Pablo Tamayo

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

Ph.D. Statistical Physics

About

454
Publications
88,603
Reads
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139,397
Citations
Additional affiliations
May 1999 - August 2015
Oracle Corporation
Position
  • Consulting Member of Technical Staff
December 1997 - August 2015
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 (454)
Article
Full-text available
Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo, however, remains elusive. Here we employ spatiotemporally controlled oncogene activation and tumor suppressor inhibition together with multiomics to unveil the processe...
Article
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers; thus, identifying more effective therapies is a major unmet need. In this study, we characterized the super enhancer (SE) landscape of human PDAC to identify drivers of the disease that might be targetable. This analysis revealed MICAL2 as a super enhancer-associate...
Preprint
Full-text available
Gene set enrichment methods measure biological process or pathway activation in gene expression data by testing coordinate up- or down-regulation of pathway members in a ranked list of genes. These methods rely on curated, annotated gene sets whose members' coordinate expression is an indicator of a process or state. We therefore developed the Mole...
Article
Full-text available
Circular RNA (circRNA) is covalently closed, single-stranded RNA produced by back-splicing. A few circRNAs have been implicated as functional; however, we lack understanding of pathways that are regulated by circRNAs. Here we generated a pooled short-hairpin RNA library targeting the back-splice junction of 3,354 human circRNAs that are expressed a...
Preprint
Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid cancers and thus identifying more effective therapies is a major unmet need. In this study we characterized the super enhancer (SE) landscape of human PDAC to identify novel, potentially targetable, drivers of the disease. Our analysis revealed that MICAL2 is a super enhance...
Article
BACKGROUND Comprehensive molecular characterization of pediatric brain tumors has led to a more refined diagnosis. However, the feasibility of performing multi-omic and functional precision medicine approaches using ex-vivo drug screening in the clinical setting is unknown. METHODS Patients with newly diagnosed or recurrent central nervous system...
Preprint
Full-text available
Gene Set Enrichment Analysis (GSEA) is a method for quantifying pathway and process activation in groups of samples, and its single sample version (ssGSEA) scores activation using mRNA abundance in a single sample. GSEA and ssGSEA were developed for bulk samples rather than individual cell technologies such as microarrays and bulk RNA-sequencing (R...
Article
The ability to measure tumor evolution is difficult due to a lack of model systems able to capture tumor initiation, development, and invasion. We have developed a Dox-inducible spatiotemporally controlled HPV- and YAP-driven model of head and neck squamous cell carcinoma (HNSCC) with a well-defined cancer stem cell population. In order to better u...
Article
Full-text available
Introduction Most patients with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) have an excellent response to chemoradiation, and trials are now investigating de-escalated treatment. However, up to 25% of patients with HPV-positive OPSCC will experience recurrence, and up to 5% will even progress through primary treatment. Currently, the...
Article
534 Background: With numerous advances in systemic therapy for advanced hepatocellular carcinoma (HCC) over the past several years, there are now multiple first-line treatment options which can be considered. These options include combination atezolizumab with bevacizumab (atezo/bev), programmed cell death protein 1/programmed death ligand 1 (PD-1/...
Article
Non-negative matrix factorization (NMF) is an unsupervised learning method well suited to high-throughput biology. However, inferring biological processes from an NMF result still requires additional post hoc statistics and annotation for interpretation of learned features. Here, we introduce a suite of computational tools that implement NMF and pr...
Preprint
Full-text available
Cancer genome data has been growing in both size and complexity, primarily driven by advances in next-generation sequencing technologies, such as Pan-cancer data from TCGA, ICGC, and single-cell sequencing. Yet, discerning the functional role of individual genomic lesions remains a substantial challenge due to the complexity and scale of the data....
Article
Full-text available
We have previously identified alveolar type II cell as the cell-of-origin of KrasG12D-induced lung adenocarcinoma using cell lineage–specific inducible Cre mouse models. Using gain-of-function and loss-of-function genetic models, we discovered that active Notch signaling and low Sox2 levels dictate the ability of type II cells to proliferate and pr...
Preprint
Full-text available
Tumor initiation represents the first step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Capturing this process as it occurs in vivo , however, remains elusive. Here we employ cell tracing approaches with spatiotemporally controlled oncogene activation and tumor suppressor inhibition to unveil the pro...
Article
Human papillomavirus-positive head and neck squamous cell carcinoma (HPV+HNSC) constitutes the most common HPV-driven malignancy in the United States, and yet the molecular and cellular mechanisms underlying carcinogenesis in HPV+HNSC remain poorly understood. The decades long latency period and incomplete penetrance linking oral HPV infection to H...
Article
