Research

Research

The Sorrell lab has discovered that the Myc family of oncogenes is involved in coordinating cell survival and migration in both normal and cancer cells. Myc is essential for embryonic development and is hyper-activated in over 70 percent of human cancers where it drives tumor initiation and progression. Therefore, developing ways to specifically target the oncogenic functions of Myc may provide an important avenue to treat multiple types of malignancies.

To date, all studies have focused on Myc as a nuclear transcriptional driver of cell proliferation. Our lab discovered an entirely new function of Myc that is independent of transcription. We found that a cytoplasmic form of Myc, named Myc-nick, drives cancer cell migration and survival in response cellular stress.

Project 1:  Define the oncogenic functions of AHR in Myc-dependent cells

Cancer cells are highly efficient at asborbing nutrients ad processing them to fenerate energy and building blocks that fuel cell proliferation.  The transcription factor MYC which is activated in majority of human tumors, is the major driver of metabolic reprogramming and cell proliferation in cancer.  Because MYC is a universal oncogene, there have been several attempts to develop inhibitors that block MYC functions specifically in tumors. However, MYC is still considered an undruggable protein.  Therefore, uncovering specific pathways that regulate biomass production downstream of MYC could lead to the identification of opportunities for therapeutic interventions.

Using RNA-seq to identify transcriptional networks downstream of MYC, we discovered that MYC directly induced the expression of the ligand-activated transcription factor, aryl hydrocarbonreceptor (AHR).  We found that AHR is required for the proliferation of MYC-expressing cells.  AHR directly binds to XRE elements within the promoter region of genes involved in ribosome biogenesis and protein synthesis and promote their transcription, thus suggesting a role for AHR in biomass production in cells overexpressing MYC.  Our more recent results indicate that upregulation of AHR and MYC occurs in colon cancer, and in other solid tumors that are dependent on MYC, such as pancreatic adenocarcinoma, thus suggesting that AHR may play a broad role in sustaining biomass production in hyperproliferative tumor cells. Currently we are investigating the regulation of AHR ligands by MYC and the contexts in which AHR functions as an oncogene using organoids and mouse models.


Project 2: Cancer cell survival and migration

The Sorrell lab has discovered that the Myc family of oncogenes is involved in coordinating cell survival and migration in both normal and cancer cells. Myc is essential for embryonic development and is hyper-activated in over 70 percent of human cancers where it drives tumor initiation and progression. Therefore, developing ways to specifically target the oncogenic functions of Myc may provide an important avenue to treat multiple types of malignancies.

To date, all studies have focused on Myc as a nuclear transcriptional driver of cell proliferation. Recently, our lab discovered an entirely new function of Myc that is independent of transcription. We found that a cytoplasmic form of Myc, named Myc-nick, drives cancer cell migration and survival in response cellular stress.

Our team showed that cancer cell survival and migration are stimulated by the acetylation of specific cytoplasmic proteins that is induced by a complex containing acetyltransferases and Myc-nick. Myc-nick-dependent acetylation of a-tubulin and ATG3 (autophagy related 3) promotes survival by increasing autophagy of cells exposed to hypoxia and starvation. Moreover, Myc-nick stimulates cell motility by promoting the expression of fascin and the activation of CDC42.

Myc is converted into Myc-nick by calpain proteases under stress conditions such as nutrient deprivation and hypoxia. Myc-nick promotes protein lysine acetylation, leading to cell and survival.

Our working model is that differences in tumor microenvironment lead to the generation of Myc-nick in the cytoplasm of sub-populations of cells. Myc-nick in turn increases survival of these cells by inducing autophagy and promotes cell motility by directly regulating the actin cytoskeleton. Based on our previous work, the conversion of Myc into Myc-nick functions as a molecular switch turning off cell proliferation and turning on a program that promotes cell survival and migration.

Model for Myc function and regulation in tumors