A Novel Approach of Inhibiting Pancreatic Cancer Metastasis via Targeting Tumour Micro-Environment Induced Autophagy

Summary

Targeting autophagy and metastasis in pancreatic cancer via NDRG1

  • Pancreatic Cancer (PC) is highly metastatic with the highest mortality of all cancers (~93%).
  • The pancreatic tumour micro-environment induces survival pathways, such as autophagy, which are shown to promote tumour growth and metastasis.
  • Developing novel therapies to suppress autophagy offers an innovative approach in the fight against aggressive and metastatic PC.
  • We propose NDRG1-induction as a novel strategy to suppress autophagy mediated metastasis.

Supervisor(s)

Dr Sumit Sahni

Research Location

Camperdown - School of Medical Sciences

Program Type

Masters/PHD

Synopsis

Significance
Pancreatic Cancer (PC) is highly metastatic and has the highest mortality rate of all major cancers (~93%). In fact, a person is more likely to die of PC in Australia than a road accident. Importantly, PC was estimated to have a global economic cost of ~$9.5 billion in 2009 alone. Considering this, it is crucial to assess the underlying driving force in PC progression and if new therapeutic strategy could offer better hope for people affected by this devastating disease.

Innovation
The pancreatic tumour micro-environment induces survival pathways, e.g., autophagy, to ensure access to energy and metabolites for tumour growth. PC cells are known to have increased autophagy. his is of interest in PC as a recent study suggest that autophagy can promote metastasis.
Moreover, the standard drug used in PC, gemcitabine, is also shown to induce autophagy, which results in drug resistance and therapy failure. This proposal aims to develop a new therapeutic strategy to suppress autophagy, in the fight against aggressive and metastatic PC.

Rationale
There is growing interest in the stress response and metastatic suppressor protein, N-myc Downstream Regulated Gene 1 (NDRG1), in a potential anti-cancer therapeutic strategy. Although NDRG1 plays a role in cellular signalling, its role in tumour micro-environment induced cell survival pathways, such as autophagy, remains elusive. Our preliminary data demonstrated that NDRG1 can target and suppress tumour micro-environment stress induced autophagy in PC cells. This data forms a strong basis for investigating the role of autophagy in PC progression and metastasis, and if induction of autophagy suppressor (i.e., NDRG1) can be developed as a novel therapeutic strategy against PC. Moreover, this study will also assess the ability of potent NDRG1-inducers, to suppress tumour micro-environment induced autophagy. In addittion, we will also assess if induction of NDRG1 (via NDRG1-inducers) in combination with gemcitabine could overcome autophagy mediated gemcitabine resistance.

Hypothesis and Specific Objectives:
We hypothesise that NDRG1-induction could offer a novel therapeutic strategy, via suppression of tumour micro-environment induced autophagy, leading to inhibition of metastasis in PC. The hypothesis will be addressed in Specific Objective 1-4:

  1. To examine the detailed mechanism via which NDRG1 affects tumour micro-environment induced autophagy in PC.
  2. To investigate the role of NDRG1 on upstream and downstream pathways of autophagy in PC.
  3. To examine the effect of NDRG1 on tumour micro-environment autophagy-metastasis axis in vivo.
  4. To assess autophagy & NDRG1 levels in PC metastasis progression in biopsies from PC patients.

Methodology
A wide range of latest cellular and molecular techniques will be employed (e.g., mammalian cell culture, western blot, confocal microscopy, gene silencing, qRT-PCR) to determine the molecular mechanisms by which NDRG1 suppressess tumour microenvironment stress induced autophagy and metastasis.

Additional Information

Resources
The laboratory is well supported by both NHMRC, Cancer Australia and CINSW funding. The laboratories contain a dedicated cell culture facility containing 6 cell culture incubators that include isolated micro-incubators for assessing hypoxic conditions, ultra-freezing equipment for storing cell lines, 4 sterile biological safety cabinets, centrifuges, light microscope and a phase-contrast/fluorescence microscope that includes a photographic system.

The lab also includes a certified radiation laboratory, dark room, 2 general use chemical fume hoods, γ-counter, computerized plate reader, spectrophotometer, sonicator, preparative and analytical balances, pH meter, water baths, and a broad range of basic equipment for molecular and cellular biology e.g. electrophoresis equipment (vertical/ horizontal gel tanks, power packs, transfer and blotting equipment etc.). A wide variety of core equipment is found in the Department and within the Bosch Institute Molecular Biology Facility. This includes high speed centrifuges, gel-doc facilities, imaging systems, etc.

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Keywords

Cancer, metastasis, pancreatic cancer, Tumour Microenvironment, autophagy, Cell survival

Opportunity ID

The opportunity ID for this research opportunity is: 180