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SRP189905
Danio rerio
7 Downloadable Samples
Illumina HiSeq 2000
Description
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with limited treatment options. Familial predisposition to PDAC occurs in ~10% of cases, but causative genes have not been identified in most families. Uncovering the genetic basis for PDAC susceptibility has immediate prognostic implications for families and can provide mechanistic clues to PDAC pathogenesis. Here, we perform whole-genome sequence analysis in a family with multiple cases of PDAC and identify a germline nonsense mutation in the member of RAS oncogene family-like 3 (RABL3) gene never before directly associated with hereditary cancer. The truncated mutant allele (RABL3_p.S36*) co-segregates with cancer occurrence. To evaluate the contribution of the RABL3 mutant allele in hereditary cancer, we generated rabl3 heterozygous mutant zebrafish and found increased susceptibility to cancer formation in two independent cancer models. Unbiased approaches implicate RABL3 in RAS pathway regulation: the transcriptome of juvenile rabl3 mutants reveals a KRAS upregulation signature, and affinity-purification mass spectrometry for proteins associated with RABL3 or RABL3_p.S36* identifies Rap1 GTPase-GDP Dissociation Stimulator 1 (RAP1GDS1, SmgGDS), a chaperone that regulates prenylation of RAS GTPases. Indeed, we find that RABL3_p.S36* accelerates KRAS prenylation and requires RAS proteins to promote cell proliferation. Furthermore, rabl3 homozygous mutant zebrafish develop severe craniofacial, skeletal, and growth defects consistent with human RASopathies, and these defects are partially rescued with the MEK inhibitor trametinib. Finally, we identify additional germline mutations in RABL3 that impact RAS activity in vivo and have a significant burden in a cohort of patients with developmental disorders, suggesting a role in undiagnosed RASopathies. Moreover, RABL3 is upregulated in multiple human PDAC cell lines and knockdown abrogates proliferation, consistent with a broader role for RABL3 in PDAC. Our studies identify the RABL3 mutation as a new target for genetic testing in cancer families and uncover a novel mechanism for dysregulated RAS activity in development and cancer. Overall design: WT (4 replicates) and homozygous rabl3-TR41 mutant (3 replicates) larval zebrafish at 21 days of age.
Publication Title
Mutations in RABL3 alter KRAS prenylation and are associated with hereditary pancreatic cancer.
Sample Metadata Fields
Age, Specimen part, Cell line, Subject
View Samples- Mus musculus
- 45 Downloadable Samples
Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
Living organisms detect seasonal changes in day length (photoperiod), and alter their physiological functions accordingly, to fit seasonal environmental changes. This photoperiodic system is implicated in seasonal affective disorders and the season-associated symptoms observed in bipolar disease and schizophrenia. Thyroid-stimulating hormone beta subunit (Tshb), induced in the pars tuberalis (PT), plays a key role in the pathway that regulates animal photoperiodism. However, the upstream inducers of Tshb expression remain unknown. Here we show that late-night light stimulation acutely triggers the Eya3-Six1 pathway, which directly induces Tshb expression. Using melatonin-proficient CBA/N mice, which preserve the photoperiodic Tshb-expression response, we performed a genome-wide expression analysis of the PT under chronic short-day and long-day conditions. These data comprehensively identified long-day and short-day genes, and indicated that late-night light stimulation induces long-day genes. We verified this by advancing and extending the light period by 8 hours, which acutely induced Tshb expression, within one day. In a genome-wide expression analysis under this condition, we searched for candidate upstream genes by looking for expression that preceded Tshbs, and identified Eya3 gene. These results elucidate the comprehensive transcriptional photoperiodic response in the PT, revealing the complex regulation of Tshb expression and unexpectedly rapid response to light changes in the mammalian photoperiodic system.
Publication Title
Acute induction of Eya3 by late-night light stimulation triggers TSHβ expression in photoperiodism.
Sample Metadata Fields
Sex, Age, Specimen part, Time
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
In vivo reprogramming drives Kras-induced cancer development.
Sample Metadata Fields
Sex, Specimen part, Treatment
View Samples- Mus musculus
- 8 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Accumulation of genetic mutations is thought to be a primary cause of cancer. However, a set of genetic mutations sufficient for cancer development remains unclear in most cancers, including pancreatic cancer. Here, we examined the effect of in vivo reprogramming on Kras-induced cancer development. We first demonstrate that Kras and p53 mutations are insufficient to induce activation of ERK signaling and cancer development in the pancreas. We next show that short transient expression of reprogramming factors (1-3 days) in pancreatic acinar cells results in repression of acinar cell enhancers and reversible loss of acinar cell properties. Notably, the transient expression of reprogramming factors in Kras mutant mice is sufficient to induce robust and persistent activation of ERK signaling in acinar cells and rapid formation of pancreatic ductal adenocarcinoma (PDAC). In contrast, forced expression of acinar cell-related transcription factors inhibits pancreatitis-induced activation of ERK signaling and development of precancerous lesions in Kras-mutated acinar cells.
Publication Title
In vivo reprogramming drives Kras-induced cancer development.
Sample Metadata Fields
Sex, Specimen part
View Samples