Departments: Pathology - Associate Professor, Oncological Sciences - Adjunct Associate Professor
Divisions: Anatomic Pathology
Academic Office Information
1950 Circle of Hope, Room: 2726
Salt Lake City, UT 84112
- American Board of Pathology (Sub: Anatomic Path)
- Lung Cancer
- Pancreatic Cancer
- Mouse Models of Cancer
- Transcription Factors
The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis. The genetic and epigenetic changes that accumulate during cancer progression can disrupt these networks, often with lethal consequences for cancer patients. Loss of cellular identity during tumor evolution frequently endows cancer cells with an increased propensity for growth and metastasis. In some cases, tumors treated with targeted therapies can undergo radical changes in cellular identity that affect their sensitivity to standard drug regimens. Despite these observations, the field has not deciphered the master regulators that control cellular identity in most cancer types. Identifying these regulators and determining the specific consequences of their inactivation will provide critical insights into mechanisms of cancer progression and enable the development of new therapeutic strategies targeted to specific differentiation states.
Turning lung into stomach: We have shown that the transcription factor Nkx2-1 is a critical regulator of lung adenocarcinoma identity (Snyder et al., Mol Cell 2013). Engineered deletion of Nkx2-1 causes a complete loss of pulmonary differentiation in a Kras-driven mouse model of lung adenocarcinoma and enhances tumor growth. Nkx2-1-negative tumors exhibit a striking mucinous morphology and transcriptionally upregulate a gastric differentiation program. These mucinous murine lung tumors bear a close resemblance to a subtype of human lung cancer that also expresses gastric markers. Integrative gene expression/ChIP-seq analysis has implicated the Foxa1/2 transcription factors in the pulmonary to gastric differentiation state change induced by Nkx2-1 deletion.
Our overall goal is to determine how the loss of cellular identity and acquisition of alternative differentiation states contributes to cancer progression and alters therapeutic response. Ongoing projects are focused on two major themes:
- Regulation of cellular identity in lung and pancreatic cancer. We are studying the mechanisms by which transcription factors (including Nkx2-1, Foxa1, Foxa2 and Hnf4a) and their downstream targets control cancer differentiation state.
- Impact of changes in cellular identity on oncogenic signaling and response to targeted therapies. Our preliminary data indicates that changes in cellular identity can alter the activity of signaling pathways that are regulated by driver oncogenes such as Kras. We are investigating whether these changes have a direct impact on the growth and metastasis of tumors. We are also evaluating whether these changes affect the intrinsic sensitivity of tumors to targeted cancer therapies.
Massachusetts Institute of Technology
||Postdoctoral Research Fellow|
Brigham and Women's Hospital
University of California, San Diego
Washington University School of Medicine in St. Louis
Pennsylvania State University
Biology with Honors
- Orstad G, Fort G, Parnell TJ, Jones A, Stubben C, Lohman B, Gillis KL, Orellana W, Tariq R, Klingbeil O, Kaestner K, Vakoc CR, Spike BT, Snyder EL (2022). FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. Dev Cell, 57(15), 1866-1882.e10.
- Kong R, Patel AS, Sato T, Jiang F, Yoo S, Bao L, Sinha A, Tian Y, Fridrikh M, Liu S, Feng J, He X, Jiang J, Ma Y, Grullon K, Yang D, Powell CA, Beasley MB, Zhu J, Snyder EL, Li S, Watanabe H (2022). Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small Cell Lung Cancer. Am J Respir Crit Care Med.
- Ingram K, Samson SC, Zewdu R, Zitnay RG, Snyder EL, Mendoza MC (2021). NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene, 41(2), 293-300.
- Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, Shea J, Stubben C, Moffitt R, Gertz J, Snyder EL (2020). Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut, 70(5), 900-914.
- Camolotto SA, Belova VK, Snyder EL (2019). The role of lineage specifiers in pancreatic ductal adenocarcinoma. [Review]. J Gastrointest Oncol, 9(6), 1005-1013.
- Camolotto SA, Pattabiraman S, Mosbruger TL, Jones A, Belova VK, Orstad G, Streiff M, Salmond L, Stubben C, Kaestner KH, Snyder EL (2018). FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. Elife, 7.
- Caswell DR, Chuang CH, Ma RK, Winters IP, Snyder EL, Winslow MM (2018). Tumor Suppressor Activity of Selenbp1, a Direct Nkx2-1 Target, in Lung Adenocarcinoma. Mol Cancer Res, 16(11), 1737-1749.
- Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, Camolotto SA, Mosbruger TL, Stubben CJ, Conley CJ, Bhutkar A, Vahrenkamp JM, Berrett KC, Cessna MH, Lane TE, Witt BL, Salama ME, Gertz J, Jones KB, Snyder EL, Oliver TG (2018). The Lineage-Defining Transcription Factors SOX2 and NKX2-1 Determine Lung Cancer Cell Fate and Shape the Tumor Immune Microenvironment. Immunity, 49(4), 764-779.e9.
- Li CM, Gocheva V, Oudin MJ, Bhutkar A, Wang SY, Date SR, Ng SR, Whittaker CA, Bronson RT, Snyder EL, Gertler FB, Jacks T (2015). Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes Dev, 29(17), 1850-62.
- Sioletic S, Czaplinski J, Hu L, Fletcher JA, Fletcher CD, Wagner AJ, Loda M, Demetri GD, Sicinska ET, Snyder EL (2014). c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. J Pathol, 234(2), 190-202.
- Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Meyerson M, Kimura S, Jacks T (2013). Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol Cell, 50(2), 185-99.
- Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, Peng S, Snyder EL, Tata PR, Izzo F, Schinzel AC, Cho J, Hammerman PS, Verhaak RG, Hahn WC, Rajagopal J, Jacks T, Meyerson M (2013). Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. Genes Dev, 27(2), 197-210.
- Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, Hubbard DD, DuPage MJ, Whittaker CA, Hoersch S, Yoon S, Crowley D, Bronson RT, Chiang DY, Meyerson M, Jacks T (2011). Suppression of lung adenocarcinoma progression by Nkx2-1. Nature, 473(7345), 101-4.
- Snyder EL, Bailey D, Shipitsin M, Polyak K, Loda M (2009). Identification of CD44v6(+)/CD24- breast carcinoma cells in primary human tumors by quantum dot-conjugated antibodies. Lab Invest, 89(8), 857-66.
- Snyder EL, Sandstrom DJ, Law K, Fiore C, Sicinska E, Brito J, Bailey D, Fletcher JA, Loda M, Rodig SJ, Dal Cin P, Fletcher CD (2009). c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programme. J Pathol, 218(3), 292-300.
- Snyder EL, Saenz CC, Denicourt C, Meade BR, Cui XS, Kaplan IM, Dowdy SF (2005). Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anticancer peptides. Cancer Res, 65(23), 10646-50.
- Snyder EL, Meade BR, Saenz CC, Dowdy SF (2004). Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biol, 2(2), E36.