Biology subjects

Simpson, C. M.

Publications and source records attributed to Simpson, C. M..

3 recordsLinked to original sources

bioRxiv2023

Identification of chemotherapy targets reveals a nucleus-to-mitochondria ROS sensing pathway

Multiple chemotherapies are proposed to cause cell death in part by increasing the steady-state levels of cellular reactive oxygen species (ROS). However, for most of these drugs exactly how the resultant ROS function and are sensed is poorly understood. In particular, its unclear which proteins the ROS modify and their roles in chemotherapy sensitivity/resistance. To answer these questions, we examined 11 chemotherapies with an integrated proteogenomic approach identifying many unique targets for these drugs but also shared ones including ribosomal components, suggesting one mechanism by which chemotherapies regulate translation. We focus on CHK1 which we find is a nuclear H2O2 sensor that promotes an anti-ROS cellular program. CHK1 acts by phosphorylating the mitochondrial-DNA binding protein SSBP1, preventing its mitochondrial localization, which in turn decreases nuclear H2O2. Our results reveal a druggable nucleus-to-mitochondria ROS sensing pathway required to resolve nuclear H2O2 accumulation, which mediates resistance to platinum-based chemotherapies in ovarian cancers.

molecular biology↗

bioRxiv2022

Cancer Cells in all EMT States Lack Rigidity Sensing Depletion of Different Tumor Suppressors Causes Loss of Rigidity Sensing in Cancer Cells

Cancer cells have many different behaviors from epithelial to mesenchymal forms. We report here that 36 distinct tumor cell lines regardless of EMT form or other features lack the ability to sense rigidity and will grow on soft surfaces. In the majority of lines, cells were missing at least one protein needed for rigidity sensing (primarily tropomyosin2.1 (Tpm2.1) but also PTPN12, FilaminA (FLNA), and myosinIIA) while all had high levels of Tpm3. In the few cases where the major rigidity sensing components were present, those tumor cells were not able to sense rigidity. Thus, we suggest that tumor cells can lose the ability to sense rigidity by many different means and that the loss of rigidity sensing is sufficient to cause the transformed phenotype that enables targeted treatments.

cancer biology↗

bioRxiv2018

The dynamics of ERK signaling in melanoma, and the response to BRAF or MEK inhibition, are cell cycle dependent.

Activating BRAF mutations drive melanoma tumorigenesis and metastasis by constitutively activating MEK and ERK, and small molecule inhibitors (SMIs) of BRAF or MEK have shown promise as melanoma therapeutics. However, the development of resistance to these inhibitors in both the short- and longterm is common; warranting investigation into how these SMIs influence ERK signaling dynamics. By quantitative single cell imaging of an ERK activity reporter in living cells, we describe both intra- and inter-cell heterogeneity in ERK activity in isogenic melanoma populations harboring a BRAFV600E mutation. This heterogeneity is largely due to a cell-cycle dependent bifurcation in ERK activation. Moreover, we show there are cell-cycle dependent responses in ERK activity following BRAF or MEK inhibition. Prior to, but not following, CDK4/6-mediated passage through the Restriction Point (RP) ERK activity is sensitive to BRAF and MEK inhibitors. In contrast, in cells that have passed the RP, ERK activity will remain elevated even in the presence of BRAF or MEK inhibition until mitosis. We propose that ERK activity in the presence of activating BRAF mutations is regulated by both positive and negative feedback loops that are engaged in cell-cycle dependent fashions. CDK4/6 inhibition sensitizes ERK activity to BRAF or MEK inhibition by preventing passage the transition from a BRAF/MEK dependent to independent state. Our results have implications for the use of MEK and BRAF inhibitors as melanoma therapeutics, and offer a rational basis for the use of these inhibitors in combination with CDK4/6 inhibition during cancer therapy.

cancer biology↗