Identification of molecular networks linking inflammation to cancer

In 1863, Rudolf Virchow proposed that chronic inflammation may lead to development of cancer, and there are now clinical, epidemiological and molecular links between inflammation and oncogenic transformation. However, molecular pathways linking inflammation to cellular transformation have not been extensively characterized in large part because of the lack of experimental systems that can follow the process by which a non-transformed cell becomes transformed. We have developed novel cellular inducible models of oncogenic transformation to study the transformation process in breast and liver cancers. By using these models, we have identified that microRNA-inflammatory feedback loop circuits underlie the “epigenetic switch” from a non-transformed cell type to a transformed cell type which is capable of forming self-renewing stem cells. In these studies, we have proposed that the epigenetic switch requires cells to be at an intermediate stage in the transition between a primary cell and a cancer cell. The feedback loop circuit could be activated at any step of the loop through intracellular and/or extracellular stimuli. Taken together, our results provide a new paradigm in which a key step in cancer progression involves an epigenetic switch in response to an inflammatory (or other environmental) signal as opposed to a mutational change in a tumor suppressor or oncogene.

A. Iliopoulos D, Hirsch HA, Struhl K. An epigenetic switch involving NF-κB, Lin28, let-7 microRNA, and IL6 links inflammation to cell transformation. Cell, 139:693-706, 2009. Preview article by Drost J & Agami R in the same issue. This article was presented in Research Highlights of Nature Reviews Immunology (9: 822, 2009) and Science (326, 2009). This article was presented in the Focus Magazine (April 23, 2010) and websites of Harvard Medical School, Dental School and School of Public Health. Evaluated as an “exceptional” paper by Faculty of 1000 Biology and as a “recommended” paper by Faculty of 1000 Medicine.

B. Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell, 2010; 39:493-506.

C. He G, Dhar D, Nakagawa H, Font-Burgada J, Ogata H, Jiang Y, Shalapour S, Seki E, Yost SE, Jepsen K, Frazer KA, Harismendy O, Hatziapostolou M, Iliopoulos D, Suetsugu A, Hoffman RM, Tateishi R, Koike K, Karin M. Identification of liver cancer progenitors whose malignant progression depends on autocrine IL-6 signaling. Cell 2013; 155:384-96.

D. Hatziapostolou M, Polytarchou C, Aggelidou E, Drakaki A, Poultsides GA, Jaeger SA, Ogata H, Karin M, Struhl K, Hadzopolou-Cladaras M, Iliopoulos D. An HNF4a-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis. Cell 2011; 147:1233-47.

E. Iliopoulos D. MicroRNA circuits regulate the cancer-inflammation link. Sci Signal, 7:pe8, 2014. 

Identification of drugs (metformin) targeting tumor-initiating and chemotherapy resistant cells

Recent studies have revealed the presence of cell subpopulations in human tumors that harbor tumor-initiating potential and also they are resistant to chemotherapy and/or radiotherapy. Thus, it is important to identify the molecular mechanisms involved in the formation and maintenance of these subpopulations and develop new drugs that have the ability to selectively inhibit their growth. We have first performed an FDA-approved drug screen and found that metformin, an anti-diabetic drug, targets these populations and suppresses tumor growth in vitro and in vivo, prolonging tumor relapse. Our studies have reinforced the idea of drug repositioning studies in the cancer field. Furthermore, we found that inflammatory mediators, such as IL-6, are important for the interplay between non-stem cells and stem cell populations. Furthermore, we established the role of chromatin and histone modifications in the formation of tumor-initiating cells.

A. Iliopoulos D, Polytarchou C, Hatziapostolou M, Kottakis F, Maroulakou IG, Struhl K, Tsichlis PN. MicroRNAs differentially regulated by Akt isoforms control EMT and stem cell renewal in cancer cells. Sci Signal 2009;2:ra62.

B. Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol Cell 2010; 39:761-72.

C. Iliopoulos D, Hirsch HA, Wang G, Struhl K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011; 108:1397-402.

D. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011; 71:3196-201.

E. Hirsch HA*, Iliopoulos D*, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res, 69:7507-11, 2009. *equal contribution

Evaluated as a “must read” paper by Faculty of 1000 Biology Cover of October 1st Cancer Research Issue. This work made an impact all over the world as more than 30 prominent media publications announced these findings. Examples of media reports that featured this work include: In United States (Forbes, US News & World Report, Reuters and Wall Street Journal), in France (AFP), in UK (BBC News, Cancer Research UK), in Germany (Wissenschaft), in Portugal (Publico), in Canada (CTV), in Australia (Sidney Morning Herald), in Qatar (Gulf Times) and in India (Press Trust of India).

Identification of a novel drug target for triple negative breast cancer 

Triple negative breast cancer is a very aggressive type of breast cancer with few treatment options. Analysis in breast cancer patient samples and cell lines showed that XBP1 is activated specifically in triple negative breast cancer but not in any other breast cancer subtype. XBP1 ChIP-sequencing revealed a significant enrichment of hypoxia inducible factor 1a binding sites. HIF1A and XBP1 were found to physically interact. Importantly XBP1 suppression inhibited triple negative breast cancer growth and metastasis in mice, suggesting the potential use of XBP1 inhibitors in triple negative breast cancer patients.

Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M, Lim E, Tam WL, Ni M, Chen Y, Mai J, Shen H, Hu DZ, Adoro S, Hu B, Song M, Tan C, Landis MD, Ferrari M, Shin SJ, Brown M, Chang JC, Lix XS, Glimcher LH. XBP1 promotes triple-negative breast cancer by controlling the HIF1a pathway. Nature, 508: 103-7, 2014.

This is the first study identifying a biomarker unique for triple negative breast cancer. These findings were published in different media all over the world (Genetic Engineering News, Cornell Chronicle, Bionews Texas, EurekAlert, Oncologgy Nurse Advisor, Capital New York, Informationsdienst Wissenschaft). Previews for this article were written in the following journals: Cancer Discovery, April 3, 2014, Breast Cancer Research, 16: 471, 2014, ASCO Post, March 27, 2014.