The overall goal of the Brainson Lab is to define precision therapy options for genotype- and subtype-specific lung cancer using ideas and techniques from stem cell biology and epigenetic research.

Non-small cell lung cancer (NSCLC) is a devastating disease with extensive genetic, cellular and epigenetic complexity. For example, an average human lung tumor has over 200 non-synonymous mutations and can contain cells that have markers of several different lung lineages. The lineage relationship and epigenetic differences between the two major subtypes of non-small cell lung cancer, namely lung adenocarcinoma (ADC) and lung squamous cell carcinoma (SCC), are unclear.

Cells of Origin of Lung Cancer

The mammalian lung is a complex organ containing numerous stem/progenitor cell populations, any of which may serve as cells-of-origin for lung carcinomas in various genetic and microenvironmental contexts. Our lab is directly testing cell-of-origin fitness by isolating lung stem and progenitor cells and introducing specific genetic events into the isolated populations. During the transformation process, we culture the cells in 3-dimensional organoid culture systems. Once genetically modulated organoids are established, they are then implanted into immunocompomised mice to assess malignancy and tumor subtype. Using this system, the epigenetic changes that cells undergo during transformation will be assessed. Understanding which epigenetic states are permissive for lung cancer initiation, and in which microenvironmental contexts, will help us to target the root causes of the disease. In addition, studying the earliest stages of disease may suggest new methods of early detection for lung cancer.

Epigenetic Precision Medicine for Lung Cancer

While our cell-or-origin approaches will give valuable insight into the early stages of lung tumorigenesis, more clinically important is finding methods to incorporate epigenetic inhibitors to treat established lung tumors. Therefore, our lab uses primary tumors from genetically engineered mouse models (GEMMs) of lung cancer to explore the effects of epigenetic inhibitors on tumor cell growth, differentiation and response to other chemotherapies. While many lung cancer cells cannot grow as 2-dimensional cultures, we can grow cells of diverse genotypes, including KRASG12D, KRASG12D/Lkb1-null, EGFRT790M/L858R and Lkb1-null/Pten-null in 3-dimensional cultures. Using these cultures, our main focus is to link the genotype and subtype of the lung tumor cells to efficacy of the epigenetic inhibitors. To validate our findings in human tumors, we are also establishing several patient-derived organoid models of lung cancer.

Integrating studies of lung stem cell biology and epigenetics for lung cancer therapies.
Pathological Subtypes of Non-Small Cell Lung Cancer

Figure 1

Lung adenocarcinomas tend to arise in more distal alveolar space and have glandular features and markers consistent with distal lung, including surfactant protein C (SPC) and the transcription factor TTF1. Lung squamous cell carcinomas arise in the more proximal airway and are characterized by fully stratified squamous epithelial layers of cells. Many questions exist about these two types of non-small cell lung cancer, and our laboratory aims to address these questions.

Schematic for Lung Cancer Cell-of-Origin Studies

Figure 2

After isolation by fluorescence activated cell sorting (FACS), the genetics of the normal lung cells are modulated and the cells are grown in 3-dimensional organoid culture systems. In these cultures, cells grow in Matrigel that is exposed to air from above and liquid media below. This air-liquid-interface type culture, along with the specialized media and support cells that we use in the cultures, allow the cells to retain lung specification. We have successfully transformed several lung cell types, as judged by growth of tumors after cell implantation into immunocompromised mouse lungs. Our current studies are interrogating the epigenetic changes that take place during the transformation process.

Schematic for Lung Cancer Cell-of-Origin Studies

Figure 3

Primary tumor cells of known genotypes are isolated from GEMMs and cultured in 3-dimensional culture systems. Epigenetic inhibitors are applied to cultures during serially passaging. Therapies that work well to inhibit tumor organoid growth will be further explored for mechanism of efficacy and in vivo efficacy. Our goal is to identify epigenetic therapies that target specific genotypes and subtypes on non-small cell lung cancer, with the end goal of finding new precision medicine options for patients.

The overall goal of the Brainson Lab is to define precision therapy options for genotype- and subtype-specific lung cancer using ideas and techniques from stem cell biology and epigenetic research.

