专访复旦优秀学子 直击“狡猾”癌细胞真相

　　

编者按：p53与癌症一直是研究热点，一名毕业于复旦大学曾获复旦大学优秀毕业生奖的青年学者近期在权威杂志《Cancer Cell》发表脑癌与p53关联的研究新成果。科学家可能攻克癌症吗？来听听密歇根大学朱源博士的见解！

 

朱源博士在百忙中抽空接受了生物通记者张欢的采访，我们从发表的文章说起。

（文章报道页面：http://www.ebiotrade.com/newsf/2009-6/2009611171915336.htm）

 

朱源博士现任密歇根大学医学院内科学和细胞发育生物学系助理教授，是学院的项目执行首席研究员。

 

生物通：脑瘤相比其他癌症来说，由于其癌症发生部位的特殊性，研究脑部的癌症更具难度，在您的研究过程中，您以哪种动物为模型？遇到哪些难题？您是如何克服的？

 

朱源：我们实验室组用小鼠为模型动物来研究脑癌。我们使用的实验方法很直观，我们有一个神经元特异的Cre转基因驱动（neural-specific Cre transgenic driver），它以肿瘤抑制基因为靶位直观的观察脑细胞中肿瘤抑制基因的突变情况。

 

生物通：在您的研究中，神经干细胞发生p53突变导致恶性胶质瘤，您是否认同有癌症干细胞理论，您认为这些突变的癌细胞就是癌症干细胞吗？

 

朱源：在研究模型中，我们进行了多种实验，诱导各种脑细胞（包括神经干细胞，各种祖细胞和分化细胞）的p53基因发生突变。

 

癌症干细胞的学说理论目前还充满争议。通常来说，癌症干细胞理论在某些癌症中是适用的，比如白血病、脑癌和结肠癌，其他如黑色素瘤等癌症却并不适用癌症干细胞理论。我认为在我实验中发生突变的脑癌细胞不一定是癌症干细胞。这一点需要有坚实的证据来证实它是或它不是。

 

生物通：在您研究的过程中，主要用哪些技术？有特别之处吗？

 

朱源：在研究中，我们应用的有特色的技术是：检测脑癌细胞在不同阶段p53蛋白的突变蓄积量。其中的关键在于p53的标记，通过这一特别的标记物，我们可以在癌症发生的不同阶段来检测p53的突变。尤其是我们观察到神经干细胞是首个出现p53蛋白突变蓄积的细胞系；在脑癌发生的转移扩散阶段，transit-amplifying 祖细胞的p53蛋白开始出现高水平的突变量。

 

这使得我们在癌症早期从单细胞水平上监测早期的脑癌细胞突变情况。这些动物模型为我们研究人类癌症的发展发生提供了十分重要的依据。

 

生物通：拿到这个科研成果后，下一步的打算是什么？

 

朱源：下一步，我们将继续研究神经干细胞和transit-amplifying祖细胞在脑癌发展过程中的作用。但是，在某些程度上，脑癌的早期阶段癌细胞与正常的脑细胞的很相似，但如果细胞层面来看，脑癌细胞同时具有神经干细胞和分化祖细胞的特征。

 

比如说，正常的神经干细胞具有高度的自我更新能力，但没有迁移能力；而其他分化的祖细胞却拥有迁移能力，但自我更新能力很低。而脑癌细胞却同时拥有两种细胞的特征，既具有自我更新能力，又具有迁移能力。因此说，脑癌的发生可能是由于神经干细胞的异常分化所致。

 

我们下一步主要是研究在脑癌发生过程中，神经干细胞异常分化的机制。

 

生物通：以您的知识背景，您对癌症有什么综合的看法？人类有可能完全破译癌症吗？未来对癌症预防和治疗最大的突破点可能在哪？

 

朱源：我认为，癌症远比我们想象的要复杂的多。我认为，在不久的将来人类想攻克癌症具有很高的难度。比如说，我们研究发现脑癌细胞基因组上的p53具有很强的可塑性，它们能通过各种突变来支持癌细胞的发育。因此说，癌细胞可能很快对一种治疗方法产生抵抗性，它通过突变基因组来改变癌细胞的发育方式以适应新环境。这一点与病毒很相似，病毒总在不断的变异以躲避免疫攻击。

