Molecular Oncology and Biomarkers


Nahid Mivechi

Nahid F. Mivechi, PhD

Co-leader, Molecular Oncology and Biomarkers Program 
Professor, Radiology, Biochemistry and Molecular Biology
Professor, Radiology and Imaging
Professor, Radiation Oncology
Professor, Graduate Studies


 
Georgia Cancer Center
1120 15th Street, CN 3153
Phone:
706-721-8759 office    706-721-8764 laboratory
NMIVECHI@augusta.edu

Research Summary

Heat shock transcription factors (HSFs) are proteins that are involved in the cell’s response to stress.  In addition, many of the HSFs are highly expressed in multiple tumor types and are involved in cancer initiation and progression. Targeting HSFs leads to significant reduction in tumor development, suggesting that they may be excellent targets for cancer therapy.    My laboratory studies the role of several different HSFs in liver cancer, hematopoietic malignancies, and breast cancer, as well as in neurodegenerative diseases such as Parkinson's disease. 

Research Interests

The primary focus of research in my laboratory, over the past two decades, has been to investigate the regulation and function of mammalian heat shock transcription factors (HSFs) (HSF1, HSF2, HSF4) in the cellular stress response. A second, more recent focus has been to study the cellular processes via which organelle-specific molecular chaperones (cytosolic, mitochondrial and endoplasmic reticulum-resident heat shock proteins) mediate the host response to environmental stressors and the role of these processes in human diseases including cancer.

Research on Heat Shock Transcription Factors in Cancer

Project 1: HSF1 in liver cancer development:

This project is on the role of HSF1 in hepatocellular carcinoma (HCC) development. Basic and pre-clinical studies on mouse models and cancer samples from patients will explore the therapeutic potential of HSF1 inactivation on established liver cancers.

It is worth noting that HCC is the most common liver malignancy, accounting for a large proportion of cancer deaths worldwide. The therapeutic options for HCC are limited, with potential curative treatment available for less than one third of patients, due to the fact that HCC is, in general, refractory to chemotherapy treatment and because HCC becomes clinically symptomatic and detectable only at a late stage. This underscores the urgent need for further research on the mechanisms driving hepatic injury and on the molecular pathways that are vital to HCC progression and metastasis.

Recently, our laboratory has discovered a novel pathogenic mechanism whereby HSF1 activation promotes growth of pre-malignant hepatocytes and HCC development by regulating malignant cell metabolism and obesity. Thus, HSF1 is a potential target for control of hepatic steatosis, insulin resistance, and HCC development. Ongoing research will examine the therapeutic effects of targeting HSF1 on established HCC and investigate the underlying mechanisms by which HSF1 inactivation interferes with tumor progression. In addition, we will investigate a possible causal relationship between alterations in hepatic or total body metabolism (obesity) and HCC development using novel mouse models as well as innovative biochemical and genetic tools. A central hypothesis driving this project predicts that tissue-specific or total body inactivation of HSF1 will result in HCC tumor growth retardation and prevent cancer development by inhibiting tumor-promoting metabolic reprogramming. In addition, our hypothesis predicts that HSF1 inactivation from total or metabolic active organs (e.g., liver, adipose tissues) will prevent or attenuate liver cancer development caused by dietary obesity and metabolic syndrome by interfering with tumor promoting metabolic pathways as well as inflammation.

Our research should have major implications for an understanding of HSF1 function in regulation of tissue-specific and total body metabolism and inflammation, which are critical factors for malignant cell proliferation and cancer development. In addition, it will provide the rationale to develop novel strategies to prevent, and perhaps treat, cancers, including HCC, that arise on the background of chronic hepatic injury due to impaired liver metabolism and proteostasis.

Project 2: Role of heat shock factors (HSFs) in tumorigenesis:

This project is on the role of HSFs in hematopoietic malignancies.  Acute lymphoblastic leukemia (T-ALL) originates from the T cell lineage. The disease represents 15% of pediatric and 25% of adult ALL cases annually, making it the most common cancer in the very young and elderly populations. Disease relapse occurs frequently, and more than 80% of the relapse T-ALL cases harbor the TP53 mutation. These patients develop resistance to chemotherapy that is associated with very poor prognosis. Furthermore, those patients who do go into remission are faced with severe complications due to their prior aggressive chemotherapy. It is therefore critical to understand the molecular mechanisms that cause and drive T-ALL in order to discover novel therapeutic targets with better specificity and reduced toxicity.

