Experimental oncology
Mechanisms of non-oncogene addiction in cancer
Pathogenetic mechanisms of tumorigenesis are centered on genetic/epigenetic deregulation of oncogenic and tumor suppressive pathways, but maintenance of cancer homeostasis and survival also depends on activation of maladaptive stress responsive mechanisms. Tumor cells are constantly exposed to cellular stresses, beginning with the oncogenic stress that is rooted in the very process of cellular transformation, and including a variety of additional stress conditions that are encountered during tumor progression, like those caused by low oxygen concentrations. Thus, eviction of cellular responses to stress is required to cope with the inherent stresses of tumor initiation and progression. Unlike mutations in bona fide cancer genes, adaptation to stress is often modulated at the non-genetic level and is described as non-oncogene addition, to distinguish it from the required presence of specific gene mutations for tumor persistence, aka oncogene addiction. Targeting of maladaptive stress response pathways is being recognized as a new way to exploit cancer vulnerabilities, one that may be applied in a more generalized fashion than targeting tumor-specific genetic events.
Research activity
In our laboratory, we pursue two main lines of research, both focused on studying the function, regulation and targetability of stress responsive genes in cancer.
One line of research is on role of hypoxia inducible transcription factors HIF1a and HIF2a in leukemia. HIF factors are activated by genetic pathways or localized hypoxia in solid tumors but have been less studied in hematologic malignancies. We identified leukemia-specific functions of HIF1a in finding that it acts as a critical regulator of leukemia-microenvironment interactions in chronic lymphocytic leukemia whilst promoting blasts dissemination via activation of epithelial-to-mesenchymal transition gene sets in acute myeloid leukemia. More recently, we found that HIF2a partakes to the myeloid differentiation block that typifies acute myeloid leukemia, suggesting new ways to induce leukemia differentiation/debulking via use of a HIF2a small molecule inhibitor developed for the treatment of renal cancer.
The second line of research is centered on the functions of the promyelocytic leukemia PML protein in solid tumors. PML is a viral restriction factor and stress responsive protein that exerts tumor suppressive or oncogenic functions depending on the tumor context. We described a crosstalk between PML and hypoxia signaling in leukemia and exported this regulatory axis to solid tumors characterized by constitutively high activation of HIF factors, such as triple-negative breast cancer and clear cell renal cell carcinoma. We are currently investigating new functions of PML in these diseases along with the possibility of inhibiting PML with the FDA-approved anti-leukemia agent arsenic trioxide
