Howard Y. Chang

Clinical Focus

• Dermatology

Administrative Appointments

• Program Committee, Cancer Biology , (2005– present )

Honors and Awards

• Elected Member, American Society for Clinical Investigation (2009)
• Vilcek Prize for Creative Promise, Vilcek Foundation (2009)
• New Faculty Award, California Institute for Regenerative Medicine (2008-2013)
• Research Scholar Award, American Cancer Society (2007-2010)
• Scholar Award, Damon Runyon Cancer Research Foundation (2006-2008)
• Clinical Scientist Career Development Award (K08), NIH (2004-2009)
• Physician-Scientist Career Development Award, Dermatology Foundation (2004)
• Young Investigator Award, American Academy of Dermatology (2003)

Professional Education

• Board Certification: Dermatology, American Board of Dermatology (2004)
• SUMC - Graduate Medical Education (2004) CA
• SUMC - Graduate Medical Education (2003) CA
• Santa Clara Valley Medical Center (2001) CA USA
• Harvard Medical School (2000) MA
• M.D., Harvard Medical School Medicine (2000)
• Ph.D., MIT Biology (1998)
• A.B., Harvard Biochemistry (1994)

Postdoctoral Advisees

• Rajnish Gupta, Miao-Chih Tsai, David Wong

Graduate & Fellowship Program Affiliations

• Cancer Biology
• Dermatology

Web Site Links

• Chang Lab, Stanford University

Research Interests

We are interested in two fundamental questions in epithelial biology: (1) the basis of positional identities in epidermal structures throughout the body, and (2) how those signals and boundaries may be abrogated to allow cancer metastasis. Although site-specific differences in epidermal structures (such as hairs on skin) on different anatomic sites are easily appreciated and are the basis of many diagnostic and treatment strategies in skin diseases, embryologic transplantation experiments have demonstrated that it is the underlying mesenchymal stroma that dictates the epithelial fates that develop. We have begun to define the organizational and developmental principles of stromal cells based on their global gene expression programs. For example, we discovered that endothelial cell (EC) diversity is primarily dictated by the vessel size of origin, and the Notch-Hey2 and left-right polarity signaling axis help to specify artery vs. vein fate. In contrast, fibroblasts from each anatomic site exhibit systematic and characteristic differences in gene expression and retain the embryonic anatomic expression pattern of Hox genes. Fibroblasts are thus excellent candidates as the bearer of positional memory in tissues and organs.

The unanticipated diversity and precision of fibroblast differentiation suggest much richer roles for stroma cells during development and diverse disease processes. Taking advantage of the unique capacities of skin for primary cell culture, gene transfer, and tissue reconstitution of site-specific features, we are pursuing the mechanisms by which the Hox code in fibroblasts specify epidermal fates, and how the embryonic Hox code is maintained in isolated adult fibroblasts.

In contrast to the orderly acquisition of positional identities in development, cancer cells can abrogate and override the positional cues in tissues and organs as they metastasize. We discovered that one way that cancer cells may accomplish this feat is by activation of an emergency “wound healing” program. The conserved genomic response of fibroblasts to serum is a wound-like gene expression signature that allows one to visualize the wound-like features in cancer samples. The genes that comprise the wound healing program include those that activate matrix synthesis, cell migration, angiogenesis, and cell survival—ideal genetic tools for cancer invasion and metastasis. We found that the wound signature is a universal and powerful prognostic predictor of metastasis in many human tumors. The wound signature thus presents previously unappreciated avenues for cancer diagnosis and therapy.

We are using a combination of computational modeling, functional genomics, molecular genetics, and animal models to dissect the wound signature. We seek to identify upstream regulators that turn on the wound-like program in cancers, the key effector genes that enhance metastasis, and how their actions can be blocked therapeutically. We are also investigating practical strategies for applying and interpreting the wound signature in real life clinical scenarios.

