3-Dimensional understanding of BRCA2-deficient cancers: BRCA2 at the kinetochore and at the telomeres
  • Hyunsook Lee Ph.D
  • SLS Colloquia / 2018.03.29.(Thu) 04:00 pm / Room N104, Bldg 110
Abstract

Germ-line mutation of BRCA2 leads to the tumorigenesis of the breast and pancreas.? Pancreas cancers are the most lethal disease due to late diagnosis and lack of appropriate treatment.? Understanding of panceratic cancer is quite poor and the fact that 90 percent of patients cannot take surgery makes the case worse. Pancreatic ductal adenocarcinoma (PDA) is the major form of cancer found in the pancreas. ?PDAs exhibit high degree of chromosome instability, yet the molecular basis of it is unknown.? The major problem for understanding of pancreas cancer comes from the lack of appropriate culture system.

In this talk, three questions linked with the function of BRCA2 will be tackled: 1) function of BRCA2 in mitosis; 2) How BRCA2 functions at the telomeres; 3) the application of 3-D organoid cultures and molecular analysis in precision medicine.

The breast cancer susceptibility gene, BRCA2, is critically required for homology-directed repair (HDR).? In addition, we have found that BRCA2 fine-tunes the spindle assembly checkpoint by reinforcing BubR1 acetylation, which serves as the molecular switch for APC/C in mitosis. In S phase, BRCA2 is also required for the homeostasis of the telomere lagging strand synthesis.? Using the 3-D pancreas organoid culture methods, combined with MEF analysis, I will present data showing the molecular basis of chromosome instability in BRCA2-deficient cells. First, we confirmed that BRCA2 serves as the platform for BubR1 acetylation/deacetylation for checkpoint maintenance and mitotic exit.

To understand the paradoxical tumorigenesis in the absence of BRCA2, which progressively shortens telomeres, we asked the possibility of BRCA2 functioning as the suppressor of ALT (Alternative lengthening of telomeres).? We have now compelling lines of evidences, from C. elegans and mice, that dysfunctional BRCA2 in the absence of telomerase will provoke an illegitimate repair pathway at the telomeres, which instigates ALT. Molecular pathways that leads to BRCA2-deficient ALT will be discussed. ????

We have succeeded in robust cultures and analysis of 3-D organoid cultures from the fine-needle biopsy (FNB) samples of human patients.? With the understanding of molecular pathways from mouse models, the characterization of the pancreatic organoid of human FNA samples will let us understand better on this deadly disease.? Lastly, FNB-derived human pancreas organoids have promising future in the application of patient-specific therapy; how we approach to this question will be discussed.

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