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Eric Snyder

Associate Professor of Anatomic Pathology and Adjunct Associate Professor of Oncological Sciences

Lineage Plasticity in Cancer

Eric Snyder


Molecular Biology Program


B.S. Pennsylvania State University

M.D., Ph.D. Washington University in St. Louis



Studying How Lineage Plasticity Contributes to Cancer Progression

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. In many types of cancer, cell identity dictates not only intrinsic malignant potential, but also response to therapy, even in tumors harboring the same targetable mutations. Although tissue of origin is a major determinant of cancer cell identity, cancer cells can also undergo lineage switching in the course of their natural history and in response to the selective pressure of targeted therapy.

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:

  1. Mechanisms of lineage switching in lung and pancreatic cancer. We have identified key transcription factors that control cell identity in lung and pancreatic cancer. For example, NKX2-1 enforces a pulmonary differentiation program in lung adenocarcinoma (Snyder et al., Mol Cell 2013). Loss of NKX2-1, in both mouse models or human tumors, causes a pulmonary to gastric transdifferentiation that is driven by FoxA1/2 (Camolotto et al., eLife 2018). Thus, lung adenocarcinomas can be toggled between two dichotomous identities based on the activity of these lineage specifying transcription factors. In pancreatic cancer, we have found that HNF4α and SIX4 enforce dichotomous identities and regulate clinically relevant molecular subtypes (Camolotto et al. Gut 2021).


    In contrast to the discrete and dichotomous identities adopted by many cancer cells, there are some circumstances in which individual cancer cells can simultaneously express multiple identity programs. We have uncovered a novel role for FoxA1/2 in maintaining a dual identity (mixed-lineage) state in NKX2-1-positive lung adenocarcinoma (Orstad et al. Dev Cell 2022). FoxA1/2 are critical drivers of proliferation in this disease and can activate both pulmonary and gastric differentiation programs within the same cell, leading to a hybrid state that is critical for cancer progression.

  2. Therapeutic implications of lineage switching in cancer. Cell identity can have a profound effect on the way tumors respond to targeted therapy. We have found that NKX2-1 levels dictate the response of lung tumors to targeted inhibition of the RAF/MEK pathway (Zewdu et al. eLife 2021). These experiments also demonstrated a surprising degree of crosstalk between cell identity programs and oncogenic signaling pathways. In particular, the activity of RAF/MEK and WNT oncogenic signaling pathways dictated the specific gastric cell type that NKX2-1-negative lung tumor cells most closely resembled. Current experiments are seeking to determine whether this novel crosstalk can be exploited for therapeutic benefit. Our long term translational goal is to uncover novel therapeutic strategies that target lung and pancreatic tumors based on vulnerabilities associated with both their cell identity and genetic driver mutations.