Publications

• SIRT6 links histone H3 lysine 9 deacetylation to NF-kappaB-dependent gene expression and organismal life span. Kawahara TL,  Michishita E, Adler AS, Damian M, Berber E, Lin M, McCord RA, Ongaigui KC, Boxer LD, Chang HY, Chua KF.  Cell.  2009; 136 (1): 62-74
• Module map of stem cell genes guides creation of epithelial cancer stem cells. Wong DJ,  Liu H, Ridky TW, Cassarino D, Segal E, Chang HY.  Cell Stem Cell.  2008; 2 (4): 333-44
• A dermal HOX transcriptional program regulates site-specific epidermal fate. Rinn JL,  Wang JK, Allen N, Brugmann SA, Mikels AJ, Liu H, Ridky TW, Stadler HS, Nusse R, Helms JA, Chang HY.  Genes Dev.  2008; 22 (3): 303-7
• Functional demarcation of active and silent chromatin domains in human HOX loci by noncoding RNAs. Rinn JL,  Kertesz M, Wang JK, Squazzo SL, Xu X, Brugmann SA, Goodnough LH, Helms JA, Farnham PJ, Segal E, Chang HY.  Cell.  2007; 129 (7): 1311-23
• Genetic regulators of large-scale transcriptional signatures in cancer. Adler AS,  Lin M, Horlings H, Nuyten DS, van de Vijver MJ, Chang HY.  Nat Genet.  2006; 38 (4): 421-30
• Tumor vasculature is regulated by PHD2-mediated angiogenesis and bone marrow-derived cell recruitment. Chan DA,  Kawahara TL, Sutphin PD, Chang HY, Chi JT, Giaccia AJ.  Cancer Cell.  2009; 15 (6): 527-38
• Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression. Reuter JA,  Ortiz-Urda S, Kretz M, Garcia J, Scholl FA, Pasmooij AM, Cassarino D, Chang HY, Khavari PA.  Cancer Cell.  2009; 15 (6): 477-88
• Genome-wide views of chromatin structure. Rando OJ,  Chang HY.  Annu Rev Biochem.  2009; 78 245-71
• Gene dates, parties and galas. Symposium on Chromatin Dynamics and Higher Order Organization. Chang HY,  Cuvier O, Dekker J.  EMBO Rep.  2009; 10 (7): 689-93
• Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Chan KS,  Espinosa I, Chao M, Wong D, Ailles L, Diehn M, Gill H, Presti J, Chang HY, van de Rijn M, Shortliffe L, Weissman IL.  Proc Natl Acad Sci U S A.  2009; 106 (33): 14016-21
• Molecular framework for response to imatinib mesylate in systemic sclerosis. Chung L,  Fiorentino DF, Benbarak MJ, Adler AS, Mariano MM, Paniagua RT, Milano A, Connolly MK, Ratiner BD, Wiskocil RL, Whitfield ML, Chang HY, Robinson WH.  Arthritis Rheum.  2009; 60 (2): 584-91
• ING4 mediates crosstalk between histone H3 K4 trimethylation and H3 acetylation to attenuate cellular transformation. Hung T,  Binda O, Champagne KS, Kuo AJ, Johnson K, Chang HY, Simon MD, Kutateladze TG, Gozani O.  Mol Cell.  2009; 33 (2): 248-56
• Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Somervaille TC,  Matheny CJ, Spencer GJ, Iwasaki M, Rinn JL, Witten DM, Chang HY, Shurtleff SA, Downing JR, Cleary ML.  Cell Stem Cell.  2009; 4 (2): 129-40
• Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Wang KC,  Helms JA, Chang HY.  Trends Cell Biol.  2009; 19 (6): 268-75
• Global expression profiling in atopic eczema reveals reciprocal expression of inflammatory and lipid genes. Sääf AM,  Tengvall-Linder M, Chang HY, Adler AS, Wahlgren CF, Scheynius A, Nordenskjöld M, Bradley M.  PLoS One.  2008; 3 (12): e4017
• Stemness, cancer and cancer stem cells. Wong DJ,  Segal E, Chang HY.  Cell Cycle.  2008; 7 (23): 3622-4
• Control of differentiation in a self-renewing mammalian tissue by the histone demethylase JMJD3. Sen GL,  Webster DE, Barragan DI, Chang HY, Khavari PA.  Genes Dev.  2008; 22 (14): 1865-70
• Mechanisms of an autoimmunity syndrome in mice caused by a dominant mutation in Aire. Su MA,  Giang K, Zumer K, Jiang H, Oven I, Rinn JL, Devoss JJ, Johannes KP, Lu W, Gardner J, Chang A, Bubulya P, Chang HY, Peterlin BM, Anderson MS.  J Clin Invest.  2008; 118 (5): 1712-26
• CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression. Adler AS,  Littlepage LE, Lin M, Kawahara TL, Wong DJ, Werb Z, Chang HY.  Cancer Res.  2008; 68 (2): 506-15