The pursuit of this research project is based on the observation that deletion of heat shock factors (HSFs) HSF1, HSF2, or HSF4 on a p53-deficient genetic background leads to significant protection against development of T-ALL. A central focus of ongoing research is to explore the clinically relevant possibility that while HSFs are not essential for T cell development, they may cooperate with oncogenes and tumor suppressor genes to drive T-ALL development. From a therapeutic perspective, assessing HSFs in T-ALL might guide treatment choices in early-stages of cancer. Thus, this research may provide the rationale to develop novel strategies to prevent and perhaps treat cancers, including T-ALL.

Project 3: Exploiting the therapeutic effects of targeting HSF1 in breast cancer:

This project is on the role of HSF1 on breast cancer development. HSF1 has significant effects on the initiation and progression of breast cancer. Our laboratory has a major interest in unraveling the role of HSF1 in diverse types of breast cancer, and we propose basic and pre-clinical research on several clinically important issues of this disease.

Breast cancer is the most common malignancy among women, with greater than 1,300,000 cases and 450,000 deaths each year worldwide. Despite the availability of treatment options for ER+ and Her2+ breast cancer patients, e.g., endocrine therapies or combination of antibody treatment with multiple chemotherapeutic agents, intrinsic and acquired resistance limits the long-term efficacy of these treatments. In addition, patients with triple-negative breast cancer (TNBC), which comprises approximately 20% of breast cancers, have a poor prognosis because of the propensity for recurrence and metastasis and the lack of effective targeted therapeutics. Thus, a major challenge is to identify novel, therapeutically tractable pathways for major biological subtypes of breast cancer, particularly the aggressive TNBCs.

In recent studies we have discovered that HSF1, which is a master regulator of the heat shock response, has a central role, along with other signaling molecules, in breast cancer development. Relevant to this, high levels of nuclear HSF1 expression is an independent prognostic indicator of poor outcome in breast cancer patients, and mouse model studies, including ours, have established its essential role in initiation, progression and metastasis of Her2-driven mammary tumors. However, due to the multifaceted role of HSF1 in transformation, the precise mechanism by which HSF1 promotes mammary cancer is currently unclear. In addition, the therapeutic potential of HSF1 inactivation on established breast cancers of diverse genetic and histological subtypes remains unclear. Exploring the full extent to which HSF1 inactivation may influence breast cancer progression and potentially prevent organ metastasis is a necessary step to establish the selectivity and efficacy of such an approach in the treatment of breast cancer patients. Together, studies in our laboratory are expected to improve the diagnosis, prognosis and clinical treatment of high-risk breast cancer subtypes. Future efforts will evaluate HSF1 as a central regulator of human breast cancer invasion and metastasis and identify drugs that specifically target HSF1 function.

Additional Projects on HSFs and Cancer

Ongoing research in my laboratory is focused on the distinct role of HSF1 in lung and pancreatic cancers.

Research on Heat Shock Transcription Factor Regulation

Project 4: Role of heat shock factor binding protein 1 in regulating HSF1 activity:

Heat shock factor binding protein 1 (HSBP1,) originally isolated by Dr. R. Morimoto’s laboratory in the mid 1990s, has been proposed to repress HSF1 activity in cell lines. However, its function in vivo remains largely elusive. To approach this issue using a conventional and conditional targeting strategy to disrupt the HSBP1 gene, our laboratory has generated two mouse models. In a recent report, we presented evidence that HSBP1 plays an essential role in embryonic development by regulating endoderm specification programs (Eroglu, B., et al., Dev Biology, 2014. 386: 448-460). The physiological role of HSBP1 in cellular function and disease conditions remains unknown and this is currently a focus of the ongoing research in my laboratory.

Project 5: Signaling pathways regulating HSF1 activity:

HSF1 is phosphorylated by multiple protein kinases that regulate its activity. However, the contribution of phosphorylation in regulation of HSF1 activity in vivo has remained elusive. To approach this issue, my laboratory has generated a knock-in mouse model in which S307 and S303 have been substituted with alanine. It was predicted that these modifications might confer HSF1 to be constitutively active. In fact, our results confirmed this prediction. Ongoing research will further explore the potential role of the mutant HSF1 in hepatic metabolism and nutrient-induced obesity.

Research on HSPs and HSFs in Neurodegenerative Diseases

Project 6: Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta.

