Professor
+1 415 476-7781

Biography

Our goal is to identify novel therapeutic approaches for cancer that target the genetic mutations and altered signaling networks that are specific to cancer cells and their microenvironment. We use functional genomics applied to mouse and human systems (genetically engineered models, patient derived xenografts) to understand the signaling pathways and transcriptional networks that regulate the outcome of specific oncogenic mutations and to identify new approaches for cancer therapy. We have two primary disease interests: lung cancer and pediatric sarcomas. Our research spans the continuum from basic discovery to preclinical target development, done in a dynamic and interactive environment that is highly collaborative.

In our lung cancer work, we use functional genomic approaches to study how KRAS functions as an oncogene and to identify novel therapeutic opportunities. We performed one of the first mouse and human in vivo functional screens to identify WT1 loss as a synthetic vulnerability for KRAS-driven NSCLC (Vicent et al, 2010, JCI). More recently, we described a key role of oncogenic KRAS in regulation of the response to nutrient stress (Gwinn et al 2018, Cancer Cell). Through a multidisciplinary collaboration we have performed a high-throughput proteomic and genomics screen to characterize novel KRAS specific combinatorial vulnerabilities (Kelly, Kostyrko and Han, Cancer Discovery 2020). We are also interested in identifying and characterizing the role of tumor-propagating cells (also called cancer stem cells) in NSCLC. Using a combination of mouse and human systems, we identified a key role for Notch3 as a self-renewal pathway in mouse and human NSCLC (Zheng et al, 2013, Cancer Cell). We also have identified novel methods for targeting tumor-stroma interactions in lung cancer (Kim and Marquez et al, Nature Medicine, 2019). Ongoing projects are seeking to identify other KRAS specific vulnerabilities using 2D and 3D systems in both mouse and human. We are also using single-cell sequencing and other genomics approaches (ATACseq, etc) to study the role of TPCs in lung cancer.

In our sarcoma work, we study mechanisms driving Osteosarcoma and Ewing sarcoma metastatic progression and therapy resistance using in vivo patient-derived xenograft models. These two diseases provide an interesting contrast as clinically they are similar but from a genomic stand point they are quite distinct. We identified EWSAT1 as the first lncRNA involved in the pathogenesis of Ewing sarcoma (Howarth et al, JCI, 2014) and ongoing work is focused on understanding how lncRNAs regulate the oncogenic capacity of the EWS/FLI1 fusion. In osteosarcoma, we are performing translational studies to evaluate the use of targeted therapies for this disease and to understand mechanisms of metastatic progression using PDX and GEM models. Recently, we described how genomic analysis of osteosarcoma can help identify targeted therapies for this disease (Sayles and Breese et al, Cancer Discovery 2019). Our sarcoma work is facilitated by access to a large collection of patient-derived xenograft models and primary tumor samples which have been analyzed by Whole genome sequencing and RNAseq. We are using these models to explore the genomic evolution of sarcomas and define novel therapeutics that are informed by the alterations present in individual tumors.

We make extensive use of computational genomic approaches in our work and we have wide experience in generating and using next-generation sequencing data for gene and network discovery. We lead a multidisciplinary effort to apply next-generation sequencing (WGS/RNAseq etc.) to advance the care of relapsed and other high-risk pediatric cancer patients at UCSF/Benioff Children’s Hospitals (San Francisco and Oakland). To date, our laboratory has sequenced over 200 pediatric tumors by Whole Genome Sequencing and RNAseq. These datasets provide ample research opportunity for trainees interested in the intersection of cancer biology, functional genomics and computational biology. We have an active collaboration with the Genome Institute at the University of California Santa Cruz (D. Haussler and O. Vaske) to develop advance the care of relapsed and metastatic cancer patients using transcriptome analysis (Vaske et al JCI insight, 2019, Pfeil et al Plos Computational Biology, 2020).