• Combining biological gene expression signatures in predicting outcome in breast cancer: An alternative to supervised classification. Nuyten DS,  Hastie T, Chi JT, Chang HY, van de Vijver MJ.  Eur J Cancer.  2008; 44 (15): 2319-29
• A systems biology approach to anatomic diversity of skin. Rinn JL,  Wang JK, Liu H, Montgomery K, van de Rijn M, Chang HY.  J Invest Dermatol.  2008; 128 (4): 776-82
• Revealing targeted therapy for human cancer by gene module maps. Wong DJ,  Nuyten DS, Regev A, Lin M, Adler AS, Segal E, van de Vijver MJ, Chang HY.  Cancer Res.  2008; 68 (2): 369-78
• Deletional tolerance mediated by extrathymic Aire-expressing cells. Gardner JM,  Devoss JJ, Friedman RS, Wong DJ, Tan YX, Zhou X, Johannes KP, Su MA, Chang HY, Krummel MF, Anderson MS.  Science.  2008; 321 (5890): 843-7
• Systematic functional characterization of cis-regulatory motifs in human core promoters. Sinha S,  Adler AS, Field Y, Chang HY, Segal E.  Genome Res.  2008; 18 (3): 477-88
• Reversal of aging by NFkappaB blockade. Adler AS,  Kawahara TL, Segal E, Chang HY.  Cell Cycle.  2008; 7 (5): 556-9
• SIRT6 is a histone H3 lysine 9 deacetylase that modulates telomeric chromatin. Michishita E,  McCord RA, Berber E, Kioi M, Padilla-Nash H, Damian M, Cheung P, Kusumoto R, Kawahara TL, Barrett JC, Chang HY, Bohr VA, Ried T, Gozani O, Chua KF.  Nature.  2008; 452 (7186): 492-6
• Motif module map reveals enforcement of aging by continual NF-kappaB activity. Adler AS,  Sinha S, Kawahara TL, Zhang JY, Segal E, Chang HY.  Genes Dev.  2007; 21 (24): 3244-57
• A histone H3 lysine 27 demethylase regulates animal posterior development. Lan F,  Bayliss PE, Rinn JL, Whetstine JR, Wang JK, Chen S, Iwase S, Alpatov R, Issaeva I, Canaani E, Roberts TM, Chang HY, Shi Y.  Nature.  2007; 449 (7163): 689-94
• Turning skin into embryonic stem cells. Chang HY,  Cotsarelis G.  Nat Med.  2007; 13 (7): 783-4
• Genome-wide analysis of KAP1 binding suggests autoregulation of KRAB-ZNFs. O'Geen H,  Squazzo SL, Iyengar S, Blahnik K, Rinn JL, Chang HY, Green R, Farnham PJ.  PLoS Genet.  2007; 3 (6): e89
• GSK3 beta mediates suppression of cyclin D2 expression by tumor suppressor PTEN. Huang W,  Chang HY, Fei T, Wu H, Chen YG.  Oncogene.  2007; 26 (17): 2471-82
• Patterning skin pigmentation via dickkopf. Chang HY,  J Invest Dermatol.  2007; 127 (5): 994-5
• A transcriptional program mediating entry into cellular quiescence. Liu H,  Adler AS, Segal E, Chang HY.  PLoS Genet.  2007; 3 (6): e91
• Decoding global gene expression programs in liver cancer by noninvasive imaging. Segal E,  Sirlin CB, Ooi C, Adler AS, Gollub J, Chen X, Chan BK, Matcuk GR, Barry CT, Chang HY, Kuo MD.  Nat Biotechnol.  2007; 25 (6): 675-80
• From description to causality: mechanisms of gene expression signatures in cancer. Adler AS,  Chang HY.  Cell Cycle.  2006; 5 (11): 1148-51
• Microarray analysis of stem cells and differentiation. Chang HY,  Thomson JA, Chen X.  Methods Enzymol.  2006; 420 225-54
• Bone morphogenetic protein antagonist gremlin 1 is widely expressed by cancer-associated stromal cells and can promote tumor cell proliferation. Sneddon JB,  Zhen HH, Montgomery K, van de Rijn M, Tward AD, West R, Gladstone H, Chang HY, Morganroth GS, Oro AE, Brown PO.  Proc Natl Acad Sci U S A.  2006; 103 (40): 14842-7
• Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. DeVoss J,  Hou Y, Johannes K, Lu W, Liou GI, Rinn J, Chang H, Caspi RR, Caspi R, Fong L, Anderson MS.  J Exp Med.  2006; 203 (12): 2727-35
• MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species. Ray S,  Atkuri KR, Deb-Basu D, Adler AS, Chang HY, Herzenberg LA, Felsher DW.  Cancer Res.  2006; 66 (13): 6598-605
