The Schieke lab studies functional diversity and plasticity of normal and cancer cells. We are interested in how cells coordinate metabolic states with their functional properties.
- How does the metabolic state modulate functional properties of cells?
- Which functional properties benefit from specific metabolic states?
- How do cells regulate their metabolic and functional dynamics?
Understanding phenotypic dynamics in cancer will ultimately help to define novel drug targets and therapeutic strategies to lock cells into treatment-sensitive, vulnerable states.
The lab’s focus areas are (i) dynamics of phenotypic heterogeneity and metabolic states in cancer development and progression, and (ii) experimental therapeutics targeting cell plasticity. The goal of this work is to characterize the role of distinct phenotypic states of cancer cells during disease development and progression to identify novel treatment targets during various disease stages. While our work focuses on cutaneous T-cell lymphoma, several aspects of this work apply to the broader category of systemic T-cell leukemia and lymphoma and other cancers.
Phenotypic plasticity and drug-resistance
Cellular heterogeneity provides a high degree of “fitness” necessary to withstand evolutionary pressure during environmental stress. Transition between non-genetic phenotypic states creates a significant degree of plasticity leading to functional heterogeneity among populations of normal as well as cancer cells.
Tumor cell heterogeneity is one of the major obstacles for successful treatment of cancer. Mechanisms underlying functional heterogeneity and population dynamics in T-cell lymphoma remain largely unknown. The lack of a molecular phenotype for any drug-resistant lymphoma cells makes it impossible to selectively target the cancer cell subpopulation that critically affects our ability to cure the disease. Identification of the molecular regulators and metabolic requirements of cancer cells on the “escape route” will ultimately allow us to design treatment strategies that successfully eradicate the malignant clones.
Return to Top »
Metabolic dynamics during cancer progression
While increased glycolysis under normoxic conditions is commonly viewed as one of the hallmarks of cancer, the exact contribution of the ‘Warburg effect’ to specific functional properties of cancer cells remains an intense focus of research. Metabolic state and mitochondrial function underlie complex dynamics resulting in significant temporal and spatial heterogeneity of cancer cell metabolic profiles which are also lineage-dependent. While metabolic rewiring provides flexibility, it remains to be fully characterized how distinct metabolic states contribute to functional properties and phenotypes in normal and cancer cells.
Therapeutic target selection among the heterogeneous metabolic profiles in cancer requires definition of specific metabolic needs of different stages of cancer evolution. Our work on metabolic profile and requirements of the invasive phenotype will provide important insight into the dynamics of disease progression and novel treatment targets to block dissemination of T-cell leukemia and lymphoma. This work will allow us to identify the metabolic factors that determine a cell’s position on the spectrum of invasive heterogeneity providing the basis for pharmacologic strategies targeting limiting metabolic dependencies to reverse the highly invasive state.
Return to Top »
Targeting the mitochondrial stress response
Tumor cell metabolism has been the focus of intense research efforts over the past several years to identify cancer-specific aberrations serving as novel treatment targets. However, the high degree to which metabolic plasticity allows cancer cells to adapt to microenvironment changes hinders efficacy of metabolic drugs.
This part of our work focuses on the metabolic adaptation and underlying signaling pathways in response to mitochondrial stress in T cell lymphoma/leukemia. We have identified an adaptation mechanism that seems to be specific for malignant T cells and represents a cancer-specific metabolic vulnerability that might provide a basis for selective metabolic targeting in T cell lymphoma/leukemia.
Return to Top »
Ashish Anshu, PhD
Wasakorn (Ten) Kittipongdaja, MD
Select peer-reviewed journal articles are listed below. A complete list of publications can be found at PubMed (external link).
- Saleh JZ, Lee LH, Schieke SM, Hosking PR, Hwang ST. Methotrexate-induced CD30(+) T-cell lymphoproliferative disorder of the oral cavity. JAAD Case Rep. 2016 Aug 27;2(4):354-6.
- Robson A, Shukur Z, Ally M, Kluk, Liu K, Pincus L, Sahni D, Sundram U, Subtil A, Karai L, Kempf W, Schieke S, Coates P. Immunocytochemical p63 expression discriminates between primary cutaneous follicle centre cell and diffuse large B-cell lymphoma-leg type, and is of the TAp63 isoform. Histopathology. 2016 Jul;69(1):11-9.
- Yu J, Plaza JA, Schieke SM. Metastatic Sarcomatoid Lung Cancer: A Rare Cutaneous Spindle Cell Neoplasm. Am J Dermatopathol. 2016 Mar;38(3):e36-e39
- Kittipongdaja W, Wu X, Garner J, Liu X, Komas SM, Hwang ST, Schieke SM. Rapamycin suppresses tumor growth and alters the metabolic phenotype in T-cell lymphoma. J Invest Dermatol. 2015 Sept;135(9):2301-8
- Yu J, Ravikumar S, Plaza JA, Troy JL, Schieke SM. Targeting the Adnexal Epithelium: An Unusual Case of Syringometaplasia in a Patient on Vemurafenib. Am J Dermatopathol. 2015 May;37(5):e57-60
- Ginsberg D, Hill H, Wilson B, Plaza JA, Schieke SM. Pseudocarcinomatous hyperplasia mimicking squamous cell carcinoma in a case of CD56-positive cytotoxic T-cell lymphoma. J Cutan Pathol. 2015 Mar;42(3):194-8
- Plaza JA, Kacerovska D, Sangueza M, Schieke S, Buonaccorsi N, Suster S, Kazakov DV. Can Cutaneous Low-Grade B-cell Lymphoma Transform Into Primary Cutaneous Diffuse Large B-cell Lymphoma? An Immunohistochemical Study of 82 cases. Am J Dermatopathol. 2014 Jun;36(6):478-82
- Schieke SM, Sharaf MA, Lerner A, Rünger TM, Mahalingam M. Primary cutaneous CD56 positive lymphoma: a diagnostic conundrum in an unusual case of lymphoma. J Cutan Pathol. 2012 May;39(5):540-4
- Jacob RS, Silva CY, Powers JG, Schieke SM, Mendese G, Burlingame RW, Miller DD, Wolpowitz D, Graber E, Mahalingam M. Levamisole-induced vasculopathy: a report of 2 cases and a novel histopathologic finding. Am J Dermatopathol. 2012 Apr;34(2):208-13
- Schieke SM, Ma M, Cao L, McCoy JP Jr, Liu C, Hensel NF, Barrett AJ, Boehm M, Finkel T. Mitochondrial metabolism modulates differentiation and teratoma formation capacity in mouse embryonic stem cells. J Biol Chem. 2008 Oct 17;283(42):28506-12
- Schieke SM, McCoy JP Jr, Finkel T. Coordination of mitochondrial bioenergetics with G1 phase cell cycle progression. Cell Cycle. 2008 Jun 15;7(12):1782-7
- Schieke SM, Phillips D, McCoy JP Jr, Aponte AM, Shen RF, Balaban RS, Finkel T. The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem. 2006 Sep 15;281(37):27643-52