Members

Chris Fillmore Brainson

cfbrainson@uky.edu

Born and raised in Massachusetts, Chris has always wanted a career in cancer research. Chris joined the faculty of UK in the Toxicology and Cancer Biology department in October of this year. She previously worked as a post-doctoral fellow at Boston Children's Hospital, where she was part of the Harvard Medical School Department of Genetics, the Boston Children's Hospital Stem Cell Program, and the Harvard Stem Cell Institute. Her research focuses on defining precision medicine opportunities for lung cancer by leveraging ideas and techniques from stem cell biology and epigenetics. Her research is currently funded through the NCI K22 career transition award, and the American Cancer Society.

Yanming Zhao M.D.

yzhao@uky.edu

Yanming has extensive experience in cancer biology research and has worked in the UK system for over 14 years. She currently splits her time between the Brainson lab and the Rangnekar lab, and has also worked and published with the St. Clair lab.

Abigail Edgin

abigail.edgin@uky.edu

Abby graduated in May 2017 from the University of Kentucky with a Bachelor’s of Science degree in Biology and a minor in Italian Studies. She is currently applying to medical school and will be working in the Brainson Lab for the duration of her gap year.  When she isn’t in the lab, Abby enjoys running and cheering on the Cats at sporting events.

Fan Chen

john.fan.chen@uky.edu

Fan is a graduate student who joined the lab in March of 2017. Previously, he received his M.D. degree and medical license from Shandong University, China. Aiming to be an oncologist in the future, he is focusing on the epigenetic precision medicine for lung cancer, specifically on Ezh2and PRC2 function.

Aria Byrd

aria.byrd@uky.edu

Aria Byrd is an Atlanta, Georgia native who received her B.S. in Biology with a concentration in biotechnology from Albany State University, and her M.S. in biology from North Carolina Agricultural and Technical State University. Her growing fascination with understanding how the body responds to both voluntary and involuntary environmental exposures has led her to pursue a doctoral degree in Toxicology. In the Brainson lab, she is acquiring advanced laboratory and research training that will prepare her to effectively investigate environmental perturbations that affect human health. Her long-term goal is to conduct research on underserved populations, specifically, to investigate the physiological changes that are currently taking and have taken place as a result of environmental stressors. Her life-long aspiration is to play an integral role in influencing national and global health policy that better cater to underserved populations.
Our lab is directly testing cell-of-origin fitness by isolating lung stem and progenitor cells and introducing specific genetic events into the isolated populations.

Gallery

Understanding which epigenetic states are permissive for lung cancer initiation, and in which microenvironmental contexts, will help us to target the root causes of the disease.