• Predicting a local recurrence after breast-conserving therapy by gene expression profiling. Nuyten DS,  Kreike B, Hart AA, Chi JT, Sneddon JB, Wessels LF, Peterse HJ, Bartelink H, Brown PO, Chang HY, van de Vijver MJ.  Breast Cancer Res.  2006; 8 (5): R62
• Anatomic demarcation by positional variation in fibroblast gene expression programs. Rinn JL,  Bondre C, Gladstone HB, Brown PO, Chang HY.  PLoS Genet.  2006; 2 (7): e119
• Learning more from microarrays: insights from modules and networks. Wong DJ,  Chang HY.  J Invest Dermatol.  2005; 125 (2): 175-82
• Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Chang HY,  Nuyten DS, Sneddon JB, Hastie T, Tibshirani R, Sørlie T, Dai H, He YD, van't Veer LJ, Bartelink H, van de Rijn M, Brown PO, van de Vijver MJ.  Proc Natl Acad Sci U S A.  2005; 102 (10): 3738-43
• Kinetics and specificity of fas ligand induction in toxic epidermal necrolysis. Chang HY,  Cooper ZA, Swetter SM, Marinkovich MP.  Arch Dermatol.  2004; 140 (2): 242-4
• Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds. Chang HY,  Sneddon JB, Alizadeh AA, Sood R, West RB, Montgomery K, Chi JT, van de Rijn M, Botstein D, Brown PO.  PLoS Biol.  2004; 2 (2): E7
• Endothelial cell diversity revealed by global expression profiling. Chi JT,  Chang HY, Haraldsen G, Jahnsen FL, Troyanskaya OG, Chang DS, Wang Z, Rockson SG, van de Rijn M, Botstein D, Brown PO.  Proc Natl Acad Sci U S A.  2003; 100 (19): 10623-8
• Eruptive xanthomas associated with olanzapine use. Chang HY,  Ridky TW, Kimball AB, Hughes E, Oro AE.  Arch Dermatol.  2003; 139 (8): 1045-8
• Genomewide view of gene silencing by small interfering RNAs. Chi JT,  Chang HY, Wang NN, Chang DS, Dunphy N, Brown PO.  Proc Natl Acad Sci U S A.  2003; 100 (11): 6343-6
• Myelogenous leukemia cutis resembling stasis dermatitis. Chang HY,  Wong KM, Bosenberg M, McKee PH, Haynes HA.  J Am Acad Dermatol.  2003; 49 (1): 128-9
• Diversity, topographic differentiation, and positional memory in human fibroblasts. Chang HY,  Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, Brown PO.  Proc Natl Acad Sci U S A.  2002; 99 (20): 12877-82
• Proteases for cell suicide: functions and regulation of caspases. Chang HY,  Yang X.  Microbiol Mol Biol Rev.  2000; 64 (4): 821-46
• Dissecting Fas signaling with an altered-specificity death-domain mutant: requirement of FADD binding for apoptosis but not Jun N-terminal kinase activation. Chang HY,  Yang X, Baltimore D.  Proc Natl Acad Sci U S A.  1999; 96 (4): 1252-6
• Activation of apoptosis signal-regulating kinase 1 (ASK1) by the adapter protein Daxx. Chang HY,  Nishitoh H, Yang X, Ichijo H, Baltimore D.  Science.  1998; 281 (5384): 1860-3
• Autoproteolytic activation of pro-caspases by oligomerization. Yang X,  Chang HY, Baltimore D.  Mol Cell.  1998; 1 (2): 319-25
• Essential role of CED-4 oligomerization in CED-3 activation and apoptosis. Yang X,  Chang HY, Baltimore D.  Science.  1998; 281 (5381): 1355-7
• Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Yang X,  Khosravi-Far R, Chang HY, Baltimore D.  Cell.  1997; 89 (7): 1067-76
• Asymmetric retraction of growth cone filopodia following focal inactivation of calcineurin. Chang HY,  Takei K, Sydor AM, Born T, Rusnak F, Jay DG.  Nature.  1995; 376 (6542): 686-90
• Activation of CLN1 and CLN2 G1 cyclin gene expression by BCK2. Di Como CJ,  Chang H, Arndt KT.  Mol Cell Biol.  1995; 15 (4): 1835-46
• Active site mutants of human cyclophilin A separate peptidyl-prolyl isomerase activity from cyclosporin A binding and calcineurin inhibition. Zydowsky LD,  Etzkorn FA, Chang HY, Ferguson SB, Stolz LA, Ho SI, Walsh CT.  Protein Sci.  1992; 1 (9): 1092-9
• Cyclosporin-mediated inhibition of bovine calcineurin by cyclophilins A and B. Swanson SK,  Born T, Zydowsky LD, Cho H, Chang HY, Walsh CT, Rusnak F.  Proc Natl Acad Sci U S A.  1992; 89 (9): 3741-5