Cell Communication and epigenetics in GYN disease -
Cellular communication via secreted factors and direct cell-cell interactions has be the focus of investigation in endometriosis, a benign inflammatory gynecologic disease, and endometrial cancer. Cytokine signaling by TGF-beta and macrophage colony stimulating factor and intracellular signaling Raf-1/MAPK pathway were implicated in the invasiveness of endometriotic lesions. Recently, intercellular gap junction communication was examined as another mode of cellular communication between endometrial cells and the target of invasion in endometriosis, the mesothelium. Using traditional cell assays as well as single-cell analysis, specific gap junction proteins (channel forming connexins) were identified that may be involved in endometrial cell invasiveness leading to endometriotic lesion development. In endometrial cancer, epigenetic reactivation increased gap junction communication, which was associated with increase in expression of connexin regulatory kinases, suggesting an epigenetic component in the regulation of gap junction activity. In another line of studies, the epithelial cell adhesion molecule (EpCAM) was shown to mediate EGFR actions in endometrial cancer. This EGFR/EpCAM axis seems to modulate target genes via epigenetic regulation. Currently the interplay between cell signaling and epigenetics in gynecologic disease is under investigation. |
Epigenetics and Biomarkers of Oral Cancer -
Studies published in Carcinogenesis (2013) and Oral Oncology (2016) suggest that loci exhibiting low promoter methylation (i.e., hypomethylation) may exist in an open transcriptional configuration, allowing their induction during malignant progression. One of these loci, the anaplastic lymphoma kinase (ALK), was found to be expressed in late-stage oral squamous cell carcinoma (OSCC) and implicated in the invasiveness of OSCC cell lines. Based on in vitro and in vivo data, targeting ALK may be a potential therapeutic strategy for invasive OSCC in conjunction with epidermal growth factor (EGFR) activation. The cross-talk between ALK and EGFR in aggressive OSCC behavior is under investigation based on findings that both pathways converge on AKT. In addition, an innovative biomarker discovery pipeline includes the use of non-surgical oral brush biopsy sampling from OSCC patients, isolation of single cells by the DepArray platform, and microfluidic PCR to assess single-cell expression profiles of OSCC cells as well as direct multiplex salivary RNA expression assays. The overall goal is to validate putative biomarkers identified by our research and implement their use as non-invasive, point-of care prognostic tools. |
Hormone and Nutrition Epigenetics in Cancer -
Research has focused on elucidating the effects of steroid hormones, namely estrogen, and xenoestrogens on breast cancer. The molecular mechanisms of gene regulation relevant to enhanced mitogenic signaling in hormone- and growth factor-responsive breast cancer are studied. Additionally, the role of nutrient based phytochemicals, including phytoestrogens, and environmental estrogen disruptors affecting estrogenic actions and epigenetics in normal and malignant development of breast tissue is under investigation. Collaborative effort has also focused on the effects of estrogenic stimulation on chromatin looping and rearrangement and DNA methylation in breast cancer cells. |
Abstract |
| Hsu Y, Osmulskim P, Wang Y, Huang Y, Ruan J, Jin V, , Gaczynsca M, Kirma NB, Huang TH. EpCAM and LEF-1 Co-regulated Transcription Alters Nanomechanical Phenotypes of Endometrial Cancer Cells for Promoting Invasion; 2015 Oct. (Innovations in Cancer Prevention and Research Conference; vol. IV).
|
| Kirma NB, Chen CL, Jin V, Wang CM, Huang TH. Single Cell Biopsy and Charactrization; 2015 Oct. (Innovations in Cancer Prevention and Research Conference; vol. IV).
|
| Kirma NB, Nicholson BJ, Huang TH. Transcriptome screening for diagnostic differences in the endometrium of women with endometriosis; 2015 May. (Oxford Nanopore Technologies London Calling Conference).
|
Journal Article |
| Horning AM, Wang Y, Lin CK, Louie AD, Jadhav RR, Hung CN, Wang CM, Lin CL, Kirma NB, Liss MA, Kumar AP, Sun L, Liu Z, Chao WT, Wang Q, Jin VX, Chen CL, Huang TH. Single-Cell RNA-seq Reveals a Subpopulation of Prostate Cancer Cells with Enhanced Cell-Cycle-Related Transcription and Attenuated Androgen Response Cancer Research 2018 Feb;78(4):853-864.
