Overview
Our laboratory focuses on understanding the roles of the heat shock or stress response in tumor evolution. The stress response is an evolutionarily highly conserved adaptive mechanism that enhances cell survival in the face of a large variety of stressful insults from without and from within. In mammals, the master transcriptional regulator of this systemic cellular response is heat shock factor 1, HSF1, a pleiotropic molecule that coordinates a network of cellular pathways to fight stresses. Understanding how the stress response functions during cancer initiation, maintenance, and progression, which still remains largely unknown, has the potential to revolutionize our knowledge of cancer evolution and to ultimately translate into innovative anti-cancer prevention and therapy in humans.
In sharp contrast to their role in promoting malignancy, HSF1 and the stress response antagonize neurodegeneration. Thus, our laboratory is very interested in understanding how this ancient protective mechanism acts to balance the two major age-related diseases, cancer and neurodegeneration, and ultimately determines the lifespan of mammals.
Scientific report
The stress response and tumor evolution
Tumorigenesis is a dynamic and multi-step process that involves initiation, promotion, maintenance and progression stages. From a normal cell to a premalignant lesion to a malignant tumor and finally to a lethal metastatic tumor, the whole process can be envisioned as a model of somatic evolution following the same Darwinian principles. Cancer is initiated by the activation of oncogenes or inactivation of tumor suppressor genes. However, numerous other genetic, epigenetic and environmental factors constantly interact with cancer-causing events to exert marked impacts on the susceptibility to cancer development, the ability of tumor cells to invade and metastasize, and the responses of tumors to therapies.
The stress response and tumor initiation
The HSF1-mediated stress response has been implicated in antagonizing a broad range of human pathophysiological conditions, such as hyperthermia, ischemia/reperfusion and neurodegeneration. Surprisingly, its involvement in human malignancies has remained uncertain until very recently. By taking advantage of Hsf1 knockout mice, we discovered that the stress response plays an enabling role in skin carcinogenesis initiated by a chemical mutagen and multiple tumorigeneses initiated by a hot-spot Trp53 point mutation. These results demonstrate that the HSF1-mediated stress response acts as a potent modifier of tumor initiation by altering cellular susceptibility to oncogenic transformation.
Exploitation of the stress response as a general cancer target depends on determining whether the enabling role of the stress response is universal and predominates in tumor initiation regardless of causal defects and histological origins. One ongoing project is to investigate the enabling role of the HSF1-mediated stress response in malignancies associated with Neurofibromatosis type I (NF1), the most common human cancer predisposition syndrome that afflicts 1 in 3,500 people worldwide. The tumor suppressor NF1 gene encodes a ~ 280KD protein called neurofibromin, a negative regulator of the RAS oncoprotein. NF1 patients frequently develop multiple types of malignancy, including neurofibromas, brain tumors and myeloid leukemia. Our results clearly indicate that ablation of HSF1 markedly suppresses the tumorigenic process associated with Nf1 deficiency in mice and impairs the growth and survival of human NF1 tumor cells in culture. These studies provide strong evidence that targeting the stress response is an innovative and promising strategy to prevent malignancy in NF1 patients. Our current efforts are to understand why NF1-associated tumor initiation depends on the stress response. Aberrant RAS signaling and oxidative stress resulting from Nf1 deficiency are the two primary areas of inquiry.
The stress response and tumor maintenance
Although the current evidence points to an enabling role of the stress response in tumor initiation, it is still unknown whether established tumor cells become addicted to this powerful adaptive mechanism. This question is pivotal to targeting the HSF1-mediated stress response as a novel anti-cancer therapeutic strategy. Two discrete but complementary model systems will be incorporated to examine the dependence of established tumors on the HSF1-mediated stress response in vivo. A novel transgenic mouse model in which the Hsf1 gene expression is temporarily repressible by doxycycline has been developed. After full tumor induction in these mice, Hsf1 expression will be repressed and tumor responses will be monitored. In addition, we are developing a xenograft model, in which human cancer cells are engineered to express HSF1-targeted shRNAs in an inducible fashion. To gain mechanistic insights at a system level, global gene expression profiles of tumors before and after HSF1 repression will be analyzed by microarray technology.
