Kufe Lab Discoveries and Related Publications 1984 Identification of human DF3/MUC1 carcinoma-associated antigen. Overexpression in breast carcinomas.
1988-9 Cloned the MUC1 cDNA. Identified the 20 amino acid tandem repeats in the MUC1 N-terminal ectodomain. Identified sequences in the MUC1-C transmembrane domain and cytoplasmic tail.
1997 First demonstration that fusions of dendritic cells and tumor cells can be used in the treatment of cancer. Approach shown to induce immunity against MUC1.
2007 Showed that the MUC1-C subunit undergoes dimerization through a CQC motif in the cytoplasmic domain. Dimerization is necessary for its oncogenic function.
2009 Developed the first direct inhibitor of the MUC1-C cytoplasmic domain and showed activity against breast and prostate cancer in vitro and in animal models.
Developed anti-MUC1-C CAR T-cells that are entering clinical evaluation in late 2020/early 2021. 2021 Showed that MUC1-C promotes immune cell-depleted "cold" TNBCs.
Showed that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.
Revealed a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Also uncovered involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.
Demonstrated that MUC1-C drives pluripotency, lineage plasticity and neuroendocrine dedifferentiation in pancreatic ductal carcinomas.
www.ncbi.nlm.nih.gov/pmc/articles/PMC8832436/
2022 Demonstrated that MUC1-C dictates pancreatic ductal adenocarcinoma neuroendocrine (NE) lineage specification and is a potential target for the treatment of recalcitrant pancreatic carcinomas with NE dedifferentiation.
Discovered that MUC1-C plays a major role in remodeling of chromatin accessibility across the genome and specifically at enhancer signatures in cancer cells.
Showed that MUC1-C remodels chromatin accessibility of genes encoding effectors of the type II IFN pathway with their chronic activation and suppression of the tumor immune microenvironment in prostate cancer.
www.ncbi.nlm.nih.gov/pmc/articles/PMC8812775/
Showed that SCLC cells are addicted to MUC1-C and determined that MUC1-C is a potential new target for SCLC treatment.
Determined that MUC1-C induces STING and DNA damage resistance in TNBC and is a target for treatment with anti-MUC1-C agents that are under preclinical and clinical development.
MUC1-C dictates the CSC state and resistance to treatment. These studies demonstrated that MUC1-C activates the PBRM1/PBAF complex in reprogramming chromatin accessibility and expression of IFN type I/II genes that promote DNA damage resistance and immunosuppression.
2023 Our development of an anti-cancer vaccine by fusing MUC1-C-expressing cancer cells with autologous dendritic cells captures repertoires of cancer-associated antigens for presentation to T cells. The present study demonstrated that this personalized vaccine approach is effective for inducing immunity against pancreatic cancers that express high MUC1-C levels and are largely unresponsive to immunotherapy.
MUC1-C has been linked to depletion and dysfunction of T cells in the tumor microenvironment. These studies uncovered a role for MUC1-C in governing evasion of cancer cells to NK cell recognition and destruction by suppressing MICA/B expression and regulating exosome secretion.
Identified that MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors by suppressing the feedback MAPK pathway.
MUC1-C drives resistance of cancer cells to genotoxic and targeted agents. This work identified MUC1-C is a target for the treatment of BRAF(V600E) CRCs and for reversing their resistance to BRAF inhibitors, in further supporting a memory response to cancer treatment.
MUC1-C links chronic inflammation with cancer progression. These findings revealed that MUC1-C integrates chronic NF-kB inflammatory signaling with activation of the COMPASS family of H3K4 methyltransferases in the epigenetic reprogramming of pluripotency and stemness genes that drive the CSC state.
MUC1-C conveys resistance of cancer cells to diverse classes of genotoxic drugs and targeted agents. These studies extended involvement of MUC1-C to driving pleotropic mechanisms of acquired resistance to osimertinib in EGFR mutant NSCLCs and uncover a role for MUC1-C in an unrecognized inflammatory memory response to anti-cancer treatment.
MUC1-C is necessary for the CSC state and self-renewal capacity. In studies of TNBC CSCs, we discovered that MUC1-C integrates self-renewal with regulation of redox balance by activating aerobic glycolysis and suppressing OXPHOS in concert with promoting the Warburg effect.