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1.
J Cell Biol ; 222(4)2023 04 03.
Article in English | MEDLINE | ID: mdl-36828547

ABSTRACT

The transcription factor Prdm16 functions as a potent suppressor of transforming growth factor-beta (TGF-ß) signaling, whose inactivation is deemed essential to the progression of pancreatic ductal adenocarcinoma (PDAC). Using the KrasG12D-based mouse model of human PDAC, we surprisingly found that ablating Prdm16 did not block but instead accelerated PDAC formation and progression, suggesting that Prdm16 might function as a tumor suppressor in this malignancy. Subsequent genetic experiments showed that ablating Prdm16 along with Smad4 resulted in a shift from a well-differentiated and confined neoplasm to a highly aggressive and metastatic disease, which was associated with a striking deviation in the trajectory of the premalignant lesions. Mechanistically, we found that Smad4 interacted with and recruited Prdm16 to repress its own expression, therefore pinpointing a model in which Prdm16 functions downstream of Smad4 to constrain the PDAC malignant phenotype. Collectively, these findings unveil an unprecedented antagonistic interaction between the tumor suppressors Smad4 and Prdm16 that functions to restrict PDAC progression and metastasis.


Subject(s)
Carcinoma, Pancreatic Ductal , DNA-Binding Proteins , Pancreatic Neoplasms , Smad4 Protein , Transcription Factors , Animals , Humans , Mice , Carcinoma, Pancreatic Ductal/genetics , Carcinoma, Pancreatic Ductal/pathology , Cell Line, Tumor , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/pathology , Smad4 Protein/genetics , Smad4 Protein/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Pancreatic Neoplasms
2.
Life Sci Alliance ; 3(6)2020 06.
Article in English | MEDLINE | ID: mdl-32371554

ABSTRACT

Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease that remains incurable because of late diagnosis, which renders any therapeutic intervention challenging. Most PDAC patients develop de novo diabetes, which exacerbates their morbidity and mortality. How PDAC triggers diabetes is still unfolding. Using a mouse model of KrasG12D-driven PDAC, which faithfully recapitulates the progression of the human disease, we observed a massive and selective depletion of ß-cells, occurring very early at the stages of preneoplastic lesions. Mechanistically, we found that increased TGF beta (TGF-ß) signaling during PDAC progression caused erosion of ß-cell mass through apoptosis. Suppressing TGF-ß signaling, either pharmacologically through TGF-ß immunoneutralization or genetically through deletion of Smad4 or TGF-ß type II receptor (TßRII), afforded substantial protection against PDAC-driven ß-cell depletion. From a translational perspective, both activation of TGF-ß signaling and depletion of ß-cells frequently occur in human PDAC, providing a mechanistic explanation for the pathogenesis of diabetes in PDAC patients, and further implicating new-onset diabetes as a potential early prognostic marker for PDAC.


Subject(s)
Carcinoma, Pancreatic Ductal/complications , Carcinoma, Pancreatic Ductal/metabolism , Diabetes Mellitus/etiology , Insulin-Secreting Cells/metabolism , Pancreatic Neoplasms/complications , Pancreatic Neoplasms/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Transforming Growth Factor beta1/metabolism , Animals , Antibodies, Neutralizing/pharmacology , Apoptosis/drug effects , Apoptosis/genetics , Cells, Cultured , Diabetes Mellitus/metabolism , Disease Models, Animal , Disease Progression , Gene Deletion , Mice , Mice, Inbred C57BL , Mice, Transgenic , Prognosis , Receptor, Transforming Growth Factor-beta Type II/genetics , Smad4 Protein/genetics , Transforming Growth Factor beta1/immunology , Transforming Growth Factor beta1/pharmacology
3.
Dev Cell ; 45(6): 712-725.e6, 2018 06 18.
Article in English | MEDLINE | ID: mdl-29920276

ABSTRACT

Cancer cachexia is characterized by extreme skeletal muscle loss that results in high morbidity and mortality. The incidence of cachexia varies among tumor types, being lowest in sarcomas, whereas 90% of pancreatic ductal adenocarcinoma (PDAC) patients experience severe weight loss. How these tumors trigger muscle depletion is still unfolding. Serendipitously, we found that overexpression of Twist1 in mouse muscle progenitor cells, either constitutively during development or inducibly in adult animals, caused severe muscle atrophy with features reminiscent of cachexia. Using several genetic mouse models of PDAC, we detected a marked increase in Twist1 expression in muscle undergoing cachexia. In cancer patients, elevated levels of Twist1 are associated with greater degrees of muscle wasting. Finally, both genetic and pharmacological inactivation of Twist1 in muscle progenitor cells afforded substantial protection against cancer-mediated cachexia, which translated into meaningful survival benefits, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients.


Subject(s)
Cachexia/metabolism , Muscle Cells/metabolism , Muscular Atrophy/metabolism , Nuclear Proteins/metabolism , Stem Cells/metabolism , Twist-Related Protein 1/metabolism , Animals , Cachexia/pathology , Cell Line, Tumor , Colorectal Neoplasms/metabolism , Colorectal Neoplasms/pathology , HEK293 Cells , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Male , Mice , Mice, Inbred C57BL , Muscle Cells/cytology , Muscle, Skeletal/metabolism , Muscular Atrophy/genetics , Myoblasts/metabolism , Signal Transduction , Stem Cells/cytology
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