Cancer stem cells (CSCs) contribute to intra-tumor heterogeneity by providing the tumor with cells that can differentiate and de-differentiate according to the stress of the environment. CSC utilize many of the same developmental pathways used by normal stem/progenitor cells during embryogenesis, including those for energy consumption, increased proliferation, overcoming hypoxic conditions, and inducing migration. The RNA binding protein, Lin28 and the microRNA, (miRNA) let-7 are part of an evolutionarily conserved developmental feedback loop that acts as a heterochronic regulator of developmental timing in metazoans from worms to m...

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Cancer stem cells (CSCs) contribute to intra-tumor heterogeneity by providing the tumor with cells that can differentiate and de-differentiate according to the stress of the environment. CSC utilize many of the same developmental pathways used by normal stem/progenitor cells during embryogenesis, including those for energy consumption, increased proliferation, overcoming hypoxic conditions, and inducing migration. The RNA binding protein, Lin28 and the microRNA, (miRNA) let-7 are part of an evolutionarily conserved developmental feedback loop that acts as a heterochronic regulator of developmental timing in metazoans from worms to mammals.

The fundamental objective of this proposal is to define functional gene signatures of cancer stem cells/tumor-initiating cells that regulate metastasis and chemoresistance. Our central hypothesis is that the ‘stemness’ of the cell of origin may be important to the relative ‘stemness’ of the cancer cell and that the Lin28/let-7 axis is transcriptionally synchronized by either SOX2 and/or SOX9 at distinct intervals of tumorigenesis to facilitate cancer stem cell maintenance, drug resistance, and metastasis.

The first half of Aim 1 will focus on understanding the requirements of the SOX2/SOX9/Lin28/let-7 axis in de novo CSC formation from immortalized human bronchial epithelial cells (HBECs). The second half of Aim 1 will take advantage of already established patient-derived cell lines and xenograft models to study maintenance and metastatic potential. Aim 2 will use established and novel genetically engineered mouse models to understand the contribution of the immune system, niche/tumor microenvironment, and cell of origin to CSC formation and metastatic potential.

These studies will provide insight into developmental pathways that regulate metastasis and chemoresistance, particularly those involved in miRNA and mRNA regulation.

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