Research in the Feldser Laboratory

One of the major goals of cancer biology is to understand the evolutionary process of tumorigenesis; from identification of the cell type of origin for a particular cancer to understanding how acquired mutations initiate the neoplastic process and ultimately lead to malignant disease. We employ an integrative approach utilizing quantitative molecular and biochemical techniques, effective gene engineering technologies, and powerful in vivo cancer models. Our objective is to uncover the oncogenic networks that are usurped by cancer cells to drive tumor progression as well as those tumor-suppressive pathways that are disabled during tumorigenesis. A detailed molecular understanding of the cellular state changes that occur both within the cancer cell itself and within cells in the tumor microenvironment will undoubtedly lead to better strategies to eradicate malignant cells.
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The multistep process of tumorigenesis: Initiating mutagenic events convert normal somatic cells to hyperplastic lesions. In the case of lung adenocarcinoma this is often due to oncogenic Kras mutations and mutation of a single copy of Kras is likely sufficient to initiate hyperplasia in certain cell types. Like all cancer types, lung adenocarcinoma evolves as a consequence of the selection of diverse of genetic driver mutations, or ‘Progression Events’. From our work, and that of many other laboratories, we have developed a unifying model of lung adenocarcinoma progression that identifies two critical barriers that tumors must overcome to acquire the ability to metastasize:

‘Early Barrier’ limits the adenoma to carcinoma transition. We have identified that amplification of the MAPK signaling pathway (i.e. RAS>RAF>MEK>ERK) causally drives tumor progression to an early carcinomatous state (Cicchini et al. 2017 red cells in figure). However, amplification of MAPK signaling strength activates the tumor suppressive functions of p53 which acts to suppress tumor cell proliferation and promote the selective clearance of carcinoma cells from the tumor mass ostensibly by immune cells (Feldser et al. 2010, Stokes et al. 2019). The major selective requirement for amplifying MAPK signal transduction is to repress the RB tumor suppressor pathway, such that in the absence of RB, MAPK amplification is no longer required for carcinoma progression (Walter et al. 2019). Thus the Early Barrier to tumor progression is controlled by both the p53 and RB tumor suppressors.

The ‘Late Barrier’ to lung adenocarcinoma progression limits the acquisition of metastatic competency. Much like in the human disease, in our lung adenocarcinoma model these metastases can be found in the draining lymph node, adrenal glands, liver, pleural cavity, and in other sites in the lung. In the models, metastatically competent cells have altered cell states, which are exemplified by a loss of lung cell lineage commitment and conversion to poorly differentiated phenotype (
Winslow et al. 2011). Our work has highlighted a second critical role for the RB tumor suppressor pathway at this Late Barrier. We found that loss of the RB pathway promotes lineage infidelity, the development of poorly differentiated cell states, and the onset of metastatic competency. Further confirming the power and relevance of these models, we also have identified that the molecular constraints controlled by p53 and RB that that create the Early and Late Barriers to tumor progression are also present in human lung adenocarcinoma (Walter et al. 2019).

Models of human lung cancer

Our laboratory exploits the outstanding genetic powers of the mouse in order to achieve our goal of deconstructing the multistep process that leads to the formation of lung cancer. In these models tumor initiation occurs in single cells that expand within the appropriate tissue microenvironment and undergo multiple cell state changes that ultimately result in the development of primary malignant carcinomas in the lung, some of which possess metastatic potential. We focus on adenocarcinoma and small cell carcinoma of the lung. These diseases represent two prevalent subtypes of human lung cancer that have disparate etiology but for which conventional genetically engineered mouse models exist.
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Two models of lung cancer: Inhalation of viral particles that express cre recombinase initiate tumor formation in each model. Lung adenocarcinoma is initiated by activation of a latent oncogenic allele of Kras and deletion of p53 (Jackson et al. 2005). Small cell lung cancer is initiated by deletion of tumor suppressors p53 and Rb (Meuwissen et al. 2003).

Current Research

Building on the lessons from our previous work, we are focused on elucidating the downstream functions of tumor-suppressor genes in lung cancer as well as the oncogenic Ras signaling in tumor initiation and progression. To this end, we have developed multiple novel tools and experimental systems to dissect tumor suppressor gene function, oncogene signaling, and the role of the tumor microenvironment in carcinogenesis. We are exploiting these tools in important in vivo contexts that are relevant to cancer biology in order to gain a more complete understanding of the etiology of these cancers.
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