Biology subjects

Penson, A.

Publications and source records attributed to Penson, A..

4 recordsLinked to original sources

bioRxiv2021

ERα-LBD, a novel isoform of estrogen receptor alpha, promotes breast cancer proliferation and endocrine resistance

Estrogen receptor alpha (ER) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of a novel ER isoform, ER-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ER-LBD is found to promote breast cancer growth and resistance to the ER antagonist fulvestrant. ER-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ER-LBD expression and function does not appear to be restricted to cancers that express full length ER but also promotes growth of triple negative breast cancers and ER-LBD transcript (ESR1-LBD) is also present in BC samples from both ER(+) and ER(-) human tumors. These findings point to ER-LBD as a potential mediator of breast cancer progression and therapy resistance. SIGNIFICANCE STATEMENTEndocrine resistant and metastatic breast cancer (BC) is a clinically significant problem. Our study of fulvestrant resistant cancer cells led to the discovery of a novel ER isoform which we call ER-LBD. Encoded by a truncated transcript variant (ESR1-LBD) and lacking the N-terminal domains (activation of transcription and DNA binding), ER-LBD displays a unique role in BC tumorigenesis and progression by mechanisms that may involve metabolic and cell growth advantages, stemness and therapy resistance. Importantly, ESR1-LBD is preferentially expressed in human breast tumor tissues and may be used as prognostic marker in BC.

cancer biology↗

bioRxiv2021

Arylsulfonamide mediated RBM39 degradation causes aberrant splicing of mitotic kinesins

Certain arylsulfonamides (ArSulfs) induce an interaction between the E3 ligase substrate adaptor DCAF15 and the critical splicing factor RBM39, ultimately causing its degradation. Although molecules like the ArSulfs, which interfere with splicing decisions, are exciting potential medicines, the molecular glue mechanism of RBM39 degradation introduces complex pleiotropic effects that are difficult to untangle. For example, DCAF15 inhibition, RBM39 degradation, and the downstream proteome effects of splicing changes will all cause different yet overlaid effects. As such the precise cell-killing mechanism by RBM39 loss is largely unknown. By overlaying transcriptome and proteome datasets, we distinguish transcriptional from post-transcriptional effects, pinpointing those proteins most impacted by splicing changes. Our proteomic profiling of several ArSulfs suggests a selective DCAF15/ArylSulf/RBM39RRM2 interaction with a narrow degradation profile. We identify two mitotic kinesin motor proteins that are aberrantly spliced upon RBM39 degradation, and we demonstrate that these are likely contributors to the antiproliferative activity of ArSulfs.

molecular biology↗

bioRxiv2020

SF3B1 mutant-induced missplicing of MAP3K7 causes anemia in myelodysplastic syndromes

ABSTRACTSF3B1 is the most frequently mutated RNA splicing factor in multiple neoplasms, including ~25% of myelodysplastic syndromes (MDS) patients. Mortality in MDS frequently results from severe anemia, but the underlying mechanism is largely unknown. Here we elucidate the detailed, elusive pathway by which SF3B1 mutations cause anemia. We demonstrate, in CRISPR-edited cell models, normal human primary cells, and MDS patient cells, that mutant SF3B1 induces a splicing error in transcripts encoding the kinase MAP3K7, resulting in reduced MAP3K7 protein levels and deactivation of downstream target p38 MAPK. We show that disruption of this MAP3K7-p38 MAPK pathway leads to premature downregulation of GATA1, a master regulator of erythroid differentiation, and that this is sufficient to trigger accelerated differentiation and apoptosis. As a result, the overproduced, late staged erythroblasts undergo apoptosis and are unable to mature in the bone marrow. Our findings provide a detailed mechanism explaining the origins of anemia in MDS patients harboring SF3B1 mutations.Competing Interest StatementThe authors have declared no competing interest.View Full Text

cancer biology↗

bioRxiv2019

Evolutionary Origins of Recurrent Pancreatic Cancer

Surgery is the only curative option for Stage I/II pancreatic cancer, nonetheless most patients will recur after surgery and die of their disease. To identify novel opportunities for management of recurrent pancreatic cancer we performed whole exome or targeted sequencing of 10 resected primary cancers and matched intrapancreatic recurrences or distant metastases. We identified that adjuvant or first-line platinum therapy corresponds to an increased mutational burden of recurrent disease. Recurrent disease is enriched for mutations that activate Mapk/Erk and PI3K/AKT signaling and develops from a monophyletic or polyphyletic origin. Treatment induced genetic bottlenecks lead to a modified genetic landscape and subclonal heterogeneity for driver gene alterations in part due to intermetastatic seeding. In one patient what was believed to be recurrent disease was an independent (second) primary tumor. These findings advocate for combination therapies with immunotherapy and routine post-treatment sampling as a component of management of recurrent pancreatic cancer.

cancer biology↗