The prognosis of pancreatic ductal adenocarcinoma (PDA) has improved only marginally in the past decade. PDA is a disease with remarkable homogeneity across several key loci, namely KRAS, p53, and the INK4A/ Arf locus;related to this, PDA has been refractory to the many genetically guided therapies targeting activated oncogenic molecules that have offered success in other tumor types. Previously, we have identified a set of ~95 genes cooperatively regulated by mutation of RAS and p53, that are critical to the malignant phenotype of a variety of epithelial cancer cells in vivo. We have termed these non-mutated genes driving the cancer phenotype 'cooperation response genes'(CRGs). CRGs control a range of cellular processes and pathways (signaling, metabolism, transport etc.) and offer novel approaches to targeted cancer interventions with potential relevance to a variety of diverse cancers. Given the high frequency of cooperating KRAS and P53 pathway mutations found in PDA (>90% of tumors) we have specifically evaluated CRG expression levels in the pancreatic epithelium where we find a subset of these genes similarly deregulated pointing towards their importance in pancreatic oncogenesis. Our preliminary data indicate that one such cooperatively regulated gene with previously unknown function, Plac8, localizes to lysosomes functionally facilitating autophagosome- lysosome (AL) fusion, and that its genetic silencing leads to a block in autophagy and inhibition of tumor growth. Furthermore, genetic inactivation of Plac8 in an engineered murine PDA model impedes the progression of advanced tumors extending survival. In contrast, Plac8 knockout mice are minimally affected by loss of this gene. Thus, Plac8 and the lysosomal processes it regulates appear well suited as therapeutic targets in PDA and other RAS/p53 mutant GI cancers, as Plac8 inhibition has both a high impact on tumor biology and a minimal impact on normal cellular function. Based on these data we hypothesize that i) Plac8 facilitates AL fusion in cancer cells, and ii) that this mechanism is essential to the malignant phenotype PDA, thus providing rationale for targeted pancreatic cancer intervention. These hypotheses will be tested in a series of experiments investigating 1) the role of Plac8 in pancreatic cancer progression and cancer maintenance, 2) the role of autophagosome-lysosome fusion as an essential function in cancer, and 3) the impact of Plac8 on lysosome integrity in cancer. The role and relevance of both autophagosome/ lysosome fusion and active protection of lysosomal integrity in cancer remains virtually unexplored. Investigation of the mechanisms involved is thus likely to reveal novel opportunities for targeted cancer-specific interventions, particularly as Plac8 is non-essential for normal tissue function.
Pancreatic ductal adenocarcinoma (PDA) affects ~45,000 people in the US each year, with poor prognosis for the majority of patients and a median survival of under a year. PDA has been refractory to the many genetically guided therapies targeting activated oncogenic molecules that have offered success in other tumor types. Recently we have discovered a set of non-mutated genes driving the cancer phenotype that control a wide range of cellular processes and pathways, including autophagic flux, and offer novel approaches to targeted cancer interventions. Here we propose to investigate whether inhibition of autophagic flux may serve as a suitable strategy for cancer interventions targeting PDA.
|Komisarof, Justin; McCall, Matthew; Newman, Laurel et al. (2017) A four gene signature predictive of recurrent prostate cancer. Oncotarget 8:3430-3440|