Assistant Professor of Anatomic Pathology and
Adjunct Assistant Professor of Oncological Sciences
B.S. Pennsylvania State University
M.D., Ph.D. Washington University in St. Louis
Eric Snyder's Lab Page
Eric Snyder's PubMed Literature Search
Molecular Biology Program
Mouse Models of Cancer
The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis. These networks can become dramatically dysregulated during cancer progression, often with lethal consequences for cancer patients. Tumors that lose much of their original cellular identity typically have a greater propensity for growth and metastasis than tumors that more closely resemble their tissue of origin. 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 master regulators of cancer cell identity and determining the 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. Engineered deletion of Nkx2-1 causes a complete loss of pulmonary differentiation in a mouse model of lung adenocarcinoma and enhances tumor growth. Nkx2-1-negative tumors exhibit a striking mucinous morphology that is accompanied by activation of a latent gastric differentiation program. These mucinous murine lung tumors bear a close resemblance to a subtype of human lung cancer that also expresses multiple gastric markers. Integrative gene expression/ChIP-seq analysis has implicated the Foxa1/2 transcription factors as potential mediators of the lineage switch induced by Nkx2-1 deletion.
The overall goal of our lab 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 several questions, including:
- What are the critical regulators of cellular identity in lung and pancreatic cancer?
- How does the activation of latent differentiation programs drive cancer progression?
- How do changes in cellular identity alter oncogenic signaling networks and sensitivity to targeted therapy?
Mollaoglu G, Jones A, Wait SJ, Mukhopadhyay A, Jeong S, Arya R, Camolotto SA, Mosbruger TL, Stubben C, 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.
Camolotto SA, Pattabiraman S*, Mosbruger TL*, Jones A, Belova VK, Orstad G, Streiff M, Salmond L, Stubben C, Kaestner KH and Snyder EL (2018). FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. eLife, eLife(7), e38579.
Kinsey CG, Camolotto SA, Boespflug AM, Gullien KP, Foth M, Shea JE, Seipp MT, Yap JT, Burrell LD, Lum DH, Whisenant JR, Gilcrease GW, Cavlieri CC, Rehbein KM, Cutler SL, Affolter KE, Welm AL, Welm BE, Scaife CL, Snyder EL and McMahon M (2019). Protective autophagy elicited by RAF-> MEK -> ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat Med 25(4): 620-627.
- Sioletic S, Czaplinksi J, Hu L, Fletcher JA, Fletcher CDM, Wagner AJ, Loda M, Demetri GD, Sicinska ET, Snyder EL. c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. Journal of Pathology 2014; 234: 190-202.
- Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Kimura S, Meyerson M, Jacks T. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Molecular Cell 2013; 50: 185-199.
- Winslow MM, Dayton TD, Verhaak RGW, Snyder EL, Kim-Kiselak CS, Feldser DM, Whitaker CA, Hubbard DD, Crowley D, Bronson RT, Chiang DY, Meyerson M and Jacks T. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 2011; 473: 101-4.
- Snyder EL, Sandstrom DJ, Law K, Fiore C, Sicinska E, Brito J, Bailey D, Fletcher JA, Loda M, Rodig SJ, Cin PD, Fletcher CDM. c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation program. Journal of Pathology 2009; 218: 292-300.
- Snyder EL, Meade BR, Saenz CC, Dowdy SF. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biology 2004; 2:186-193.
- Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, Becker-Hapak M, Ezhevsky SA, Dowdy SF. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27 induces cell migration. Nature Medicine 1998; 4:1449-1452.