 

我认为，最有效的癌症治疗法是早期诊断。我们也正在致力于这方面的研究，对癌症发育的早期阶段进行研究，便于临床医生及早做出诊断。

（生物通  张欢）

 

朱源简介

NAME Yuan Zhu, Ph.D.		POSITION TITLE Assistant Professor
eRA COMMONS USER NAME
EDUCATION/TRAINING  (Begin with baccalaureate or other initial professional education, such as nursing, and include postdoctoral training.)
INSTITUTION AND LOCATION	DEGREE (if applicable)		YEAR(s)	FIELD OF STUDY
Fudan University, Shanghai, P.R. China	B.S.		1987-1991	Biochemistry
Fudan University, Shanghai, P.R. China			1991-1994	Molecular Biology
University of Texas Southwestern Medical Center, Dallas, TX	Ph.D.		1994-2000	Neuroscience
University of Texas Southwestern Medical Center, Dallas, TX	Postdoc		2000-2002	Cancer Biology

A.    Positions and Employment

2000-2002       Research fellow, Center for Developmental Biology, University of Texas, Southwestern

Medical Center, Dallas, TX

2002-2003        Instructor, Center for Developmental Biology, University of Texas, Southwestern Medical Center, Dallas, TX

2003-present   Assistant Professor, Division of Molecular Medicine and Genetics, Departments of Internal Medicine and Cell & Developmental Biology, University of Michigan Medical School,

Ann Arbor, MI

Honors and Awards

1991                    "Excellent Graduate of Fudan University"

1992                    "Guanghua" Scholarship, Fudan University

1998                   30th Sigma Xi Chapter Award, UT, Southwestern Medical Center at Dallas

2000                    Travel Scholarship, National Neurofibromatosis Foundation Inc.

2001                    Scholar in Training Award, American Association for Cancer Research (AACR) Inc.

2001-2003           Young Investigator Award, National Neurofibromatosis Foundation Inc.

2002                    Scholar in Training Award, American Association for Cancer Research (AACR) Inc.

2002                    NF1 Research Prize, National Neurofibromatosis Foundation Inc.

2003                    Biomedical Sciences Scholars Program (BSSP) Scholar, University of Michigan

2004-2006           General Motors (GM) Cancer Research Scholars Program Scholar,

                            General Motors Cancer Research Foundation.

2006-2007           Paul Daniel Bogart Leadership Chair of Research

                            Brain Tumor Society

2006-2010           Investigator-Initiated Research Award

                            Department of Defense Neurofibromatosis Research Program

2006-2009           ACS Research Scholar

                            American Cancer Society

Professional Memberships

American Association for Cancer Research, Society for Neuroscience, Chinese Biological Investigators Society

Professional Services:

Journal Peer Reviewer: Oncogene, Glia, Molecular Cancer Therapeutics, Molecular Cancer Research, Clinical Cancer Research, Cancer Research, Molecular Cancer, J. of Translational Medicine, PLoS Biology

 

Grant Review Group: The Children's Tumor Foundation Research Advisory Board (2007, 2008, 2009), Department of Defense Neurofibromatosis (2005, 2006, 2007) and Tuberous Sclerosis Complex Research Program (2008, 2009), Research Grants Council of Hong Kong (Ad hoc, 2005)

 

 

 

B.   Selected peer-reviewed publications (in chronological order)

1.  Zhu, Y., Richardson, J.A., Parada, L.F. and Graff, J.M. (1998). Smad3 mutant mice develop metastatic colorectal   cancer.  Cell, Vol. 94 703-714.

2.  Zhu, Y. and Parada, L.F. (2001). Neurofibromin, a tumor suppressor in the nervous system. 

Experimental Cell Research, 264, 19-28.

3.  Zhu, Y. and Parada, L.F. (2001). A special GAP in mind. Nature Genetics, 27:354-355.

4.  Zhu,Y., Romero, M., Ghosh, P., Ye, Z., Charnay, P., Rushing, E.J., Marth, J.D. and Parada, L.F. (2001). Ablation of NF1 function in neurons induces abnormal development of cerebral cortex and reactive gliosis in the brain. Genes & Development, 15:859-876.