  1. FoxA1 and FoxA2 control growth and cellular identity in NKX2-1-positive lung adenocarcinoma. 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. Dev Cell. 2022 Aug 8;57(15):1866-1882.e10. doi: 10.1016/j.devcel.2022.06.017. Epub 2022 Jul 13. PMID: 35835117; PMCID: PMC9378547.
  2. Transcriptional Circuitry of NKX2-1 and SOX1 Defines an Unrecognized Lineage Subtype of Small Cell Lung Cancer. 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. Am J Respir Crit Care Med. 2022 Jul 18. doi: 10.1164/rccm.202110-2358OC. Epub ahead of print. PMID: 35848993.
  3. An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. Zewdu R, Mehrabad EM, Ingram K, Fang P, Gillis KL, Camolotto SA, Orstad G, Jones A, Mendoza MC, Spike BT, Snyder EL. Elife. 2021 Apr 6;10:e66788. doi: 10.7554/eLife.66788.
  4. Reciprocal regulation of pancreatic ductal adenocarcinoma growth and molecular subtype by HNF4α and SIX1/4. Camolotto SA, Belova VK, Torre-Healy L, Vahrenkamp JM, Berrett KC, Conway H, Shea J, Stubben C, Moffitt R, Gertz J, Snyder EL. Gut. 2021 May;70(5):900-914. doi: 10.1136/gutjnl-2020-321316.
  5. Protective autophagy elicited by RAF-> MEK -> ERK inhibition suggests a treatment strategy for RAS-driven cancers. 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. Nature Medicine 2019, 25(4), 620-627.
  6. FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. Camolotto SA, Pattabiraman S*, Mosbruger TL*, Jones A, Belova VK, Orstad G, Streiff M, Salmond L, Stubben C, Kaestner KH and Snyder EL. eLife 2018(7), e38579.
  7. The lineage-defining transcription factors SOX2 and NKX2-1 determine lung cancer cell fate and shape the tumor immune microenvironment. 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. Immunity 2018, 49(4), 764-779.
  8. Tumor Suppressor Activity of Selenbp1, a Direct Nkx2-1 Target, in Lung Adenocarcinoma. Caswell DR, Chuang CH, Ma RK, Winters IP, Snyder EL, Winslow MM. Molecular Cancer Research 2018 DOI: 10.1158/1541-7786.MCR-18-0392.
  9. Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Li CM, Gocheva V, Oudin MJ, Bhutkar A, Wang SY, Date SR, Ng SR, Whittaker CA, Bronson RT, Snyder EL, Gertler FB, Jacks T. Genes Dev 2015; 29: 1850-62.
  10. c-Jun promotes cell migration and drives expression of the motility factor ENPP2 in soft tissue sarcomas. Sioletic S, Czaplinksi J, Hu L, Fletcher JA, Fletcher CDM, Wagner AJ, Loda M, Demetri GD, Sicinska ET, Snyder EL. Journal of Pathology 2014; 23:190-202.
  11. Antiproliferative effects of CDK4/6 inhibition in CDK4-amplified human liposarcoma in vitro and in vivo. 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. Molecular Cancer Therapeutics, 2014 13(9), 2184-93.
  12. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinomaSnyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, Crowley D, Whittaker CA, Kimura S, Meyerson M, Jacks T. Molecular Cell 2013; 50:185-199.
  13. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. 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). 27:197-210.
  14. Suppression of lung adenocarcinoma progression by Nkx2-1. 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. Nature 2011; 473: 101-4.
  15. Aberrant AKT activation drives well-differentiated liposarcoma. 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 Proceedings of the National Academy of Science of the United States of America 2011, 108(39), 16386-91.
  16. Nuclear factor I/B is an oncogene in small cell lung cancer 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. Genes & Development 2011, 25(14), 1470-5.
  17. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Gidekel-Friedlander SY, Chu GC, Snyder EL, Girnius N, Dibelius G, Crowley D, Vasile E, DePinho RA, Jacks T. Cancer Cell 2009; 16:379-89.
  18. Identification of CD44v6+/CD24- breast carcinoma cells in primary human tumors by quantum dot-conjugated antibodies. Snyder EL, Bailey D, Shipitsin M, Polyak K, Loda M. Lab Invest 2009; 89: 857-866.
  19. c-Jun amplification and overexpression are oncogenic in liposarcoma but not always sufficient to inhibit the adipocytic differentiation programSnyder EL, Sandstrom DJ, Law K, Fiore C, Sicinska E, Brito J, Bailey D, Fletcher JA, Loda M, Rodig SJ, Cin PD, Fletcher CDM Journal of Pathology 2009; 218: 292-300
  20. Cell type-specific DNA methylation patterns in the human breast 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. Proceedings of the National Academy of Science of the United States of America 2008, 105(37), 14076-81.
  21. Enhanced targeting and killing of tumor cells expressing the CXC chemokine receptor 4 by transducible anti-cancer peptidesSnyder EL*, Saenz CC*, Denicourt C, Meade BR, Cui X-S, Kaplan IM, Dowdy SF. Cancer Research 2005; 65:10646-50.
  22. Treatment of terminal peritoneal carcinomatosis by a transducible p53-activating peptide
    Snyder EL, Meade BR, Saenz CC, Dowdy SF.
    PLoS Biology 2004; 2:186-193.
  23. Distinct and nonoverlapping roles for pRB and cyclin D:cyclin-dependent kinases 4/6 activity in melanocyte survival. Yu BD, Becker-Hapak M, Snyder EL, Vooijs M, Denicourt C, Dowdy SF. Proceedings of the National Academy of Science of the United States of America 2003, 100(25), 14881-6.
  24. Anti-cancer protein transduction strategies: reconstitution of p27 tumor suppressor functionSnyder EL, Meade BR, Dowdy SF. J Control Release 2003, 91(1-2), 45-51.
  25. hADA3 is required for p53 activity. Wang T, Kobayashi T, Takimoto R, Denes AE, Snyder EL, el-Deiry WS, Brachmann RK. EMBO J 2001, 20(22), 6404-13.
  26. Purified JC virus T and T' proteins differentially interact with the retinoblastoma family of tumor suppressor proteins. Bollag B, Prins C, Snyder EL, Frisque RJ. Virology 2000, 274(1), 165-78.
  27. Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27 induces cell migration. Nagahara H, Vocero-Akbani AM, Snyder EL, Ho A, Latham DG, Lissy NA, Becker-Hapak M, Ezhevsky SA, Dowdy SF. Nature Medicine 1998; 4:1449-1452.
Last Updated: 7/20/23