Dr, Palo Alto, CA 94304, USA.’ This has now been corrected in both the PDF and HTML versions of the Article.
Article
Full-text available
Although promoter-associated CpG islands have been established as targets of DNA methylation changes in cancer, previous studies suggest that epigenetic dysregulation outside the promoter region may be more closely associated with transcriptional changes. Here we examine DNA methylation, chromatin marks, and transcriptional alterations to define th...
Article
Full-text available
Despite recent advances in targeted drugs and immunotherapy, cancer remains "the emperor of all maladies" due to almost inevitable emergence of resistance. Drug resistance is thought to be driven by genetic alterations and/or dynamic plasticity that deregulate pathway activities and regulatory programs of a highly heterogeneous tumour. In this stud...
Article
Activating mutations in GNAQ/GNA11, encoding Gαq G proteins, are initiating oncogenic events in uveal melanoma (UM). However, there are no effective therapies for UM. Using an integrated bioinformatics pipeline, we found that PTK2, encoding focal adhesion kinase (FAK), represents a candidate synthetic lethal gene with GNAQ activation. We show that...
Article
Full-text available
Tumor-associated neo-antigens are mutated peptides that allow the immune system to recognize the affected cell as foreign. Cells carrying excessive mutation load often develop mechanisms of tolerance. PD-L1/PD-1 checkpoint immunotherapy is a highly promising approach to overcome these protective signals and induce tumor shrinkage. Yet, the nature o...
Article
Full-text available
Background: The translation of genomic discoveries to the clinic is the cornerstone of precision medicine. However, incorporating next generation sequencing (NGS) of hematologic malignancies into clinical management remains limited. Methods: We describe 235 patients who underwent integrated NGS profiling (406 genes) and analyze the alterations and...
Article
Full-text available
Signaling pathways are orchestrated by post-translational modifications (PTMs) such as phosphorylation. However, pathway analysis of PTM data sets generated by mass spectrometry (MS)-based proteomics is typically performed at a gene-centric level because of the lack of appropriately curated PTM signature databases and bioinformatic tools that lever...
Article
High-throughput single-cell gene expression profiling has enabled the definition of new cell types and developmental trajectories. Visualizing these datasets is crucial to biological interpretation, and a popular method is t-stochastic neighbor embedding (t-SNE), which visualizes local patterns well but distorts global structure, such as distances...
Article
Background: Recurrent somatic mutations in patients with myelodysplastic syndromes (MDS) implicate several epigenetic regulators in the molecular pathobiology of these disorders. We hypothesized that identification of MDS subtypes defined by DNA methylation patterns could improve prognostication and enhance our understanding of MDS disease biology....
Article
There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary...
Article
Full-text available
Despite extensive efforts, oncogenic KRAS remains resistant to targeted therapy. Combined downstream RAL-TBK1 and MEK inhibition induces only transient lung tumor shrinkage in KRAS-driven genetically engineered mouse models (GEMMs). Using the sensitive KRAS;LKB1 (KL) mutant background, we identify YAP1 upregulation and a therapy-induced secretome a...