5.  Gutmann, D.H., Wu, Y.L., Hedrick, N.M, Zhu, Y.,Guha, A. and Parada, L.F. (2001). Heterozygosity for the neurofibromatosis 1 (NF1) tumor suppressor results in abnormalities in cell attachment, spreading and motility in astrocytes. Human Molecular Genetics, 10 (26):3009-3016.

6.  Zhu,Y., Ghosh, P., Charnay, Burns, D.K. and Parada, L.F. (2002). Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science, 296: 920-922.

7.  Bajenaru, M.L., Zhu, Y., Hedrick, N.M., Donahoe, J. Parada, L.F. and Gutmann, D.H. (2002). Astrocyte-specific inactivation of the Neurofibromatosis 1(NF1) gene is insufficient for astrocytoma formation.

Molecular Cellular Biology, 22 (14), 5100-5113.

8.  Zhu, Y. and Parada, L.F. (2002). Molecular biology and genetics of neurologic tumors.

Nature Reviews Cancer, 2: 616-626.

9.  Gitler, A.D*., Zhu, Y*., Ismat, F.A., Lu, M.M., Yamauchi, Y., Parada, L.F. and Epstein, J.A. (2003). The type 1 Neurofibromatosis (Nf1) gene product has distinct and essential roles in neural crest and endothelial cells.

Nature Genetics, 33: 75-79. (*These authors contributed equally to this work).

10. Bajenaru, M.L., Hernandez, M.R., Perry, A., Zhu, Y., Parada, L.F., Garbow, J.R. and Gutmann, D.H. (2003). Optic nerve glioma in mice requires astrocyte NF1 inactivation and NF1 brain heterozygosity. Cancer Research, 63, 8573-8377.

11. Gitler, A.D., Kong, Y., Choi, J.K., Zhu, Y., Pear, W.S. and Epstein, J.A. (2004). Tie2-Cre-Induced Inactivation of a Conditional Mutant Nf1 Allele in Mouse Results in a Myeloproliferative Disorder that Models Juvenile Myelomonocytic Leukemia. Pediatric Research, 55 (4): 581-4.

12. Le, D.T., Kong, N., Zhu, Y., Lauchle, J.O., Aiyigari, A., Braun, B.S., Wang, E., Kogan, S.C., LeBeau M.M., Parada, L. and Shannon, K.M. (2004). Somatic Inactivation of Nf1 in Hematopoietic Cells Results in a Progressive Myeloproliferative Disorder. Blood, 103 (11): 4243-50.

13. Stemmer-Rachamimov, A.O., Louis, D.N., Nielsen, G.P., Antonescu, C., Borowsky, A., Bronson, R., Burns, D.K., Cervera, P., McLaughlin, M., Reifenberger, G., Schmale, M., MacCollin M., Chao, R., Cichowski, K., Kalamarides M., Kumar, S., McClatchey, A., Niwa-Kawakita, M., Ratner, N., Reilly, K., Zhu, Y. and Giovannini, M. (2004). Comparative pathology of nerve sheath tumors in mouse models and humans. Cancer Research, 64 (10): 3718-24.

14. Zhu, Y., Guignard, F., Zhao, D., Liu, L., Burns, D. K., Mason, R. P., and Parada, L. F (2005). Early inactivation of p53 tumor suppressor gene cooperating with NF1 loss induces malignant astrocytoma.

Cancer Cell, 8 (2): 119-130.

15.  Zhu, Y*., Harada, T., Liu, L., Lush, M.E., Guignard, F., Harada C., Burns, D.K., Bajenaru, M.L., Gutmann, D.H. and Parada, L.F. (2005). Inactivation of NF1 in CNS causes increased glial progenitor proliferation and optic glioma formation. Development, 132: 5577-5588 (* Corresponding author).

16. Parada L.F., Kwon C.H. and Zhu Y. (2005). Modeling neurofibromatosis type 1 tumors in the mouse for therapeutic intervention. Cold Spring Harbor Symposia on Quantitative Biology, 70:173-6.

