The research in Komurov lab has two components:
- Characterization of the essential aberrant cancer mechanisms and identifying their associated targetable vulnerabilities
- Developing computational methods and software for biological data mining
There are several ongoing projects on both sides.
1. Mechanisms of transcriptional defects in cancers and their role in immunotherapy response
Our lab has recently identified a novel cancer phenotype characterized by genome-wide defects in RNA polymerase II (RNAP II) mediated transcription elongation, which was observed in ~20 percent of all cancers. Using genomic, in vitro and in vivo approaches, we showed that this phenotype impairs the expression of key inflammatory response pathways, and imposes resistance to both innate and adaptive anti-cancer immune responses. Accordingly, these cancers were resistant to immunotherapeutic drugs in multiple human patient cohorts in the clinic. Our current efforts are directed toward molecular characterization of the RNAP II elongation defects, and the mechanisms of their involvement in the resistance to anti-tumor immune attacks. In addition, we are exploring innovative ways of reversing the transcription elongation defects for resensitization to immunotherapy.
2. Mechanisms of immune evasion in genomically unstable tumors
Chromosomal instability is a hallmark of cancers. As an inbuilt fail-safe mechanism, loss of mitotic fidelity and ensuing chromosomal instability trigger innate immune reactions to eliminate the faulty cells. However, most tumors with chromosomal instability manage to evade the immune surveillance and have unchecked growth. Using several in vitro and in vivo models of immune-competent mouse models, we are working on identifying the central mechanisms employed by the tumor cells to evade immune recognition and destruction.
3. Mechanisms of proteostatic defects in cancers and their exploitation for therapy
Proper maintenance of the protein homeostasis is central to cell viability. A key component of proteostasis is maintaining the balance between the client protein load (i.e., newly synthesized peptides) and the cellular capacity for their folding and processing. Many oncogenic mechanisms naturally perturb this balance and expose the cancer cell to stress. We are studying the mechanisms of how oncogenic signaling creates proteotoxic imbalance in the endoplasmic reticulum and the cytosol, and optimal therapeutic strategies to exploit this imbalance to selectively kill cancerous cells. In addition, we are also studying how the transcriptional defects in cancers lead to protein synthesis defects, and create therapeutically exploitable proteotoxic stress.
4. Comprehensive analyses of tumor-host interactions at the systems level
Cancer is as much a disease of aberrant tumor-host interactions as it is of unchecked intracellular oncogenic events. Cancers often hijack mitogenic systemic signals (e.g., estrogen receptor in breast cancers), or disrupt regulatory ones (e.g., circadian rhythm), to stimulate tumor growth. In addition, overwhelming recent evidence implicates environmental factors, such as diet, which affect host organ functions, in cancer pathology. By the use of innovative computational approaches in multi-omics cancer datasets, we are studying the functional interactions between cancers and distant host organs.
5. Computational tools and software to enhance integrated data mining from omics datasets
Our lab has been actively engaged in the development of computational methods and software to enable efficient knowledge-based data analyses. Currently, we have active projects for further development of web applications for advanced hypothesis testing and modeling by integration of multi-omics datasets.