Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells

Marc Damelin; Kenneth G. Geles; Maximillian T. Follettie; Ping Yuan; Michelle Baxter; Jonathon Golas; John F. DiJoseph; Maha Karnoub; Shuguang Huang; Veronica Diesl; Carmen Behrens; Sung E. Choe; Carol Rios; Janet Gruzas; Latha Sridharan; Maureen Dougher; Arthur Kunz; Philip R. Hamann; Deborah Evans; Douglas Armellino; Kiran Khandke; Kimberly Marquette; Lioudmila Tchistiakova; Erwin R. Boghaert; Robert T. Abraham; Ignacio I. Wistuba; Bin Bing S. Zhou

doi:10.1158/0008-5472.CAN-10-3919

Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells

Marc Damelin, Kenneth G. Geles, Maximillian T. Follettie, Ping Yuan, Michelle Baxter, Jonathon Golas, John F. DiJoseph, Maha Karnoub, Shuguang Huang, Veronica Diesl, Carmen Behrens, Sung E. Choe, Carol Rios, Janet Gruzas, Latha Sridharan, Maureen Dougher, Arthur Kunz, Philip R. Hamann, Deborah Evans, Douglas ArmellinoKiran Khandke, Kimberly Marquette, Lioudmila Tchistiakova, Erwin R. Boghaert, Robert T. Abraham, Ignacio I. Wistuba, Bin Bing S. Zhou

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Abstract

Poorly differentiated tumors in non - small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody - drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.

Original language	English (US)
Pages (from-to)	4236-4246
Number of pages	11
Journal	Cancer Research
Volume	71
Issue number	12
DOIs	https://doi.org/10.1158/0008-5472.CAN-10-3919
State	Published - Jun 15 2011

ASJC Scopus subject areas

Oncology
Cancer Research

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Damelin, M., Geles, K. G., Follettie, M. T., Yuan, P., Baxter, M., Golas, J., DiJoseph, J. F., Karnoub, M., Huang, S., Diesl, V., Behrens, C., Choe, S. E., Rios, C., Gruzas, J., Sridharan, L., Dougher, M., Kunz, A., Hamann, P. R., Evans, D., ... Zhou, B. B. S. (2011). Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells. Cancer Research, 71(12), 4236-4246. https://doi.org/10.1158/0008-5472.CAN-10-3919

Damelin, M, Geles, KG, Follettie, MT, Yuan, P, Baxter, M, Golas, J, DiJoseph, JF, Karnoub, M, Huang, S, Diesl, V, Behrens, C, Choe, SE, Rios, C, Gruzas, J, Sridharan, L, Dougher, M, Kunz, A, Hamann, PR, Evans, D, Armellino, D, Khandke, K, Marquette, K, Tchistiakova, L, Boghaert, ER, Abraham, RT, Wistuba, II & Zhou, BBS 2011, 'Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells', Cancer Research, vol. 71, no. 12, pp. 4236-4246. https://doi.org/10.1158/0008-5472.CAN-10-3919

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abstract = "Poorly differentiated tumors in non - small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody - drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.",

author = "Marc Damelin and Geles, {Kenneth G.} and Follettie, {Maximillian T.} and Ping Yuan and Michelle Baxter and Jonathon Golas and DiJoseph, {John F.} and Maha Karnoub and Shuguang Huang and Veronica Diesl and Carmen Behrens and Choe, {Sung E.} and Carol Rios and Janet Gruzas and Latha Sridharan and Maureen Dougher and Arthur Kunz and Hamann, {Philip R.} and Deborah Evans and Douglas Armellino and Kiran Khandke and Kimberly Marquette and Lioudmila Tchistiakova and Boghaert, {Erwin R.} and Abraham, {Robert T.} and Wistuba, {Ignacio I.} and Zhou, {Bin Bing S.}",

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AU - Damelin, Marc

AU - Geles, Kenneth G.

AU - Follettie, Maximillian T.

AU - Yuan, Ping

AU - Baxter, Michelle

AU - Golas, Jonathon

AU - DiJoseph, John F.

AU - Karnoub, Maha

AU - Huang, Shuguang

AU - Diesl, Veronica

AU - Behrens, Carmen

AU - Choe, Sung E.

AU - Rios, Carol

AU - Gruzas, Janet

AU - Sridharan, Latha

AU - Dougher, Maureen

AU - Kunz, Arthur

AU - Hamann, Philip R.

AU - Evans, Deborah

AU - Armellino, Douglas

AU - Khandke, Kiran

AU - Marquette, Kimberly

AU - Tchistiakova, Lioudmila

AU - Boghaert, Erwin R.

AU - Abraham, Robert T.

AU - Wistuba, Ignacio I.

AU - Zhou, Bin Bing S.

PY - 2011/6/15

Y1 - 2011/6/15

N2 - Poorly differentiated tumors in non - small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody - drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.

AB - Poorly differentiated tumors in non - small cell lung cancer (NSCLC) have been associated with shorter patient survival and shorter time to recurrence following treatment. Here, we integrate multiple experimental models with clinicopathologic analysis of patient tumors to delineate a cellular hierarchy in NSCLC. We show that the oncofetal protein 5T4 is expressed on tumor-initiating cells and associated with worse clinical outcome in NSCLC. Coexpression of 5T4 and factors involved in the epithelial-to-mesenchymal transition were observed in undifferentiated but not in differentiated tumor cells. Despite heterogeneous expression of 5T4 in NSCLC patient-derived xenografts, treatment with an anti-5T4 antibody - drug conjugate resulted in complete and sustained tumor regression. Thus, the aggressive growth of heterogeneous solid tumors can be blocked by therapeutic agents that target a subpopulation of cells near the top of the cellular hierarchy.

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Delineation of a cellular hierarchy in lung cancer reveals an oncofetal antigen expressed on tumor-initiating cells

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