Education and Training

MD, 1995 Medicine, University of California San Francisco
BS, 1989 Anthropology, Stanford University
BA, 1989 Biology, Stanford University

Publications

Levinson A, Lee AG, Martell HJ, Breese MR, Zaloudek C, Van Ziffle J, Laguna B, Leung SG, Chen MD, Chen LM, Pfeil J, Ladwig NR, Shah AT, Behroozfard I, Rao AA, Salama SR, Sweet-Cordero EA, Stieglitz E. Complete Response to PD-1 Inhibition in an Adolescent With Relapsed Clear Cell Adenocarcinoma of the Cervix Predicted by Neoepitope Burden and APOBEC Signature. JCO Precis Oncol. 2020; 4.
Kostyrko K, Sweet-Cordero EA. An Expanded Tool Kit for Modeling the Oncogenic Functions of KRAS. Cancer Discov. 2020 Nov; 10(11):1626-1628.
Hawkins C, Pfister S, Jones DTW, Shah NN, Gilbertson RJ, Sweet-Cordero EA, Dyer MA, Mossé YP, Haber M, DuBois SG. Advances and Challenges in Pediatric and Childhood Cancers. Cancer Cell. 2020 10 12; 38(4):429-432.
Broyde J, Simpson DR, Murray D, Paull EO, Chu BW, Tagore S, Jones SJ, Griffin AT, Giorgi FM, Lachmann A, Jackson P, Sweet-Cordero EA, Honig B, Califano A. Oncoprotein-specific molecular interaction maps (SigMaps) for cancer network analyses. Nat Biotechnol. 2021 02; 39(2):215-224.
Behnert A, Lee AG, Young EP, Breese MR, Leung SG, Behroozfard I, Maruffi M, Sweet-Cordero EA, Dvorak CC, Chu J, Stieglitz E. NUP98-NSD1 Driven MDS/MPN in Childhood Masquerading as JMML. J Pediatr Hematol Oncol. 2020 Aug 18.
Kelly MR, Kostyrko K, Han K, Mooney NA, Jeng EE, Spees K, Dinh PT, Abbott KL, Gwinn DM, Sweet-Cordero EA, Bassik MC, Jackson PK. Combined Proteomic and Genetic Interaction Mapping Reveals New RAS Effector Pathways and Susceptibilities. Cancer Discov. 2020 Dec; 10(12):1950-1967.
Kim JW, Marquez CP, Sperberg RAP, Wu J, Bae WG, Huang PS, Sweet-Cordero EA, Cochran JR. Engineering a potent receptor superagonist or antagonist from a novel IL-6 family cytokine ligand. Proc Natl Acad Sci U S A. 2020 06 23; 117(25):14110-14118.
Pfeil J, Sanders LM, Anastopoulos I, Lyle AG, Weinstein AS, Xue Y, Blair A, Beale HC, Lee A, Leung SG, Dinh PT, Shah AT, Breese MR, Devine WP, Bjork I, Salama SR, Sweet-Cordero EA, Haussler D, Vaske OM. Hydra: A mixture modeling framework for subtyping pediatric cancer cohorts using multimodal gene expression signatures. PLoS Comput Biol. 2020 04; 16(4):e1007753.
Valencia K, Erice O, Kostyrko K, Hausmann S, Guruceaga E, Tathireddy A, Flores NM, Sayles LC, Lee AG, Fragoso R, Sun TQ, Vallejo A, Roman M, Entrialgo-Cadierno R, Migueliz I, Razquin N, Fortes P, Lecanda F, Lu J, Ponz-Sarvise M, Chen CZ, Mazur PK, Sweet-Cordero EA, Vicent S. The Mir181ab1 cluster promotes KRAS-driven oncogenesis and progression in lung and pancreas. J Clin Invest. 2020 04 01; 130(4):1879-1895.
Han K, Pierce SE, Li A, Spees K, Anderson GR, Seoane JA, Lo YH, Dubreuil M, Olivas M, Kamber RA, Wainberg M, Kostyrko K, Kelly MR, Yousefi M, Simpkins SW, Yao D, Lee K, Kuo CJ, Jackson PK, Sweet-Cordero A, Kundaje A, Gentles AJ, Curtis C, Winslow MM, Bassik MC. CRISPR screens in cancer spheroids identify 3D growth-specific vulnerabilities. Nature. 2020 04; 580(7801):136-141.
Schott C, Shah AT, Sweet-Cordero EA. Genomic Complexity of Osteosarcoma and Its Implication for Preclinical and Clinical Targeted Therapies. Adv Exp Med Biol. 2020; 1258:1-19.