Publications

  1. Zhang H*, Fillmore CM*, Koyama S, Herter-Sprie GS, Lu G, Zhang X, Marsh BP, Tuminello SJ, Xu C, Chen Z, Akbay E, Zheng M, Palakurthi S, Bass A, Sharpless NE, Dranoff G, Hammerman PS, Ji H, Bardeesy N, Saur D, Watanabe H, Kim CF, Wong KK. Loss of polycomb repressive complex 2 complements Lkb1 loss to drive squamous transition of lung adenocarcinoma. In press at Nature Communications February 2017. (* contributed equally as first author)
  2. Zhang H, Qi J, Reyes J, Li L, Rao P, Li F, Lin C, Perry J, Lawlor M, Federation A, De Raedt T, Li Y, Liu Y, Duarte M, Zhang Y, Herter-Sprie G, Kikuchi E, Carretero J, Reibel J, Paulk J, Bronson R, Wantanbe H, Fillmore Brainson C, Kim C, Hammerman P, Brown M, Cichowski K, Long H, Bradner J, Wong KKOncogenic deregulation of EZH2 as an opportunity for targeted therapy in lung cancer. Cancer Discovery 2016 Sep;6(9):1006-21. Epub 2016 Jun 16. PMCID:  PMC5010480.
  3. Fillmore CM, Xu C, Desai PT, Berry JM, Rowbotham SP, Lin YJ, Zhang H, Marquez VE, Hammerman PS, Wong KK, Kim CF. 2014. EZH2 inhibition sensitizes BRG1 and EGFR mutant lung tumors to TopoII inhibitors.Nature 2015 Apr 9;520(7546):239-42. Epub 2015 Jan 28.  PMCID:PMC4393352.
  4. Xu C*, Fillmore CM*, Koyama S, Wu H, Zhao Y, Chen Z, Herter-Sprie GS, Akbay EA, Tchaicha JH, Altabef A, Reibel JB, Walton Z, Ji H, Watanabe H, Jänne PA, Castrillon DH, Rustgi AK, Bass AJ, Freeman GJ, Padera RF, Dranoff G, Hammerman PS, Kim CF, Wong KK. 2014.  Loss of Lkb1 and Pten leads to lung squamous cell carcinoma with elevated PD-L1 expression. Cancer Cell 2014 May 12;25(5):590-604. Epub 2014 May 1. PMCID: PMC4112370. (* contributed equally as first author)
  5. Sinkevicius KW, Kriegel C, Bellaria KJ, Lee J, Lau AN, Leeman KT, Zhou P, Beede AM, Fillmore CM, Caswell D, Barrios J, Wong KK, Sholl LM, Schlaeger TM, Bronson RT, Chirieac LR, Winslow MM, Haigis MC, Kim CF. 2014. Neurotrophin receptor TrkB  promotes lung adenocarcinoma metastasis. Proc Natl Acad Sci U S A 2014 2014 Jul 15;111(28):10299-304. Epub 2014 Jun 30.  PMCID: PMC4104911.
  6. Lau AN, Curtis SJ, Fillmore CM, Rowbotham SP, Mohseni M, Wagner DE, Beede AM, Montoro DT, Sinkevicius KW, Walton ZE, Barrios J, Weiss DJ, Camargo FD, Wong KK, Kim CF. 2014. Tumor-propagating cells and Yap/Taz activity contribute to lung tumor progression and metastasis. EMBO J. 2014 2014 Mar 3;33(5):468-81. Epub 2014 Feb 4. PMCID: PMC3989628.
  7. Gupta PB, Fillmore CM, Jiang G, Shapira SD, Tao K, Kuperwasser C, Lander ES. 2011. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells.  Cell  2011 Aug 19;146(4):633-44. PMID:  21854987.
  8. Zacharek SJ, Fillmore CM, Lau AN, Gludish D, Chou A, Ho JW, Zamponi R, Gazit R, Bock C, Jäger N, Smith ZD, Kim TM, Saunders AH, Wong J, Lee JH, Roach RR, Rossi DJ, Meissner A, Gimelbrant AA, Park PJ, Kim CF. 2011. Lung stem cell self-renewal relies on Bmi1-dependent control of expression at imprinted loci. Cell Stem Cell 2011 Sep 2;9(3):272-81. PMCID: PMC3167236.
  9. Fillmore CM, Gupta PB, Rudnick JA, Caballero S, Keller PJ, Lander ES, Kuperwasser C.  2010. Estrogen expands breast cancer stem-like cells through paracrine FGF/Tbx3 signaling. Proc Natl Acad Sci U S A. 2010 Dec 14;107(50):21737-42. Epub 2010 Nov 22. PMCID:  PMC3003123.
  10. Fillmore, CM and Kuperwasser C. 2008. Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy. Breast Cancer Res. 2008;10(2):R25. doi: 10.1186/bcr1982. Epub 2008 Mar 26. PMCID:  PMC2397524.
Our goal is to identify epigenetic therapies that target specific genotypes and subtypes on non-small cell lung cancer, with the end goal of finding new precision medicine options for patients.

Previous Research

Figure 1: Epigenetic control of lung cancer lineage

Figure 2: EZH2 inhibitors as lung cancer therapies

Figure 3: Lung stem cells and cancer stem cells

Studying the earliest stages of disease may suggest new methods of early detection for lung cancer.

Contact us

We are always looking for motivated individuals to join our team. Please contact us here:

Fillmore Brainson Lab
Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky
University of Kentucky Markey Cancer Center

Lab Address:
Health Sciences Research Building 461
1095 Veterans Drive
Lexington, KY 40536-0305

Phone: (859)323-4973

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