Grants and Contracts Details
Description
Adenocarcinomas of the lung are frequently metastatic and thus lethal. Researchers long hypothesized that
macrophages (mö) can induce a tumor to gain metastatic potential (Pollard, 2004). We postulate that
signals from M2-like polarized mö or tumor-associated mö (TAMs) can induce a gene expression program
in the tumor that influences epithelial-to-mesenchymal transition (EMT), invasion, and metastasis. Further,
we believe that expression of specific microRNA (miRNA) genes in the tumor genome is the initial
response to signaling from the immune cell component of the tumor microenvironment. The resulting
transcriptional program is characterized by activation of EMT-specific transcription factors Zeb1/2, Snail,
Slug and Twist and reduced expression of E-cadherin. We identified a 13-gene miRNA signature of
response of lung adenocarcinoma cells to the EGFR-inhibitor, erlotinib (Bryant, et al., submitted). The
signature is rich in miRNAs involved in EMT. Importantly, the 13 genes can also differentiate primary
from metastatic tumor tissue using clustering methods. Further, we have shown that treatment of A549 lung
adenocarcinoma cells and immortalized bronchial epithelial cells (Beas2B) with recombinant TGFâ1, an
inducer of EMT, can alter the expression profile of several of the 13 miRNA signature genes, induce Zeb1
and Snail expression, and reduce E-cadherin. Thus, we believe that signaling from the host immune
response to the tumor may initiate a program of miRNA gene expression necessary for induction of EMT
and loss of sensitivity to EGFR inhibition that may be dependent on TGFâ. Therefore, by identifying
mRNA targets of the 13 miRNAs and by discerning the role of TGFâ signaling on expression of the 13
gene signature, new targets for inhibitory therapeutics may be identified or modulators of TGFâ signaling
may be used as intervention therapy to prevent tumor metastasis and lessen the severity of disease.
Status | Finished |
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Effective start/end date | 11/1/11 → 10/31/12 |
Funding
- Lung Cancer Research Foundation: $50,000.00
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