Kim JW, Marquez CP, Kostyrko K, Koehne AL, Marini K, Simpson DR, Lee AG, Leung SG, Sayles LC, Shrager J, Ferrer I, Paz-Ares L, Gephart MH, Vicent S, Cochran JR, Sweet-Cordero EA. Antitumor activity of an engineered decoy receptor targeting CLCF1-CNTFR signaling in lung adenocarcinoma. Nat Med. 2019 11; 25(11):1783-1795.
Sanders LM, Rangaswami A, Bjork I, Lam DL, Beale HC, Kephart ET, Durbin A, Learned K, Currie R, Lyle AG, Pfeil J, Shah AT, Lee AG, Leung SG, Behroozfard IH, Breese MR, Peralez J, Hazard FK, Lacayo N, Spunt SL, Haussler D, Salama SR, Sweet-Cordero EA, Vaske OM. Comparative RNA-seq analysis aids in diagnosis of a rare pediatric tumor. Cold Spring Harb Mol Case Stud. 2019 10; 5(5).
Fernandez KS, Turski ML, Shah AT, Bastian BC, Horvai A, Hardee S, Sweet-Cordero EA. Ewing sarcoma in a child with neurofibromatosis type 1. Cold Spring Harb Mol Case Stud. 2019 10; 5(5).
Vaske OM, Bjork I, Salama SR, Beale H, Tayi Shah A, Sanders L, Pfeil J, Lam DL, Learned K, Durbin A, Kephart ET, Currie R, Newton Y, Swatloski T, McColl D, Vivian J, Zhu J, Lee AG, Leung SG, Spillinger A, Liu HY, Liang WS, Byron SA, Berens ME, Resnick AC, Lacayo N, Spunt SL, Rangaswami A, Huynh V, Torno L, Plant A, Kirov I, Zabokrtsky KB, Rassekh SR, Deyell RJ, Laskin J, Marra MA, Sender LS, Mueller S, Sweet-Cordero EA, Goldstein TC, Haussler D. Comparative Tumor RNA Sequencing Analysis for Difficult-to-Treat Pediatric and Young Adult Patients With Cancer. JAMA Netw Open. 2019 10 02; 2(10):e1913968.
Chao AK, Meyer JA, Lee AG, Hecht A, Tarver T, Van Ziffle J, Koegel AK, Golden C, Braun BS, Sweet-Cordero EA, Smith CC, Dvorak CC, Loh ML, Stieglitz E. Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing. Leukemia. 2020 02; 34(2):662-666.
Roberts RD, Lizardo MM, Reed DR, Hingorani P, Glover J, Allen-Rhoades W, Fan T, Khanna C, Sweet-Cordero EA, Cash T, Bishop MW, Hegde M, Sertil AR, Koelsche C, Mirabello L, Malkin D, Sorensen PH, Meltzer PS, Janeway KA, Gorlick R, Crompton BD. Provocative questions in osteosarcoma basic and translational biology: A report from the Children's Oncology Group. Cancer. 2019 10 15; 125(20):3514-3525.
Ren Y, Huang S, Dai C, Xie D, Zheng L, Xie H, Zheng H, She Y, Zhou F, Wang Y, Li P, Fei K, Jiang G, Zhang Y, Su B, Sweet-Cordero EA, Tran NL, Yang Y, Patel JN, Rolfo C, Rocco G, Cardona AF, Tuzi A, Suter MB, Yang P, Xu W, Chen C. Germline Predisposition and Copy Number Alteration in Pre-stage Lung Adenocarcinomas Presenting as Ground-Glass Nodules. Front Oncol. 2019; 9:288.
Sweet-Cordero EA, Biegel JA. The genomic landscape of pediatric cancers: Implications for diagnosis and treatment. Science. 2019 03 15; 363(6432):1170-1175.
Sayles LC, Breese MR, Koehne AL, Leung SG, Lee AG, Liu HY, Spillinger A, Shah AT, Tanasa B, Straessler K, Hazard FK, Spunt SL, Marina N, Kim GE, Cho SJ, Avedian RS, Mohler DG, Kim MO, DuBois SG, Hawkins DS, Sweet-Cordero EA. Genome-Informed Targeted Therapy for Osteosarcoma. Cancer Discov. 2019 01; 9(1):46-63.
