This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
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Professor
Co-Leader, Blood Cell Development and Function
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The Balachandran lab is interested in how cells die during host innate-immune responses to viruses and bacteria, and in exploiting these mechanisms for the treatment of human disease, whether infectious, inflammatory or malignant. In particular, the lab is interested in a form of programmed cell death termed necroptosis, driven by the kinase RIPK3. Unlike apoptosis, which proceeds via a caspase cascade that results in the ordered disassembly of the cell, necroptosis is caspase independent and driven by the RIPK3 substrate MLKL. Once activated by RIPK3, MLKL translocates to cellular membranes and induces their disruption, resulting in a form of necrotic cell death. Necroptosis is activated by several classes of innate-immune receptor (e.g., TLRs and cytokines such as TNF-α and interferons) and pathogen (e.g., RNA viruses, DNA viruses, certain gram-negative bacteria). The Balachandran lab is interested in how viruses (particularly RNA viruses), gram-negative bacteria, cytokines, and cellular stresses activate the necroptosis machinery, how necroptosis functions during acute viral and microbial infections to control pathogen spread, and how this death modality can be leveraged for immunotherapy.
The lab has recently outlined a pathway by which interferons (IFNs), a family of cytokines with well-known antiviral and immunomodulatory properties, activate RIPK1/3 kinases and trigger necroptotic death. The laboratory continues to work on how IFNs activate RIPK1/3 kinases, and the regulatory mechanisms that normally restrain these kinases in unstimulated cells and only license necroptosis in susceptible cells. We have identified two such mechanisms that protect cells from IFNs: the adaptor protein FADD and the transcription factor NF-κB. Current projects in this area are centered on how FADD (and caspases) are disabled to allow IFNs to trigger necroptosis during an active infection. An allied area of interest is to test the feasibility of NF-κB blockade as a combinatorial approach for the treatment of IFN-responsive human cancers.
More recently, the laboratory has identified RIPK3-activated cell death as an important host defense mechanism that limits spread of RNA viruses, including influenza A. Influenza A viruses produce Z-RNAs, which are novel left-handed RNA duplexes previously thought not to exist in nature; these Z-RNAs trigger the host sensor protein ZBP1, which, in turn, activates, RIPK3, and drives the activation of both MLKL-dependent necroptosis as well as a parallel pathway of FADD/caspase 8-mediated apoptosis. Molecular- and animal model-based approaches are being used to identify additional determinants and regulators of virus-induced necroptosis, relevant cell types in vivo that die by RIPK3-dependent mechanisms, and the physiological contribution of discrete cell death pathways to the control of an acute RNA virus infection.
Finally, the Balachandran laboratory is interested in leveraging necroptosis for immunotherapy, by targeting RIPK1/3 kinases in human cancers that respond to IFN therapy, or by activating ZBP1 in the tumor microenvironment by small-molecule approaches. The latter approach is of particular interest because ZBP1 can activate a form of ‘nuclear necroptosis’ that is even more immunogenic that conventional (i.e., cytoplasm-induced) necroptosis. Indeed, a major reason for the non-responsiveness of these so-called ‘cold’ tumors is that they lack an immunogenic tumor microenvironment (TME) and thus escape T-cell killing despite expressing ICB targets. How to selectively intensify the immunogenicity of the TME has been an unmet challenge. Two broad strategies are commonly pursued: the first is to increase the visibility of tumor cells to the immune system, for example, by inducing tumor cells to die by necrotic lysis, which is highly immunogenic. The second is to induce an immunogenic state in cells of the TME. We have developed small molecule approaches that straddle both strategies to directly activate ZBP1 to trigger ‘on-demand’ nuclear necroptosis in tumor cells, as well as in cells of the TME. We are currently evaluating the potential clinical benefit of these approaches in mouse models of melanoma and other solid cancers.
A Postdoctoral Associate position is available to study the molecular mechanisms by which necroptosis is activated during innate immune response to infectious, inflammatory and malignant disease. An interest in signal transduction research, cellular biology and/or immune responses, and familiarity with cell culture and mouse models of viral pathogenesis and/or cancer immunotherapy is desirable.
As one of the four original cancer centers to receive comprehensive designation from the National Cancer Institute, Fox Chase Cancer Center has been at the forefront of cancer research for almost 90 years. We are home to excellent research facilities, top clinicians and scientists, and outstanding patient care. Our singular focus on cancer, which couples discovery science with state of the art clinical care and population health, remains the foundation of our work.
The scientist training programs at Fox Chase Cancer Center provide professional development opportunities in four core areas identified as crucial for successful careers in science, research, and health care including communication, leadership, teaching, and mentorship. Upon joining the program, graduate students and postdocs develop individual development plans to help guide their growth. Training throughout the year is supplemented with free professional development opportunities, including a robust ‘How To’ series, writing courses, networking, mentorship, and teaching opportunities, a trainee-led seminar series, a trainee-led annual Research Conference, and more. Postdocs at Fox Chase Cancer Center are supported by the Temple University Postdoc Association and the Office of Academic Affairs at Fox Chase, and are compensated with competitive pay and benefits.
In addition to the robust training program, scientists at Fox Chase Cancer Center benefit from being part of the rich scientific and biotech environment in the Philadelphia region. Many of our former trainees are now employees (and contacts) at nearby institutions and companies, including The Wistar Institute, Merck, GSK, AACR, and numerous others.
Prospective candidates (PhD or MD) should send a CV and contact information for two references to Siddharth.Balachandran@fccc.edu.
The Balachandran Lab is seeking a Scientific Technician with 2+ years lab experience to serve as Lab Manager. The ideal candidate will have basic cell culture skills, experience handing mice, and looking for a long-term position.
As one of the four original cancer centers to receive comprehensive designation from the National Cancer Institute, Fox Chase Cancer Center has been at the forefront of cancer research for almost 90 years. We are home to excellent research facilities, top clinicians and scientists, and outstanding patient care. Our singular focus on cancer, which couples discovery science with state of the art clinical care and population health, remains the foundation of our work.
The scientist training programs at Fox Chase Cancer Center provide professional development opportunities in four core areas identified as crucial for successful careers in science, research, and health care including communication, leadership, teaching, and mentorship. Upon joining the program, graduate students and postdocs develop individual development plans to help guide their growth. Training throughout the year is supplemented with free professional development opportunities, including a robust ‘How To’ series, writing courses, networking, mentorship, and teaching opportunities, a trainee-led seminar series, a trainee-led annual Research Conference, and more. Postdocs at Fox Chase Cancer Center are supported by the Temple University Postdoc Association and the Office of Academic Affairs at Fox Chase, and are compensated with competitive pay and benefits.
In addition to the robust training program, scientists at Fox Chase Cancer Center benefit from being part of the rich scientific and biotech environment in the Philadelphia region. Many of our former trainees are now employees (and contacts) at nearby institutions and companies, including The Wistar Institute, Merck, GSK, AACR, and numerous others.
Prospective candidates should send a CV and contact information for two references to Siddharth.Balachandran@fccc.edu.
This Fox Chase professor participates in the Undergraduate Summer Research Fellowship.
Learn more about Research Volunteering.
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