Inappropriate cell proliferation is a hallmark of cancer. In a normal cell, the decision to divide is tightly regulated at multiple levels. However, this control is eroded in cancerous cells, as mutations in tumor suppressor genes remove the checks to restrain proliferation. The research in our laboratory is focused on the Retinoblastoma tumor suppressor protein pRB and the E2F transcription factor, so called RB tumor suppressor pathway.

One challenge to study the RB pathway arises from the complexity of the mammalian system with large RB and E2F multigene families. Model genetic organisms, such as Drosophila that we use in the lab, provide attractive alternatives due its simplicity and conservation.

The overarching goal of the research in our laboratory is to identify the cell specific functions of RB pathway that are important during normal animal development and why the loss of these functions is the key event in cancer. Towards this goal, we are using biochemical, genetic, genome-wide and single cell genomic approaches.

Over the years, we made several contributions to the field using the fly model. Among them are the finding that E2F regulation is a net result of interplay between an activator and a repressor E2Fs, linking RB pathway to metabolic regulation, pinpointing essential functions of RB during development, use of state of the art single cell genomics to profile mutations in RB pathway, demonstrating functional interaction between intronic microRNAs and the host genes they are embedded into.

RB Pathway and Cellular Metabolism

A major focus of our recent work is how RB pathway controls cellular metabolism. We discovered that in Drosophila E2F regulates mitochondrial function (Developmental Cell 2013). We used the results generated in flies to guide our studies in mammalian cells and showed that mammalian E2F operates in a highly analogous manner.

Given that muscles are highly sensitive to mitochondrial dysfunction, we followed up on this initial observation and examined the role of E2F and pRB in developing skeletal muscles. This work provided deep mechanistic insights into how E2F and pRB control the myogenic transcriptional program (Nature Communications 2016 and Cell Reports 2019). Strikingly, this highly specialized role of RB pathway is one of the reasons for the lethality of E2F deficient animals.

Single Cell Genomics

Recently, we set up Drop-seq, an innovative technology for single cell genomics (scRNA-seq). This massively parallel transcriptional profiling of tens of thousands of cells allows deciphering high-resolution landscapes of possible cellular states in complex tissues. We use scRNA-seq to map each individual cell in normal tissue and then ask how perturbations in RB pathway affect cell types, cell states and transitions between states. Recently, we have completed the first cell atlas of the developing Drosophila eye at 1X cell coverage and leveraged this new information to profile an Rb mutant eye (Nature Communications 2018). We are actively participating in The Fly Cell Atlas collaborative project that brings together researchers building comprehensive cell atlases during different developmental stages and disease models.

State of the art scRNA-seq platform that we assembled in the lab is a powerful method to address many challenging questions in cancer biology. Among them are tumor heterogeneity, metastatic potential of tumors, basis of drug resistance acquired by tumors during treatment and many others. Therefore, we are involved in several collaborations with other labs at UIC Cancer Center to employ scRNA-seq. With the support of UIC Cancer Center we are holding bi-monthly meetings of UIC Single Cell Club where UIC researchers interested in single cell approaches meet, present their data and exchange ideas.

The Leukemia & Lymphoma Society Scholar