|
| Hsu YT, Osmulski P, Wang Y, Huang YW, Liu L, Ruan J, Jin VX, Kirma NB, Gaczynska ME, Huang TH. EGFR-Dependent Regulated Intramembrane Proteolysis of EpCAM-Response Cancer Research 2017 Jan;.
|
| Gonzales CB, De La Chapa JJ, Saikumar P, Singha PK, Dybdal-Hargreaves NF, Chavez J, Horning AM, Parra J, Kirma NB. Co-targeting ALK and EGFR parallel signaling in oral squamous cell carcinoma Oral Oncology 2016 Aug;59(08):12-19.
|
| Ruan J, Jahid MJ, Gu F, Lei C, Huang YW, Hsu YT, Mutch DG, Chen CL, Kirma NB, Huang TH. A novel algorithm for network-based prediction of cancer recurrence Genomics 2016 Jan;7543(16).
|
| Hsu YT, Osmulski P, Wang Y, Huang YW, Liu L, Ruan J, Jin VX, Kirma NB, Gaczynska ME, Huang TH. EpCAM-Regulated Transcription Exerts Influences on Nanomechanical Properties of Endometrial Cancer Cells That Promote Epithelial-to-Mesenchymal Transition Cancer Research 2016 Jan;76(21):6171-6182.
|
| Hsu PY, Hsu HK, Hsiao TH, Ye Z, Wang E, Profit AL, Jatoi I, Chen Y, Kirma NB, Jin VX, Sharp ZD, Huang TH. Spatiotemporal control of estrogen-responsive transcription in ERa-positive breast cancer cells Oncogene 2015 Aug;.
|
| Mukhopadhyay KD, Liu Z, Bandyopadhyay A, Kirma NB, Tekmal RR, Wang S, Sun LZ. Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cell PLoS One 2015 Apr;10(4).
|
Federal |
| Funding Agency |
NIH/NCI |
| Title |
Systems Analysis of Epigenomic Architecture in Cancer Progression |
| Status |
Active |
| Period |
4/2017 - 3/2022 |
| Role |
Co-Investigator |
| Grant Detail |
|
| Funding Agency |
NIH/NCI |
| Title |
Novel Epigenetic paradigm in Endometrial Cancer Recurrence |
| Status |
Active |
| Period |
9/2014 - 8/2019 |
| Role |
Co-Investigator |
| Grant Detail |
This proposal focuses on epigenetic overwriting of the default state is necessary for EMT-mediated progression of endometrial cancer cells. In Aim 1, we will validate the methylation status of these candidate loci in an independent cohort of endometrial cancer. In Aim 2, we will assess whether epidermal growth factor-induced EMT leads to identification of epithelial cell adhesion molecule intarcellular domain EpICD target genes delineating novel candidate hypomethylators. In Aim 3, we will determine whether the EpICD transcription complex is a key factor of this epigenetic reprogramming. |
Private |
| Funding Agency |
Endometriosis Foundation of America |
| Title |
Enhanced endometrial-mesothelial gap junction communication in endometriosis |
| Status |
Active |
| Period |
4/2017 - 3/2018 |
| Role |
Principal Investigator |
| Grant Detail |
The lack of complete knowledge of underlying mechanisms that trigger endometriosis is a major reason for the absence of efficacious drugs for this debilitating disease. Specifically, there is a big gap in understanding the molecular communication occurring between different cell compartments during invasion and endometriosis lesion formation, especially regarding the initial heterologous interactions between invading endometrial tissue (composed of stroma and epithelial compartments) and target peritoneal mesothelium cells (PMCs) in the pelvic cavity. Our studies revealed that while gap junction intercellular coupling (GJIC) is suppressed in homotypic cultures of primary endometrial epithelial cells (EECs) derived from endometriosis compared to normal subjects, interaction with PMCs monolayer induced both homotypic and heterotypic coupling of the endometrial cells. As we have shown that these interactions are selectively enhanced in endometriosis by secreted factors from PMCs, we hypothesize that antagonists to these mesothelial cell secreted factors could be novel therapeutic agents in the treatment of endometriosis. Our studies will lead to a much better understanding of the mechanisms underlying this intercellular communication involved in endometriosis lesion establishment, and will likely lead to the design of novel therapeutic strategies that go beyond the symptomatic anti-inflammatory and hormone treatments that dominate currently. |
