Biology subjects

Grit, J. L.

Publications and source records attributed to Grit, J. L..

4 recordsLinked to original sources

bioRxiv2025

YAP signaling promotes resistance to MEK and AKT inhibition in NF1-related MPNSTs

Neurofibromatosis type 1 (NF1) is a tumor predisposition syndrome caused by loss of function of the neurofibromin protein. Malignant peripheral nerve sheath tumors (MPNSTs) are a rare and deadly sarcoma with few therapeutic options that are the leading cause of death for patients with NF1. To date, no targeted therapies have been approved for MPNST treatment, highlighting the need for an understanding of adaptive signaling mechanisms that drive resistance. We developed a preclinical model of drug resistance using a cross-over drug holiday design and evaluated patterns of response and resistance to MEK and AKT inhibitors, two pathways that are dysregulated by loss of neurofibromin. We show that the mTOR and YAP/TEAD pathways are activated by MEK inhibitor exposure, yet blockade of these pathways in resistant MPNST PDX models does not significantly reduce tumor growth, despite strong in vitro synergy between trametinib and the novel TEAD inhibitor, GNE-7883. Using spatial transcriptomics, we uncovered phenotypic inertia as a key mechanism of drug resistance in MPNST, in addition to signaling plasticity. Further, we found that resistance is mediated by sustained ERK, YAP, and MYC driven transcriptional programs. In the future, preclinical studies should focus on addressing intratumoral heterogeneity and how it evolves over time.

cancer biology↗

bioRxiv2023

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.

cancer biology↗

bioRxiv2022

Nf1 deficiency accelerates mammary development and promotes luminal-basal plasticity

The tumor suppressor NF1 is a critical driver of sporadic breast cancer and NF-related breast cancers. We utilized distinct Nf1-deficient immunocompetent rat models to investigate Nf1 function in mammary development and homeostasis. Here we demonstrate that Nf1 deficiency dramatically accelerates mammary morphogenesis, alters TEB cell organization, and proliferation. Notably, we observed a shift in luminal-basal epithelial lineage commitment within Nf1-deficient lines with early tumor onset. In addition, we detected subpopulations of hybrid EMT cells (Ecad+/CK14+) within the invasive edge and stroma of Nf1-deficient tumors. Nf1 deficiency restricted luminal progenitor potential and resulted in gene expression changes associated with decreased cell adhesion and increased EMT signatures. Together our findings support a model in which Nf1 loss of function results in lineage plasticity throughout mammary morphogenesis and promotes EMT-mediated invasion. This study reveals a previously unknown role for the tumor suppressor neurofibromin in mammary homeostasis and phenotypic plasticity during breast cancer progression.

cancer biology↗

bioRxiv2019

Distinctive epigenomic alterations in NF1-deficient cutaneous and plexiform neurofibromas drive differential MKK/P38 signaling

Benign peripheral nerve sheath tumors are the clinical hallmark of Neurofibromatosis Type 1. They account for substantial morbidity in NF1 and are difficult to manage. Cutaneous (CNF) and plexiform neurofibromas (PNF) share identical histology, but maintain different growth rates and risk of malignant conversion. The reasons for their disparate clinical behavior are not well explained on the basis of recent genome or transcriptome profiling studies. We hypothesized that CNFs and PNFs are epigenetically distinct tumor types that exhibit differential signaling due to genome-wide and site-specific methylation events. We interrogated the methylation profiles of 45 CNFs and 17 PNFs (Illumina EPIC 850K) using normal tissue controls from NF1 subjects. Based on these profiles, we confirm that CNFs and PNFs are epigenetically distinct tumors with broad differences in higher order chromatin states, and specific methylation events altering genes involved in key biological and cellular processes such as inflammatory mediator regulation of TRP channels, RAS/MAPK signaling, actin cytoskeleton rearrangement, and oxytocin signaling. Based our identification of 2 separate DMRs associated with alternative leading exons in MAP2K3, we demonstrate differential RAS/MKK3/P38 signaling between CNFs and PNFs. Epigenetic reinforcement of RAS/MKK/P38 was a defining characteristic of CNFs leading to pro-inflammatory signaling and chromatin conformational changes, whereas PNFs signaled predominantly through RAS/ERK. Tumor size also correlated with specific CpG methylation events. Taken together, these findings confirm that epigenetic regulation of RAS signaling fates accounts for observed differences in CNF and PNF clinical behavior. CNFs may also respond differently than PNFs to RAS-targeted therapeutics raising the possibility of targeting P38-mediated inflammation for CNF treatment.

genomics↗