PROOF OF CONCEPT

Somatic mutations in eIF1A, especially in the N-terminal tail (NTT), were recently found to be associated with uveal, thyroid and ovarian cancers. Presently very little is known about the biological function of eIF1A in mammalian cells and how perturbations of its function by the mutations contribute to cancer development.

We hypothesize that mechanisms underlying cell size regulation in normal cells are diverted to survival/death pathways in cancer cells, raising the prospect of selectively targeting such mechanisms as a therapeutic strategy. Identifying key hubs in intracellular networks that may shift a size-sensing mechanism to control of proliferation or survival is likely to open new avenues for therapeutic development in the future.

Anti-tumor antibodies are being produced in patients with different cancer types. Yet, they fail to mediate effective clearance of the tumor cells and to engage efficient anti-tumor immune response. We hypothesize that the Fc-glycan repertoire is a key determinant that regulate the anti-tumor antibody response. Here, we propose to develop mass-spectrometry based assay to characterize the IgG Fc-glycome in patients and mouse models of different cancer types.

B cells and B cell lymphoma depend on BCR signaling for their survival. Removal or inhibition of the immune receptor signaling lead to elimination of the malignant cell. Thus, immune-receptor signaling pathways are an excellent target for cancer treatment.

DNA damage response determines cell fate. A classical view is that under DNA damage cells either die or survive while maintaining a certain degree of genome instability and rearrangements. A significant number of these surviving cells harbor MNi. MNi has lately been reported to activate the cGAS-STING innate immunity pathway. Remarkably, the same cGAS-STING pathway plays a role in inducing senescence Our preliminary data suggest that under c-Abl inhibition/knockout the IFN-I pathway is compromised whereas the senescence program is activated.

The importance of T cells in antitumor responses is currently well recognized; however, the role of B cells in cancer immunology is only scantly probed and studied. This is presumably due to the lack of reliable models for functional analysis of distinct B cell subsets in the tumor microenvironment and their contribution to both pro- as well as antitumor immune responses. Focusing on pancreatic cancer, we wish to characterize the potential contribution of B-cells in the microenvironment to cancer control, management and therapy.

Breast cancer is the most prevalent and lethal cancer in women. 15% of breast cancers do not overexpress the estrogen, progesterone or HER2 receptors also known as Triple Negative Breast Cancers (TNBC). This type of cancers is more aggressive, has poor prognosis, and lack any targeted therapy. This stems partly from our lack of understanding of driver events in TNBC and for lack of validated targets for its pathogenicity.

Multiple types of circulating tumor cells (CTCs) metastasize into the lung parenchyma by extravasating the pulmonary vasculature. The space between the alveolus and the capillary (approximately 2 um) imposes a significant mechanical barrier on extravasating CTCs that need to squeeze their bulky and stiff nuclei through it with minimal nuclear damage.