The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic and mutations (KPC) were crossed with haploinsufficient mice (Z). Extensive PDAC was prominent in all 20-week-old KPC;Z mice, whereas only low-grade precursor lesions were detected in age-matched KPC;Z littermates, with PDAC developing eventually in KPC;Z aged animals. Zeb1 expression in myofibroblasts occurred early in tumorigenesis and haploinsufficiency retarded native expansion of stromal myofibroblasts during precursor-to-cancer progression. downregulation in mPSC repressed their activated gene profile, impaired their migratory and proliferative activity, and attenuated their tumor-supporting features. Conditioned media from Z mouse-activated (myofibroblast-like) pancreatic stellate cells (mPSC) boosted Ras activity in pancreatic cancer cells carrying mutant ; this effect was not observed when using conditioned media from Z mPSC, revealing a paracrinal cooperative axis between Zeb1-expressing PSC and oncogenic Kras-bearing tumor cells. We conclude that Zeb1-expressing stromal myofibroblasts enable a heterotypic collaboration with the Kras-fated epithelial compartment, thus supporting pancreatic malignancy. Zeb1 expression in stromal myofibroblasts supports PDAC development via collaboration with the epithelial compartment bearing oncogenic Kras mutations. .
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http://dx.doi.org/10.1158/0008-5472.CAN-17-1882 | DOI Listing |
Thyroid cancer progression from curable well-differentiated thyroid carcinoma to highly lethal anaplastic thyroid carcinoma is distinguished by tumor cell de-differentiation and recruitment of a robust stromal infiltrate. Combining an integrated thyroid cancer single-cell sequencing atlas with spatial transcriptomics and bulk RNA-sequencing, we define stromal cell subpopulations and tumor-stromal cross-talk occurring across the histologic and mutational spectrum of thyroid cancer. We identify distinct inflammatory and myofibroblastic cancer-associated fibroblast (iCAF and myCAF) populations and perivascular-like populations.
View Article and Find Full Text PDFCells
December 2024
Centre for Regenerative Medicine, Medical Research and Educational Institute, Lomonosov Moscow State University, 119192 Moscow, Russia.
Fibrotic focus is a pivotal morphofunctional unit in developing fibrosis in various tissues. For most fibrotic diseases, including progressive forms, the foci are considered unable to remodel and contribute to the worsening of prognosis. Unfortunately, the dynamics of the fibrotic focus formation and resolution remains understudied.
View Article and Find Full Text PDFCells Dev
January 2025
Department of Biomedical Engineering, University of Connecticut, Storrs, CT, United States of America; Department of Biomedical Engineering, University of Connecticut Health, Farmington, CT, United States of America; Jackson Laboratory, Farmington, CT, United States of America. Electronic address:
The maternal-fetal interface has long been considered as a frontier for an evolutionary arms race due to the close juxtaposition of genetically distinct tissues. In hemochorial species with deep placental invasion, including in humans, maternal stroma prepares its defenses against deep trophoblast invasion by decidualization, a differentiation process characterized by increased stromal cell matrix production, and contractile force generation. Decidualization has evolved from an ancestral wound healing response of fibroblast activation by the endometrial stroma.
View Article and Find Full Text PDFExp Eye Res
December 2024
Harry S. Truman Memorial Veterans' Hospital, Columbia, MO, United States; Departments of Veterinary Medicine & Surgery and Biomedical Sciences, University of Missouri, Columbia, MO, United States; Mason Eye Institute, School of Medicine, University of Missouri, Columbia, MO, United States. Electronic address:
Sulfur mustard gas (SM), an alkylating and vesicating agent, has been used frequently in many wars and conflicts. SM exposure to the eye results in several corneal abnormalities including scar/fibrosis formation. However, molecular mechanism for SM induced corneal fibrosis development is poorly understood.
View Article and Find Full Text PDFArkh Patol
December 2024
Lomonosov Moscow State University, Medical Research and Educational Institute, Moscow, Russia.
Objective: To evaluate the representation and localization of FAP-positive activated stromal cells depending on the severity of fibrotic changes in tissues of patients with a confirmed diagnosis of COVID-19.
Material And Methods: 20 autopsy observations of patients who died from COVID-19 were studied. Immunohistochemical studies were performed using antibodies to CD90, FAP and aSMA and a dual imaging system.
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