Marini KD, Croucher DR, McCloy RA, Vaghjiani V, Gonzalez-Rajal A, Hastings JF, Chin V, Szczepny A, Kostyrko K, Marquez C, Jayasekara WSN, Alamgeer M, Boolell V, Han JZR, Waugh T, Lee HC, Oakes SR, Kumar B, Harrison CA, Hedger MP, Lorensuhewa N, Kita B, Barrow R, Robinson BW, de Kretser DM, Wu J, Ganju V, Sweet-Cordero EA, Burgess A, Martelotto LG, Rossello FJ, Cain JE, Watkins DN. Inhibition of activin signaling in lung adenocarcinoma increases the therapeutic index of platinum chemotherapy. Sci Transl Med. 2018 07 25; 10(451).
Gwinn DM, Lee AG, Briones-Martin-Del-Campo M, Conn CS, Simpson DR, Scott AI, Le A, Cowan TM, Ruggero D, Sweet-Cordero EA. Oncogenic KRAS Regulates Amino Acid Homeostasis and Asparagine Biosynthesis via ATF4 and Alters Sensitivity to L-Asparaginase. Cancer Cell. 2018 01 08; 33(1):91-107.e6.
Hsieh G, Bierman R, Szabo L, Lee AG, Freeman DE, Watson N, Sweet-Cordero EA, Salzman J. Statistical algorithms improve accuracy of gene fusion detection. Nucleic Acids Res. 2017 Jul 27; 45(13):e126.
Alvarez E, Seppa M, Rivas S, Fuentes L, Valverde P, Antillón-Klussmann F, Castellanos M, Sweet-Cordero EA, Messacar K, Kurap J, Bustamante M, Howard SC, Efron B, Luna-Fineman S. Improvement in treatment abandonment in pediatric patients with cancer in Guatemala. Pediatr Blood Cancer. 2017 Oct; 64(10).
Vallejo A, Perurena N, Guruceaga E, Mazur PK, Martinez-Canarias S, Zandueta C, Valencia K, Arricibita A, Gwinn D, Sayles LC, Chuang CH, Guembe L, Bailey P, Chang DK, Biankin A, Ponz-Sarvise M, Andersen JB, Khatri P, Bozec A, Sweet-Cordero EA, Sage J, Lecanda F, Vicent S. An integrative approach unveils FOSL1 as an oncogene vulnerability in KRAS-driven lung and pancreatic cancer. Nat Commun. 2017 02 21; 8:14294.
Chuang CH, Greenside PG, Rogers ZN, Brady JJ, Yang D, Ma RK, Caswell DR, Chiou SH, Winters AF, Grüner BM, Ramaswami G, Spencley AL, Kopecky KE, Sayles LC, Sweet-Cordero EA, Li JB, Kundaje A, Winslow MM. Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis. Nat Med. 2017 Mar; 23(3):291-300.
Brady JJ, Chuang CH, Greenside PG, Rogers ZN, Murray CW, Caswell DR, Hartmann U, Connolly AJ, Sweet-Cordero EA, Kundaje A, Winslow MM. An Arntl2-Driven Secretome Enables Lung Adenocarcinoma Metastatic Self-Sufficiency. Cancer Cell. 2016 05 09; 29(5):697-710.
Mazur PK, Herner A, Mello SS, Wirth M, Hausmann S, Sánchez-Rivera FJ, Lofgren SM, Kuschma T, Hahn SA, Vangala D, Trajkovic-Arsic M, Gupta A, Heid I, Noël PB, Braren R, Erkan M, Kleeff J, Sipos B, Sayles LC, Heikenwalder M, Heßmann E, Ellenrieder V, Esposito I, Jacks T, Bradner JE, Khatri P, Sweet-Cordero EA, Attardi LD, Schmid RM, Schneider G, Sage J, Siveke JT. Combined inhibition of BET family proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma. Nat Med. 2015 Oct; 21(10):1163-71.
Marques Howarth M, Simpson D, Ngok SP, Nieves B, Chen R, Siprashvili Z, Vaka D, Breese MR, Crompton BD, Alexe G, Hawkins DS, Jacobson D, Brunner AL, West R, Mora J, Stegmaier K, Khavari P, Sweet-Cordero EA. Long noncoding RNA EWSAT1-mediated gene repression facilitates Ewing sarcoma oncogenesis. J Clin Invest. 2014 Dec; 124(12):5275-90.
Chen R, Khatri P, Mazur PK, Polin M, Zheng Y, Vaka D, Hoang CD, Shrager J, Xu Y, Vicent S, Butte AJ, Sweet-Cordero EA. A meta-analysis of lung cancer gene expression identifies PTK7 as a survival gene in lung adenocarcinoma. Cancer Res. 2014 May 15; 74(10):2892-902.
Valdmanis PN, Roy-Chaudhuri B, Kim HK, Sayles LC, Zheng Y, Chuang CH, Caswell DR, Chu K, Zhang Y, Winslow MM, Sweet-Cordero EA, Kay MA. Upregulation of the microRNA cluster at the Dlk1-Dio3 locus in lung adenocarcinoma. Oncogene. 2015 Jan 02; 34(1):94-103.
