Description of Research Expertise

EPIGENETICS AT THE INTERSECTIONS OF CANCER, IMMUNITY, AND METABOLISM

The Capell Lab seeks to answer fundamental questions regarding how the epigenome impacts cellular homeostasis (i.e. metabolism, immunity), and in turn, how this contributes to cancer, inflammatory disease, and aging of epithelial surface tissues like the skin.

By combining innovative in vivo models and human patient samples with the most cutting-edge epigenetic approaches, we aim to identify therapeutic vulnerabilities and novel targets to treat disease.


BACKGROUND

Epithelial tissues rely on a highly coordinated balance between self-renewal, proliferation, and differentiation. Epigenetic mechanisms provide this precise control through the regulation of gene expression in order to establish and maintain cell fate and identity. Disruption of these pathways can disrupt diverse cellular processes including both metabolism and immunity, and ultimately drive conditions ranging from aging and cancer to inflammatory disease.

For example, there is an exceptionally high incidence of mutations in epigenetic modifiers in cancers of self-renewing epithelial tissues such as squamous cell carcinoma (SCC). SCC is the most common type of cancer worldwide, affecting numerous epithelial tissues ranging from the skin and eyes to the lung, esophagus, and oropharynx. Despite this, precisely how disruption of epigenetic homeostasis may drive epithelial cancers such as SCC is poorly understood.

In the Capell Lab, we combine cutting-edge technologies, human patient samples, primary cells, and mouse models in order to investigate major questions at the intersection of epigenetics, epithelial biology, cancer, immunity and metabolism:


EPITHELIAL-IMMUNE INTERPLAY

As the primary barrier to the external environment, epithelial surface tissues like the skin are constantly exposed to a variety of external insults ranging from UV radiation to infection. The epigenome serves as a vital mediator and integrator of these environmental signals, allowing cells to not only respond, but to also form memories of these exposures. In responding to environmental exposures, epithelial cells can also communicate and interface with the local immune and tissue microenvironment. In the Capell Lab, we are interested in not only uncovering these underlying mechanisms, but learning how we can harness the inherent reversibility and targetability of the epigenome in order to prevent and treat common conditions like skin cancer, as well as enhance responses to existing therapies.


DIET, LIPID METABOLISM, AND FERROPTOSIS

Emerging evidence has demonstrated that alterations in lipid metabolism, including those affected by diet, can directly influence oncogenic signaling, programmed cell death pathways, and antitumor immunity. Our lab identified that a major epigenetic tumor suppressor regulates key lipid metabolism genes involved in a form of programmed cell death known as “ferroptosis”, and that ferroptosis may be critical for epithelial differentiation and tumor suppression in SCC. Given the potential to modulate ferroptosis via both small molecules and diet, this provides a great opportunity for therapeutic discovery.


SEX CHROMOSOME COMPLEMENT AND ITS ROLE IN SEX BIAS IN DISEASE

One of the biggest questions in medical research today regards what are the mechanisms that explain sex differences in disease incidence and mortality. Across autoimmune, infectious, and neoplastic disease, sex bias drives significant differences in gene expression as well as disease incidence and outcomes between men and women. While there is evidence for the earlier initiation and worse outcomes in skin cancer among males, approximately 80% of autoimmune disease occurs in females. Despite this, the mechanisms that govern these observed sex disparities have been historically understudied. We hypothesize that a key contributor to sex disparities in epithelial disease is sex chromosome complement, which can lead to gene dosage disparities. In particularly, several epigenetic enzymes exist on either the X or the Y chromosome, and have been implicated in disease pathogenesis in a wide variety of contexts. However, as their roles in skin biology and disease are poorly understood, we are actively investigating these open questions.


If you would be interested in joining our team, please contact us!

LAB PERSONNEL:
Brian Capell, MD, PhD
Ashley Anderson
Lydia Bao
Chase Chen
Eni Harito
Eun Kyung Ko, PhD
Nina Kuprasertkul
Alyssa Moore
Rachel Na
Cyria Olingou
Gina Pacella

Selected Publications

Egolf S, Zou J, Anderson A, Simpson CL, Aubert Y, Prouty S, Ge K, Seykora JT, Capell BC: MLL4 mediates differentiation and tumor suppression through ferroptosis Sci Adv 7 (50): eabj9141,2021.

Huang S, Kuri P, Aubert Y, Brewster M, Li N, Farrelly O, Rice G, Bae H, Prouty S, Dentchev T, Luo W, Capell BC, Rompolas P.: Lgr6 marks epidermal stem cells with a nerve-dependent role in wound re-epithelialization Cell Stem Cell ell Stem Cell : 1582-1596,2021.

Pacella G, Capell BC.: Epigenetic and metabolic interplay in cutaneous squamous cell carcinoma Exp Dermatol 30 (8): 1115-1125,2021.

Ko EK, Capell BC.: Methyltransferases in the Pathogenesis of Keratinocyte Cancers Cancers (Basel) 13 : 3402,2021.

Maldonado López A, Capell BC.: The METTL3-m(6)A Epitranscriptome: Dynamic Regulator of Epithelial Development, Differentiation, and Cancer Genes (Basel) 12 : 1019,2021.

Zheng Q, Capell BC, Parekh V, O'Day C, Atillasoy C, Bashir HM, Yeh C, Shim EH, Prouty SM, Dentchev T, Lee V, Wushanley L, Kweon Y, Suzuki-Horiuchi Y, Pear W, Grice EA, Seykora JT.: Whole-Exome and Transcriptome Analysis of UV-Exposed Epidermis and Carcinoma In Situ Reveals Early Drivers of Carcinogenesis J Invest Dermatol 141 : 295-307,2021.

Egolf S, Capell BC: LSD1: a viable therapeutic target in cutaneous squamous cell carcinoma? Expert opin ther targets 24 (7): 671-678,2020.

Aubert Yann, Egolf Shaun, Capell Brian C: The Unexpected Noncatalytic Roles of Histone Modifiers in Development and Disease. Trends in genetics : TIG 35 (9): 645-657,2019.

Egolf Shaun, Aubert Yann, Doepner Miriam, Anderson Amy, Maldonado-Lopez Alexandra, Pacella Gina, Lee Jessica, Ko Eun Kyung, Zou Jonathan, Lan Yemin, Simpson Cory L, Ridky Todd, Capell Brian C: LSD1 Inhibition Promotes Epithelial Differentiation through Derepression of Fate-Determining Transcription Factors. Cell reports 28 (8): 1981-1992.e7,2019.

Lin-Shiao Enrique, Lan Yemin, Coradin Mariel, Anderson Amy, Donahue Greg, Simpson Cory L, Sen Payel, Saffie Rizwan, Busino Luca, Garcia Benjamin A, Berger Shelley L, Capell Brian C: KMT2D regulates p63 target enhancers to coordinate epithelial homeostasis. Genes & development 32 (2): 181-193,2018.

Academic Contact Information

Biomedical Research Building
Office: 1007
Lab: 1020-21
Philadelphia, PA 19104
Phone: 215-746-8225
Patient appointments: 800-789-7366