An essential role of molecular chaperones in quality control is correct protein folding. This project is to study the potential function of the HSP70 machinery in tauopathy and Alzheimer’s diseases. In a published study, our laboratory has demonstrated that HSP110 forms complexes with tau and protein phosphatase 2A (PP2A), and that the function of HSP110-HSP70 in these complexes is to prevent phosphorylation and aggregation of tau during aging, thus preventing cerebral plaque formation and disease progression (tauopathy). Thus, our study has provided in vivo evidence implicating the HSP70 chaperone machinery (HSP110) in the pathogenesis of Alzheimer's disease and other tauopathies. (B. Eroglu, D. Moskophidis, and N. F. Mivechi, 2010. MCB, 19: 4623-4643).

Interestingly, HSP110-deficient mice exhibit additional complex phenotypes including age-dependent development of an autoimmune hepatitis-like disease (comparable to a similar disease in human) that is associated with liver inflammation, fibrosis and sporadic liver cancer development. This phenotype of HSP110-deficient mice is currently under further investigation.

Research on Heat Shock Proteins (in collaboration with laboratory of Dr. D. Moskofidis)

Project 7: Heat shock response and molecular chaperones in oncogenesis and viral and transformation:    

Synthesis of molecular chaperones modulate cellular transformation by interfering with stress signaling mechanisms, thus perturbing a cellular defense mechanism that would normally lead to the elimination of transformed cells by apoptosis. For example, association of mutant forms of the p53 tumor suppressor protein with molecular chaperones (HSC70/HSP70) has been demonstrated and could be a critical event associated with cell transformation. In addition, members of the cytosolic HSP70 family have been detected in complexes with viral proteins involved in cell transformation, including SV40 large T antigen and adenovirus E1A protein. HSP90, a high molecular weight chaperone, interacts with tyrosine kinase oncogene products pp60-v-src, fes, and fgr, as well as estrogen and progesterone nuclear receptors, to form stable complexes. Using various biochemical and molecular approaches, such as transgenic and knockout mice deficient in HSP70, HSC70, HSP90a or HSP90b, ongoing research in our laboratory is directed to better understand the nature of such interactions at both the cellular and whole organism levels, with the goal of identifying targets for therapeutic intervention.

Project 8: Heat shock response and molecular chaperones in angiogenesis:

Progress in understanding the dynamic interaction between cancer cells and their microenvironment and application of this knowledge to detection, diagnosis, prevention, treatment, and control of all cancers is a major goal for ongoing research in our laboratory. Mounting evidence suggests that the “tumor microenvironment” is populated with a variety of different cell types, including elements of the blood and lymphatic systems, that play a pivotal role in cancer development and can influence the delivery and processing of chemotherapy drugs to the tumor. Studies of HSP70-deficient mice generated in our laboratory have revealed that HSP70 expression is specifically regulated during angiogenesis, as visualized in endothelial cells during blood vessel formation in growth of transplanted tumors and during embryo development. Thus, a specific focus of ongoing research is to determine whether tissue-specific inactivation of HSP70 expression could influence tumor development and metastasis by interfering with blood vessel formation. Studies directed to understand the molecular basis for tissue-specific HSP70 expression promise to produce important knowledge for developing new approaches to cancer treatment. A role in angiogenesis has also been assigned to the HSP90 family of molecular chaperones, and the development of mouse models (HSP90a or HSP90b conditional knock-outs) is in progress in our laboratory and that of Dr. D. Moskofidis. These models will provide a valuable tool to study the role of these molecular chaperones in vasculogenesis and angiogenesis in tumor development as well as in cardiovascular diseases.

Selected Publications

Structural organization and promoter analysis of murine heat shock transcription factor-1 gene.  Zhang Y, Koushik S, Dai R, Mivechi NF. J Biol Chem. 1998 Dec 4;273(49):32514-21. PMID: 9829985.

Glycogen synthase kinase 3beta and extracellular signal-regulated kinase inactivate heat shock transcription factor 1 by facilitating the disappearance of transcriptionally active granules after heat shock. He B, Meng YH, Mivechi NF. Mol Cell Biol. 1998 Nov;18(11):6624-33. PMID: 9774677.

c-Jun NH2-terminal kinase targeting and phosphorylation of heat shock factor-1 suppress its transcriptional activity. Dai R, Frejtag W, He B, Zhang Y, Mivechi NF. J Biol Chem. 2000 Jun 16;275(24):18210-8. PMID: 10747973.