Background: There is a paucity of data concerning molecular heterogeneity among glottic squamous cell carcinoma, and the clinical implications thereof. Methods: Data corresponding to glottic squamous cell carcinoma were derived from The Cancer Genome Atlas. The Onco-GPS computational methodology was levied to derive four patterns of transcriptio...
Article
β-arrestins play a key role in G protein–coupled receptor (GPCR) internalization, trafficking, and signaling. Whether β-arrestins act independently of G protein–mediated signaling has not been fully elucidated. Studies using genome-editing approaches revealed that whereas G proteins are essential for mitogen-activated protein kinase activation by G...
Preprint
Tumor initiation represents the initial step in tumorigenesis during which normal progenitor cells undergo cell fate transition to cancer. Most studies investigating cancer-driving mechanisms in solid tumors rely on analyses of established malignant lesions, and thus cannot directly capture processes underlying the reprogramming of normal progenito...
Article
Full-text available
Pancreatic ductal adenocarcinoma (PDAC) is an insidious disease with a low 5-year survival rate. PDAC is characterized by infiltration of abundant tumor-associated macrophages (TAM), which promote immune tolerance and immunotherapeutic resistance. Here we report that macrophage spleen tyrosine kinase (Syk) promotes PDAC growth and metastasis. In or...
Article
Full-text available
Background Neuroblastoma (NB) is considered an immunologically cold tumor and is usually less responsive to immune checkpoint blockade (ICB). Tumor-associated macrophages (TAMs) are highly infiltrated in NB tumors and promote immune escape and resistance to ICB. Hence therapeutic strategies targeting immunosuppressive TAMs can improve responses to...
Article
5022 Background: Advances in immunotherapy have had little impact in prostate cancer (PCA). We have previously examined the immune microenvironment in both localized and metastatic PCA and found that primary PCA shows local inflammation/adaptive immunity whereas metastatic disease shows a shift towards immune suppression (Deichaite, 2022). Herein,...
Article
Full-text available
Cell-cycle control is accomplished by cyclin-dependent kinases (CDKs), motivating extensive research into CDK targeting small-molecule drugs as cancer therapeutics. Here we use combinatorial CRISPR/Cas9 perturbations to uncover an extensive network of functional interdependencies among CDKs and related factors, identifying 43 synthetic-lethal and 1...
Article
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 complicated by its high dimensionality and the difficulty of identifying biological signals within a list of differentially express...
Article
Neuroblastoma (NB) is the most common extracranial solid malignancy in children. As leading regulators of inflammation and tumor progression, tumor associated macrophages (TAMs) have gained major interest as immunotherapeutic targets in NB. Hence targeting or “re-educating” tumorigenic macrophages towards an immunostimulatory phenotype might improv...
Article
589 Background: The treatment landscape of advanced hepatocellular carcinoma (HCC) has made significant advances with the use of oral multikinase inhibitors and immunotherapy-containing regimens. However, there is minimal data with regards to which biomarkers may predict treatment responses in this population. The increased use of next-generation s...
Article
Full-text available
Background: Men of African ancestry have disproportionately high incidence rates of prostate cancer (PCa) and have high mortality rates. While there is evidence for a higher genetic predisposition for incidence of PCa in men of African ancestry compared to men of European ancestry, there have been few transcriptomic studies on PCa in men of Africa...
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...
Article
Full-text available
Background The role of the inflammatory milieu in prostate cancer progression is not well understood. Differences in inflammatory signaling between localized and metastatic disease may point to opportunities for early intervention. Methods We modeled PCa disease progression by analyzing RNA-seq of localized vs. metastatic patient samples, followed...
Article
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 complicated by its high dimensionality and the difficulty of identifying biological signals within a list of differentially express...
Preprint
Full-text available
Circular RNAs (circRNAs) are covalently closed single stranded RNAs that are produced by RNA back-splicing. A small number of circRNAs have been implicated as functional, however, we still lack systematic understanding of cellular processes and signalling pathways that are regulated by circRNAs. A major gap, in understanding circRNAs functions is t...
Preprint
Full-text available
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
Full-text available
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 and MAPK signaling. These dat...
Article
As one of the most frequently mutated oncogenes, mutant RAS has been well established to drive proliferative cell programs that are exploited by cancer. Interestingly, RAS , like many oncogenes, has been found in benign tumors that never progress to cancer. Although seemingly counterintuitive, RAS mutant tumors require an additional mutational insu...
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
Full-text available
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
Key Points Targeted DNAm profiling of MDS patient bone marrow mononuclear cells identifies several distinct DNAm clusters. Clusters enrich for specific genetic lesions and show differences in survival independent of clinical prognostic scoring systems..
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...