Associate Professor of Anatomic Pathology and Adjunct Assistant Professor of Oncological Sciences
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?
- Zewdu R, Mehrabad EM, Ingram K, Fang P, Gillis KL, Camolotto SA, Orstad G, Jones A, Mendoza MC, Spike BT, Snyder EL. (2021) An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. Elife. 10:e66788.
- Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, Shea J, Stubben C, Moffitt R, Gertz J, Snyder EL. (2021) Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Gut. 70(5):900-914.
- 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. Nature Medicine 25(4), 620-627.
- 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 e38579.
- 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.
- 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. Molecular Cancer Research DOI: 10.1158/1541-7786.MCR-18-0392.
- 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: 1850-62.
- Sioletic S, Czaplinksi J, Hu L, Fletcher JA, Fletcher CDM, 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. Journal of Pathology 23:190-202.
- Zhang YX, Sicinska E, Czaplinski JT, Remillard SP, Moss S, Wang Y, Brain C, Loo A, Snyder EL, Demetri GD, Kim S, Kung AL, Wagner AJ. (2014) Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. Molecular Cancer Therapeutics 13(9), 2184-93.
- Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Kimura S, Meyerson M, Jacks T. (2013) Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Molecular Cell 50:185-199.
- 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. 27:197-210.
- 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. (2011) Suppression of lung adenocarcinoma progression by Nkx2-1. Nature 473: 101-4.
- Gutierrez A, Snyder EL, Marino-Enriquez A, Zhang YX, Sioletic S, Kozakewich E, Grebliunaite R, Ou WB, Sicinska E, Raut CP, Demetri GD, Perez-Atayde AR, Wagner AJ, Fletcher JA, Fletcher CD, Look AT (2011) Aberrant AKT activation drives well-differentiated liposarcoma. Proceedings of the National Academy of Science of the United States of America 108(39), 16386-91.
- Dooley AL, Winslow MM, Chiang DY, Banerji S, Stransky N, Dayton TL, Snyder EL, Senna S, Whittaker CA, Bronson RT, Crowley D, Barretina J, Garraway L, Meyerson M, Jacks T. (2011) Nuclear factor I/B is an oncogene in small cell lung cancer. Genes & Development 25(14), 1470-5.
- Gidekel-Friedlander SY, Chu GC, Snyder EL, Girnius N, Dibelius G, Crowley D, Vasile E, DePinho RA, Jacks T. (2009) Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell 16:379-89.
- 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: 857-866.
- Snyder EL, Sandstrom DJ, Law K, Fiore C, Sicinska E, Brito J, Bailey D, Fletcher JA, Loda M, Rodig SJ, Cin PD, Fletcher CDM (2009) c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation program. Journal of Pathology 218: 292-300
- Bloushtain-Qimron N, Yao J, Snyder EL, Shipitsin M, Campbell LL, Mani SA, Hu M, Chen H, Ustyansky V, Antosiewicz JE, Argani P, Halushka MK, Thomson JA, Pharoah P, Porgador A, Sukumar S, Parsons R, Richardson AL, Stampfer MR, Gelman RS, Nikolskaya T, Nikolsky Y, Polyak K. (2008) Cell type-specific DNA methylation patterns in the human breast. Proceedings of the National Academy of Science of the United States of America 105(37), 14076-81.
- Snyder EL*, Saenz CC*, Denicourt C, Meade BR, Cui X-S, Kaplan IM, Dowdy SF. (2005) Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anti-cancer peptides. Cancer Research 65:10646-50.
- Snyder EL, Meade BR, Saenz CC, Dowdy SF. (2004) Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide. PLoS Biology 2:186-193.
- Yu BD, Becker-Hapak M, Snyder EL, Vooijs M, Denicourt C, Dowdy SF. (2003) Distinct and nonoverlapping roles for pRB and cyclin D:cyclin-dependent kinases 4/6 activity in melanocyte survival. Proceedings of the National Academy of Science of the United States of America 100(25), 14881-6.
- Snyder EL, Meade BR, Dowdy SF. (2003) Anti-cancer protein transduction strategies: reconstitution of p27 tumor suppressor function. J Control Release 91(1-2), 45-51.
- Wang T, Kobayashi T, Takimoto R, Denes AE, Snyder EL, el-Deiry WS, Brachmann RK. (2001) hADA3 is required for p53 activity. EMBO J 20(22), 6404-13.
- Bollag B, Prins C, Snyder EL, Frisque RJ. (2000) Purified JC virus T and T' proteins differentially interact with the retinoblastoma family of tumor suppressor proteins. Virology 274(1), 165-78.
- Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, Becker-Hapak M, Ezhevsky SA, Dowdy SF. (1998) Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27 induces cell migration. Nature Medicine 4:1449-1452.