The molecular networks that specify cellular identity and suppress alternative cell fates are tightly regulated during normal tissue homeostasis. These networks can become dramatically dysregulated during cancer progression, often with lethal consequences for cancer patients. Poorly differentiated tumors, which have lost much of their original cellular identity, typically have a greater propensity for growth and metastasis than tumors that more closely resemble their tissue of origin. In some cases, tumors treated with targeted therapies can undergo radical changes in cellular identity that affect their sensitivity to standard drug regimens. Despite these observations, the field has not deciphered the master regulators that control cellular identity in most cancer types. Identifying these regulators and determining the specific consequences of their inactivation will provide critical insights into mechanisms of cancer progression and enable the development of new therapeutic strategies targeted to specific differentiation states.
Turning lung into stomach
We have shown that the transcription factor Nkx2-1 is a critical regulator of lung adenocarcinoma identity. Engineered deletion of Nkx2-1 causes a complete loss of pulmonary differentiation in a mouse model of lung adenocarcinoma and enhances tumor growth. Nkx2-1-negative tumors exhibit a striking mucinous morphology and transcriptionally upregulate a gastric differentiation program. These mucinous murine lung tumors bear a close resemblance to a subtype of human lung cancer that also expresses multiple gastric markers. Integrative gene expression/ChIP-seq analysis has implicated the Foxa1/2 transcription factors in the pulmonary to gastric differentiation state change induced by Nkx2-1 deletion.
Our overall goal is to determine how the loss of cellular identity and acquisition of alternative differentiation states contributes to cancer progression and alters therapeutic response. Ongoing projects are focused on two major themes:
1) Regulation of cellular identity in lung and pancreatic cancer. We are studying the mechanisms by which transcription factors (including Nkx2-1, Foxa1, Foxa2 and Hnf4a) and their downstream targets control cancer differentiation state.
2) Impact of changes in cellular identity on oncogenic signaling and response to targeted therapies. Our preliminary data indicates that changes in cellular identity can alter the activity of signaling pathways that are regulated by driver oncogenes such as Kras. We are investigating whether these changes have a direct impact on the growth and metastasis of tumors. We are also evaluating whether the impact of these changes on the intrinsic sensitivity of tumors to targeted cancer therapies.