Stromal evolution of cancer-associated fibroblasts in PDAC GEMMs
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ABSTRACT:
PROVIDER: PRJEB35138 | ENA |
REPOSITORIES: ENA
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Project description:The effect of radiation therapy (RT) on tumor immunity in PDAC is not well understood. To better understand if RT can prime antigen-specific T cell responses, we analyzed human PDAC tissues and PDAC GEMMs. In both settings, we found little to support evidence of RT-induced T cell priming. Using in-vitro systems, we found tumor stromal components, including fibroblasts and collagen, synergize to both blunt RT efficacy and impair RT-induced interferon signaling. Focal Adhesion Kinase (FAK) inhibition rescued RT efficacy in-vitro and in-vivo, leading to tumor regression, T cell priming, and enhanced long-term survival in PDAC mouse models. Based on these data, we initiated a clinical trial of VS-6063 in combination with SBRT in PDAC patients (NCT04331041). Analysis of PDAC tissues from these patients showed stromal reprogramming mirroring our findings in GEMMs. Finally, the addition of checkpoint immunotherapy to RT and FAKi in animal models led to complete tumor regression and long-term survival.
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Project description:Senescence of stromal fibroblasts has been linked to establishment of cancer associated fibroblasts (CAF) and aging-associated increase of tumors. However, in clinically occurring carcinomas, density and proliferation of CAFs are frequently increased rather than decreased. We previously showed that genetic deletion or down-modulation of the canonical Notch effector CSL/RBP-Jκ in skin dermal fibroblasts is sufficient for CAF activation with consequent development of multifocal keratinocyte tumors. We now show that CSL deletion or knockdown induces senescence of primary fibroblasts derived from dermis, oral mucosa, breast and lung. CSL functions in these cells as a constitutive direct repressor of multiple senescence- and CAF-effector genes. At the same time, it physically interacts with p53, repressing its activity, and p53 activation provides a failsafe mechanism against compromised CSL function. Concomitant loss of CSL and p53 overcomes fibroblast senescence, enhances expression of CAF effector genes and, in vivo, promotes tumour and stromal cell expansion. Together, the findings support a CAF activation/stromal evolution model under convergent CSL/p53 control. Human Dermal Fibroblasts were transfected with two different siRNA against CSL in parallel with a control siRNA. Total RNA was extracted 3 days post-transfection, followed by RNA-Seq analysis.
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