Insights into regulation and function of the major stress-induced hsp70 molecular chaperone in vivo: analysis of mice with targeted gene disruption of the hsp70.1 or hsp70.3 gene. Huang L, Mivechi NF, Moskophidis D. Mol Cell Biol. 2001 Dec;21(24):8575-91. PMID: 11713291

Targeted disruption of Hsf1 leads to lack of thermotolerance and defines tissue-specific regulation for stress-inducible Hsp molecular chaperones.   Zhang Y, Huang L, Zhang J, Moskophidis D, Mivechi NF. J Cell Biochem. 2002;86(2):376-93. PMID: 12112007.

Unique contribution of heat shock transcription factor 4 in ocular lens development and fiber cell differentiation. Min JN, Zhang Y, Moskophidis D, Mivechi NF. Genesis. 2004 Dec;40(4):205-17. PMID: 15593327.

Association and regulation of heat shock transcription factor 4b with both extracellular signal-regulated kinase mitogen-activated protein kinase and dual-specificity tyrosine phosphatase DUSP26. Hu Y, Mivechi NF. Mol Cell Biol. 2006 Apr;26(8):3282-94. PMID: 16581800

Loss of Hsp110 leads to age-dependent tau hyperphosphorylation and early accumulation of insoluble amyloid beta. Eroglu B, Moskophidis D, Mivechi NF. Mol Cell Biol. 2010 Oct;30(19):4626-43. PMID: 20679486.

Heat shock transcription factor 1 is a key determinant of HCC development by regulating hepatic steatosis and metabolic syndrome. Jin X, Moskophidis D, Mivechi NF. Cell Metabolism. 2011 Jul 6;14(1):91-103. PMID: 21723507.

Inactivation of heat shock factor Hsf4 induces cellular senescence and suppresses tumorigenesis in vivo. Jin X, Eroglu B, Cho W, Yamaguchi Y, Moskophidis D, Mivechi NF. Molecular Cancer Research. 2012 Apr;10(4):523-34. PMID: 22355043

Heat shock factor Hsf1 cooperates with ErbB2 (Her2/Neu) protein to promote mammary tumorigenesis and metastasis. Xi C, Hu Y, Buckhaults P, Moskophidis D, Mivechi NF. J Biol Chem. 2012 Oct. 12;287(42):35646-57. Epub 2012 Jul 30. PMID: 22847003.

An essential role for heat shock transcription factor binding protein 1 (HSBP1) during early embryonic development. Eroglu B, Min JN, Zhang Y, Szurek E, Moskophidis D, Eroglu A, Mivechi NF. Developmental Biology 2014 Feb 15; 386(2):448-60. PMID: 24380799.

Inhibitor of differentiation 1 transcription factor promotes metabolic reprogramming in hepatocellular carcinoma cells. Sharma BK, Kolhe R, Black SM, Keller JR, Mivechi NF, Satyanarayana A. (2016) FASEB J. Jan 30, 262-275.

GT198 Defines Reactive Tumor Stroma in Human Breast Cancer. Zheqiong Yang, Min Peng, Liang Cheng, Kimya Jones, Nita J. Maihle, Nahid F. Mivechi and Lan Ko.   (2016) American Journal of  Pathology, 186: 1340-1350.

Abrogation of heat shock factor 1 (Hsf1) phosphorylation  deregulates Hsf1 activity and lowers its activation threshold, leading to obesity in mice. Jin, X., Qiao, A. Mivechi, N. F. (2017).   Journal of Biological Chemistry, In press.

The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis. Qiao, A., Jin, X., D. Moskophidis and N.F. Mivechi. (2017).  Journal of Cell Biology, 216: 723-741. 

Malignant pericytes expressing GT198 give rise to tumor cells through angiogenesis.  Liyong Zhang, Yan Wang, Mohammad H. Rashid, Min Liu, Kartik Angara, Nahid F. Mivechi, Nita J. Maihle, Ali S. Arbab and Lan Ko. (2017)

Oncotarget, In press

 

Research Team

Binnur Eroglu, PhD
Assistant Professor
beroglu@augusta.edu 

 Xiongjie Jin
Assistant Research Scientist
xjin@augusta.edu 

 Aijun Qiao
Postdoctoral Fellow
aqiao@augusta.edu