Winter Meeting 2011 - The Pathological Society of Great Britain ...

Detailed Programme – Friday 7 January 2011
Presenter = P · Abstract numbers are shown in bold and square brackets eg [S123]
in vivo. Since tumours often have an increased lysosomal compartment, this could render them more susceptible to
drugs that induce LM-PCD. Thus, our findings will be of major importance in the design of treatments for cancers
such as breast, colon and liver where cathepsins are commonly over-expressed and Stat3 is hyper-activated.
10.30–11.00 Coffee / Poster Viewing / Trade Exhibition [Cloisters]
11.00–11.30 [S7] How Tumour Suppression Works to Kill Cancer Cells
P Prof G Evan 1 ; L Soucek 2 ; C Martins 2 ; K Shchors 2 ; D Murphy 2 ; M Junttila 2 ; D Garcia 2
University of Cambridge, Cambridge, United Kingdom; 2 UCSF Helen Diller Family Comprehensive
Cancer Center, San Francisco, United States
Myc and p53 are pleiotropic transcription factors that, respectively, drive and suppress cancer. Myc levels are
elevated and deregulated in most cancers, implicating a pivotal role for Myc in oncogenic signaling. However,
Myc mutations are relatively rare and the aberrant Myc in most tumours appears to be a consequence of aberrant
upstream signals. The extent to which such endogenous Myc, acting as a mere client of upstream oncogenes, might
be a therapeutic target depends on the degree to which it coordinates functions essential for tumour maintenance.
To investigate the therapeutic potential of Myc inhibition we have constructed switchable genetic mouse models in
which endogenous Myc can be systemically and reversibly inhibited in normal and tumour tissues in vivo. Our data
indicate that inhibiting Myc has a remarkably efficacious therapeutic impact on multiple cancer types, triggering
widespread tumour cell apoptosis while eliciting surprisingly only mild, reversible and non-cytotoxic side effects
in normal tissues. The p53 tumour suppressor, or its attendant pathway, is functionally inactivated in almost all
human cancers. However, the mechanism by which p53 suppresses tumorigenesis remains obscure. p53 mediates
the cellular apoptotic and senescence response to DNA damage, and this is thought to be critical for both tumour
suppression and for the progressive erosion of somatic regenerative capacity that characterizes aging. However,
using a unique mouse model in which the endogenous p53 gene is replaced by one encoding a ligand-dependent,
reversibly switchable variant of p53, we show that the p53-mediated DNA damage response is dispensable for
tumour suppression. Hence, by selectively manipulating the DNA damage and tumour suppressor functions of p53
it may be possible to potentiate tumour suppression and cancer therapy whilst simultaneously extending life-span.
11.30–12.15 [S8] Autophagy in the Involution of Normal Tissue
P Prof B Levine 1 ; KJ Jia 2 ; SH Huang 1 ; XQ Qu 3
UT Southwestern Medical Center, Dallas, United States; 2 Florida Atlantic University, Boca Raton,
United States; 3 Genentech, San Francisco, United States
Autophagy, a lysosomal degradation pathway, is commonly observed in metazoan organisms during programmed
cell death (PCD). However, its function in dying cells has been controversial. Our laboratory has used genetic
approaches in mouse embryonic stem cells and in C. elegans to address this question. In published studies, we
examined the role of autophagy in embryonic cavitation, the earliest PCD process in mammalian development.
We found that embryoid bodies (EBs) derived from cells lacking the autophagy genes, Atg5 or beclin 1, failed
to cavitate. This defect was due to persistence of cell corpses, rather than an impairment of PCD. Dying cells in
autophagy gene null EBs failed to express the ‘eat-me’ signal, phosphatidylserine exposure, and secreted lower
levels of the ‘come-get-me’ signal, lysophosphatidylcholine. These defects were associated with low levels of
cellular ATP and were reversed by treatment with the metabolic substrate, methylpyruvate. Moreover, mice
lacking Atg5 displayed a defect in apoptotic corpse engulfment during embryonic development. In unpublished
studies, we also found that autophagy genes are essential in the clearance of apoptotic corpses during nematode
embryonic development. The defects observed in apoptotic corpse clearance in C. elegans with null mutations in
the autophagy genes, bec-1 or atg18, can be rescued by re-introducing the autophagy genes in both the dying and
engulfing cells, but not in only the dying cells. Thus, taken together, our results in mammal and nematode systems
suggest that the autophagy pathway is important in both dying and phagocytic cells for normal tissue involution
during development.
Cloisters
12.15–13.15 Lunch / Poster viewing / Trade Exhibition
Francis Crick Auditorium
12.45–13.30 Meet the experts – Trainees’ Session: Liver Pathology
Chair: Dr I Proctor, University College London
Speaker: Dr SE Davies, Addenbrooke’s Hospital, Cambridge University NHS Trust
Scientific Programme | Winter Meeting (199 th ) 6 – 7 January 2011 | Visit our website: www.pathsoc.org
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