17. Romero, M.I., Lu, M., Lush, M.E., Lei, L., Parada L.F. and Zhu, Y. (2007). Deletion of Nf1 in neurons induces increased axon collateral branching after dorsal root injury. Journal of Neuroscience, 27 (8): 2124-2134.

18. Zheng, H.*, Chang, L.*, Patel, N., Yang, J., Lowe, L., Burns, D.K. and Zhu, Y. (2008). Induction of abnormal proliferation by non-myelinating Schwann cells triggers neurofibroma formation. Cancer Cell, 13:117-128.

19. Joseph, N.M., Mosher, J.T., Buchstaller, J., Snider, P., McKeever, P.E., Lim, M., Conway, S.J., Parada, L.F., Zhu, Y and Morrison, S.J. (2008). The loss of Nf1 transiently promotes self-renewal but not tumorigenesis by neural crest stem cells. Cancer Cell, 13:129-140.

20. Roth, T.M., Ramamurthy, P., Muir, D., Wallace, M.R., Zhu, Y., Chang, L. and Barald, K.F. (2008). Influence of hormones and hormone metabolites on the growth of Schwann Cells derived from embryonic stem cells and tumor cell lines expressing variable levels of neurofibromin. Development Dynamics, 237:513-524.

21. Cui, Y., Costa, R.M., Murphy, G.G., Elgersma, Y., Zhu, Y., Gutmann, D.H., Parada, L.F., Mody, I. and Silva, A.J. (2008). Neurofibromin regulation of Ras/ERK signaling modulates GABA release and learning. Cell, 135(3):549-560.

22.Yang, F.C., Ingram, D.A., Chen, S., Zhu, Y., Yuan, J., Li, X., Yang, X., Knowles, S., Horn, W., Li, Y., Zhang, S., Yang, Y., Vakili, S.T., Yu, M., Burns, D., Robertson, K., Hutchins, G., Parada, L.F. and Clapp, D.W. (2008). Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell, 135(3):437-48.

23.Tan, M., Davis, S.W., Saunders, T.L., Zhu, Y. and Sun, Y. (2009). RBX1/ROC1 disruption results in early embryonic lethality due to proliferation failure, partially rescued by simultaneous loss of p27. PNAS, 106(15):6203-8.

24. Wang, Y.*, Yang, J.*, Zheng, H., Tomasek, G.J., Zhang, P., McKeever, P.E., Lee, E.Y.P. and Zhu, Y. (2009). Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model. Cancer Cell, 15(6):514-26.

 

 

C. Research Support

Ongoing Research Support

American Cancer Society   Yuan Zhu (PI)                                                           1/1/2006 – 12/31/2009

“The cellular and molecular basis of peripheral nerve sheath tumor     “

The goals of this grant are to identify molecular and cellular mechanisms that underlie benign and malignant peripheral nerve sheath tumor.

 

Department of Defense    Yuan Zhu (PI)                                                                    1/25/2006 – 2/24/2010

“Characterization of neurofibromas of the skin and spinal roots in a mouse model”

The goals of this grant are to examine the differences in genotypes, dependence on the tumor microenvironment and malignant transformation potential between two types of neurofibromas in the skin and spinal roots

 

NIH Grant (R01)    Yuan Zhu (PI)                                                                         7/1/2006 – 6/30/2011

“Cellular and molecular basis of malignant astrocytoma”

The goals of this grant are to identify roles of tumor suppressor genes p53 and NF1 in growth regulation and transformation of neural stem cells in the adult brain.

 

Completed Research Support

The General Motor Cancer Research Foundation Yuan Zhu (PI)                 7/1/2004 – 6/30/2006

“The role of neural stem cells in the development of malignant astrocytoma”

The goals of this award are to understand the role of neural stem cells in the development of malignant astrocytoma and to determine the roles of tumor suppressor genes in the growth regulation and transformation of neural stem cells.

 

Brain Tumor Society        Yuan Zhu (PI)                                                                            10/1/2005 – 9/30/2007

“Identification of molecular and cellular targets of malignant astrocytoma in a mouse model”

The goals of this grant are to identify molecular and cellular targets of malignant astrocytomas