Goal 1. Define biological role of squalene accumulation in tumors

Objective:

1. Identify mechanism by which squalene accumulation protects cancer cells from oxidative cell death.
2. Define relevance of squalene in growth of hypoxic pancreatic ductal adenocarcinomas and breast cancers.
3. Test whether inhibiting squalene synthesis sensitizes hypoxic tumors to therapies that induce oxidative stress.

Goal 2. Identify new antioxidant pathways and define their roles in cancer progression

Objective:

1. Determine how synthesis of glycosaminoglycans protects cancer cells from lipid peroxidation and ferroptosis. 

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Goal 1. Define biological role of squalene accumulation in tumors

Objective:

1. Identify mechanism by which squalene accumulation protects cancer cells from oxidative cell death.
2. Define relevance of squalene in growth of hypoxic pancreatic ductal adenocarcinomas and breast cancers.
3. Test whether inhibiting squalene synthesis sensitizes hypoxic tumors to therapies that induce oxidative stress.

Goal 2. Identify new antioxidant pathways and define their roles in cancer progression

Objective:

1. Determine how synthesis of glycosaminoglycans protects cancer cells from lipid peroxidation and ferroptosis.
2. Assess whether glycosaminoglycans biosynthesis impacts the metastatic capacity of melanomas and lung tumors.
3. Use parallel CRISPR-Cas9 screens to test whether tumors arising from different tissues rely on alternative antioxidant mechanisms.

Goal 3. Identify organellar antioxidant systems dedicated to counteracting lipid peroxidation.

Objective:

1. Map organelle-restricted systems mitigating lipid peroxidation in tumors.
2. Define antioxidant mechanism and relevant cancer models for identified pathways.
3. Determine whether inhibition of these pathways blunts cancer metastasis or sensitizes tumors to radiation therapy.

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