Zheng Y, de la Cruz CC, Sayles LC, Alleyne-Chin C, Vaka D, Knaak TD, Bigos M, Xu Y, Hoang CD, Shrager JB, Fehling HJ, French D, Forrest W, Jiang Z, Carano RA, Barck KH, Jackson EL, Sweet-Cordero EA. A rare population of CD24(+)ITGB4(+)Notch(hi) cells drives tumor propagation in NSCLC and requires Notch3 for self-renewal. Cancer Cell. 2013 Jul 08; 24(1):59-74.
Chen R, Sweet-Cordero EA. Two is better than one: combining IGF1R and MEK blockade as a promising novel treatment strategy against KRAS-mutant lung cancer. Cancer Discov. 2013 May; 3(5):491-3.
Gwinn D, Sweet-Cordero EA. The phosphatase PP2A links glutamine to the tumor suppressor p53. Mol Cell. 2013 Apr 25; 50(2):157-8.
Zheng Y, Moore H, Piryatinska A, Solis T, Sweet-Cordero EA. Mathematical modeling of tumor cell proliferation kinetics and label retention in a mouse model of lung cancer. Cancer Res. 2013 Jun 15; 73(12):3525-33.
Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, Ross S, Goldenberg D, Merchant M, Tien J, Shao L, Roth L, Tsai SP, Stawicki S, Jin Z, Wyatt SK, Carano RA, Zheng Y, Sweet-Cordero EA, Wu Y, Jackson EL. Blocking NRG1 and other ligand-mediated Her4 signaling enhances the magnitude and duration of the chemotherapeutic response of non-small cell lung cancer. Sci Transl Med. 2013 Feb 06; 5(171):171ra18.
Hegde GV, de la Cruz C, Eastham-Anderson J, Zheng Y, Sweet-Cordero EA, Jackson EL. Residual tumor cells that drive disease relapse after chemotherapy do not have enhanced tumor initiating capacity. PLoS One. 2012; 7(10):e45647.
Vicent S, Sayles LC, Vaka D, Khatri P, Gevaert O, Chen R, Zheng Y, Gillespie AK, Clarke N, Xu Y, Shrager J, Hoang CD, Plevritis S, Butte AJ, Sweet-Cordero EA. Cross-species functional analysis of cancer-associated fibroblasts identifies a critical role for CLCF1 and IL-6 in non-small cell lung cancer in vivo. Cancer Res. 2012 Nov 15; 72(22):5744-56.
Vicent S, Chen R, Sayles LC, Lin C, Walker RG, Gillespie AK, Subramanian A, Hinkle G, Yang X, Saif S, Root DE, Huff V, Hahn WC, Sweet-Cordero EA. Wilms tumor 1 (WT1) regulates KRAS-driven oncogenesis and senescence in mouse and human models. J Clin Invest. 2010 Nov; 120(11):3940-52.
Schaffer BE, Park KS, Yiu G, Conklin JF, Lin C, Burkhart DL, Karnezis AN, Sweet-Cordero EA, Sage J. Loss of p130 accelerates tumor development in a mouse model for human small-cell lung carcinoma. Cancer Res. 2010 May 15; 70(10):3877-83.
Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, Cheng MH, Subramanian A, Mu D, Powers S, Crowley D, Bronson RT, Whittaker CA, Bhutkar A, Lippard SJ, Golub T, Thomale J, Jacks T, Sweet-Cordero EA. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. 2010 Apr 15; 24(8):837-52.
Sweet-Cordero A, Tseng GC, You H, Douglass M, Huey B, Albertson D, Jacks T. Comparison of gene expression and DNA copy number changes in a murine model of lung cancer. Genes Chromosomes Cancer. 2006 Apr; 45(4):338-48.
Sweet-Cordero A, Mukherjee S, Subramanian A, You H, Roix JJ, Ladd-Acosta C, Mesirov J, Golub TR, Jacks T. An oncogenic KRAS2 expression signature identified by cross-species gene-expression analysis. Nat Genet. 2005 Jan; 37(1):48-55.