Jen-Tsan Ashley Chi, MD, PhD
Center for Genomic and Computational Biology
Box 3382 DUMC
Durham, N.C. 27708
Phone: (919) 668-4759
Fax: (919) 668-4777
The extreme heterogeneity of human cancers is due to several factors including inherited germline variations, multiple somatic mutations, and varying degrees of micro-environmental stresses. While many research efforts have focused on genetic alterations during the processes of tumor initiation and progression, it is equally important to understand how the resulting microenvironmental stresses and nutrient availability will impact such processes and modify tumor phenotypes. We are both interested in both the short-term transcriptional response and essential adaptive mechanisms as well as the long-term consequences through the selection processes under stresses. We apply genomic analysis to define transcriptional responses to hypoxia, lactic acidosis, and various nutrient deprivation on cancer cells and used these responses as surrogates to dissect their influences on tumor heterogeneity and clinical outcomes. The important concept is the use of gene expression to facilitate the information exchanges between in vitro perturbations and in vivo tumors to investigate the biological processes relevant in vivo. In addition, we have applied forward genetic screen to identify genetic determinants of survival under various stresses and nutrient deprivation (1-3). For example, genome-wide RNAi screens under hypoxia that intact novel lipogenesis is essential for the hypoxia-induced apoptosis through the regulation of ETV4 oncogenic programs (4). One recent area of emphasis is to match the nutrient addictions with particular genetic alterations of cancer cells. We have applied nutri-genetic screen by dropping out individual nutrients in a wide variety of cancer types to identify nutrient addictions, metabolic phenotypes and therapeutic options. For example, we have found a dramatic glutamine addiction among a subset of breast tumors. In addition, we have found that methionine deprivation caused an extensive transcriptional reprogramming through the affecting epigenetic regulation that intimately intersect with creatine biosynthesis (5). Recently, we have also found that VHL-null renal cell carcinoma cells are extremely addicted to outside cystine. The deprivation of cystine trigger cell death by RIPK1-dependent canonical necrosis (6). Interestingly, the restoration of VHL abolished this cystine addiction by repressing many of pathways required for the cystine-deprived cell death. Therefore, the elevated TNFα and other oncogenic process induced by VHL loss also render these cells susceptible to cystine-deprived death. We are identifying the genetic determinants and exploring the therapeutic potential of these observations.
The second area of research focus is on the interaction between red blood cell (RBC) and malaria (P. falciparum). We have discovered that mature RBC possess abundant and diverse microRNAs as well as mRNAs(7, 8). Although this unexpected finding was contrary to conventional wisdom, similar findings have been independently reported by several groups. The RBC transcriptome has allowed us to apply genomic analysis to identify their contribution to RBC functionality and pathology, such as sickle cell disease (SCD). We have analyzed these genetic materials to identify that miR-144-mediated reduced NRF2 as potential causes of reduced oxidative capacity of sickle erythrocytes (9). These observation led to a clinical trial of Nrf2 activators in SCD. In addition, we have found that elevated miR-451 play a role in the host-pathogen interactions through the formation of cross-species fusion transcripts (10). The increased miR-451 reduced the translation of PKAR and increased the sexual differentiation of P. falciparum. While the majority of malaria parasites propagate asexually, a small number of parasites mature into the male or female gametocytes capable of transmission to the mosquito vector for further dissemination. Therefore, sexual differentiation represents the critical life-cycle stage for transmission of P. falciparum. However, very little is known about the sex determinants of P. falciparum. However, there are no reliable early sex-specific markers and most gametocytes are only identifiable by morphological features. We are applying single cell RNA and DNA analysis to understand the sexual differentiation and identify sex determinants of P. falciparum.
- 1. Tang X, Lucas JE, Chen JL, LaMonte G, Wu J, Wang MC, et al. Functional interaction between responses to lactic acidosis and hypoxia regulates genomic transcriptional outputs. Cancer Res. 2012;72(2):491-502.
2. Lamonte G, Tang X, Chen JL, Wu J, Ding CKC, Keenan MM, et al. Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress. Cancer & Metabolism. 2014.
3. Tang X, Lin CC, Spasojevic I, Iversen E, Chi JT, Marks JR. A joint analysis of metabolomics and genetics of breast cancer Breast Cancer Res. 2014;16(4):415.
4. Keenan MM, Liu B, Tang X, Wu J, Cyr D, Stevens RD, et al. ACLY and ACC1 Regulate Hypoxia-Induced Apoptosis by Modulating ETV4 via alpha-ketoglutarate. PLoS Genet. 2015;11(10):e1005599.
5. Tang X, Keenan MM, Wu J, Lin CA, Dubois L, Thompson JW, et al. Comprehensive profiling of amino acid response uncovers unique methionine-deprived response dependent on intact creatine biosynthesis. PLoS Genet. 2015;11(4):e1005158.
6. Tang X, Wu J, Ding C-K, Lu M, Keenan MM, Lin C-C, et al. Cystine deprivation triggers programmed necrosis in VHL-deficient renal cell carcinomas. Cancer Research. 2016.
7. Chen SY, Wang Y, Telen MJ, Chi JT. The genomic analysis of erythrocyte microRNA expression in sickle cell diseases. PLoS One. 2008;3(6):e2360.
8. Doss J, Corcoran D, Jima D, Telen M, Dave S, Chi J-T. A comprehensive joint analysis of the long and short RNA transcriptomes of human erythrocytes. BMC Genomics. 2015;16(1):952.
9. Sangokoya C, Telen MJ, Chi JT. microRNA miR-144 modulates oxidative stress tolerance and associates with anemia severity in sickle cell disease. Blood. 2010;116(20):4338-48.
10. LaMonte G, Philip N, Reardon J, Lacsina JR, Majoros W, Chapman L, et al. Translocation of sickle cell erythrocyte microRNAs into Plasmodium falciparum inhibits parasite translation and contributes to malaria resistance. Cell Host Microbe. 2012;12(2):187-99.