The stress response and tumor progression
Whether the stress response affects tumor cells' evolvability and tumor progression is completely unknown. Genomic instability is a major cause of tumor progression; it increases the genetic diversity of tumor cells that can be selected by tumor microenvironments for evolution. There are two possible mechanisms by which the activated stress response may contribute to genomic instability. By enhancing the expression of heat shock proteins, which chaperone protein folding, and orchestrating the transcription of an extensive network of genes, the stress response can allow many otherwise deleterious mutations to accumulate in a silent or tolerable state inside tumor cells and further release them for environmental selections, a phenomenon referred as "genetic buffering." By preventing premature exposure of critical mutations, the stress response may enrich genetic diversity and facilitate tumor progression. Alternatively, HSF1 itself may directly enhance genomic instability by blocking mitotic exit and promoting aneuploidy in tumors. Elucidation of these intriguing questions may provide crucial evidence that modulating the stress response is a new way to impair tumor cells' ability to evolve. The skin carcinogenesis model, a classic somatic tumor evolution process, will be adopted in the inducible Hsf1 transgenic mice. Tumor progression is indicated by the rate of malignant conversion of skin tumors and the rate of further generating metastatic lesions. Global genomic abnormalities of skin tumors with and without enhanced HSF1 will be profiled using array Comparative Genomic Hybridization technology (aCGH).
The stress response and aging, longevity
Although the stress response has a fascinating role in prolonging the lifespan of lower organisms, its influence on mammalian longevity is elusive. Particularly in humans, aging is associated with two major diseases, cancer and neurodegeneration, and the stress response happens to be involved in both. Ironically, while the stress response protects neurons from death and antagonizes neurodegeneration, the very same mechanism promotes cancer. With access to numerous genetic murine models of premature aging and lifespan extension and an extensive collection of naturally aging inbred mouse strains, The Jackson Laboratory provides us with an unparalleled opportunity to understand how this ancient mechanism's effects on cancer and neurodegeneration are balanced and how they impact longevity in mammals. These studies may ultimately lead to new ways of fighting aging and increasing longevity.
Lab staff
Postdoctoral Associate: Junxia Cao, Ph.D.
Publication listings
Dai C, Whitesell L, Rogers A, Lindquist S. 2007. Heat shock factor 1 (HSF1) is a powerful multifaceted modifier of carcinogenesis. Cell 130(6):1005-1018.
Selected Perspectives and Press Coverage:
1. Non-Oncogene Addiction and the Stress Phenotype of Cancer Cells. Cell 2007; 130(6):986-988.
2. Cancer Cells Chill Out to Survive. (http://sciencenow.sciencemag.org/cgi.content/full/2007/920/1)
3. Cancer Biology: Shock Strategy. Nature 2007; 449(7161):380-381.
4. A Shocking Enabler of Tumour Growth. Nature Reviews Cancer 2007; 7(11):817.
5. Aiding and Abetting: A longevity gene also promotes cancer. Science News 2007; 172(12):179-180.
Dai C, Whitesell L. 2005. Hsp90: a rising star on the horizon of anticancer targets. Future Oncol 1:529-540, review.
Dai C, Lyustikman Y, Shih A, Hu X, Fuller GN, Rosenblum M, Holland EC. 2005. The characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable signaling formats. Neoplasia 7(4):397-406.
Lassman A, Dai C, Fuller GN, Vickers AJ, Holland EC. 2004. Overexpression of c-MYC promotes an undifferentiated phenotype in cultured astrocyts and allows elevated Ras and Akt signaling to induce gliomas from GFAP-expressing cells in mice. Neuron Glia Biology 1(2):157-163.
Shih A, Dai C, Hu X, Rosenblum MK, Koutcher JA, Holland EC. 2004. Dosage-dependent effects of PDGF-B on glial tumorigenesis. Cancer Res 64(14):4783-4789.
Dai C, Holland EC. 2003. Astrocyte differentiation states and glioma formation. Cancer J 9(2):72-81, review.
Wolf RM, Draghi N, Liang X, Dai C, Uhrbom L, Eklof C, Westermark B, Holland EC, Resh MD. 2003. p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human chromosome 19q13.3. Genes Dev 17(4):476-487.
Uhrbom L, Dai C, Celestino J, Rosenblum MK, Fuller GN, Holland EC. 2002. Ink4a-Arf loss cooperates with Kras activation in astrocytes and neural progenitors to generate glioblastomas of various morphologies depending on amount of Akt activity. Cancer Res 62(19):5551-5558.
Fults D, Pedone C, Dai C, Holland EC. 2002. MYC expression promotes the proliferation of neural progenitor cells in culture and in vivo. Neoplasia 4(1):32-39.
Dai C, Holland EC. 2001. Glioma Models. Biochim Biophys Acta 1551:M19-M2, review.
Dai C, Celestino JC, Okada Y, Louis DN, Fuller GN, Holland EC. 2001. PDGF autocrine stimulation dedifferentiation cultured astroctyes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 15:1913-1925.
Holland EC, Li Y, Celestino JC, Dai C, Schaefer L, Sawaya RE, Fuller GN. 2000. Astrocytes give rise to oligodendrogliomas and astrocytomas after gene transfer of polyoma virus middle T antigen in vivo. Am J Pathol 157(3):1031-1037.
Holland EC, Celestino JC, Dai C, Schaefer L, Sawaya RE, Fuller GN. 2000. Combined activation of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nat Genet 25(1):55-57.
