Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment

Lung cancer is a deadly treatment refractory disease that is biologically heterogeneous. To understand and effectively treat the full clinical spectrum of ...

Yale University School of Medicine

Metastasis is a complex clinical and biological problem presently under intense study, and several model systems are in use to experimentally recapitulate and dissect the various steps of the metastatic process. Genetically engineered mouse models provide faithful renditions of events in tumor progression, angiogenesis, and local invasion that set the stage for metastasis, whereas engrafting of human or mouse tumor tissues into mouse hosts has been successfully exploited to investigate metastatic dissemination and colonization of distant organs. Real-time, high-resolution microscopy in live animals, and comprehensive genetic and molecular profiling are effective tools to interrogate diverse metastatic cancer cell phenotypes as well as the metastatic tumor microenvironment in different organs. By integrating the information obtained with these complementary approaches the field is currently obtaining an unprecedented level of understanding of the biology, molecular basis, and therapeutic vulnerabilities of metastasis.

Modeling metastasis in the mouse.

Cancer metastasis is often considered an orderly sequence of events leading to the colonization of distal organs by malignant cells. In fact, the evolution of metastatic disease is a dynamic process that is influenced by unique cellular lineages, altered microenvironments, distinct anatomical restrictions and multiple genetic and epigenetic alterations. These factors all contribute to variable clinical courses, likely requiring tailored therapy. As we inch closer towards personalized medicine, there is a renewed conceptual and technological focus on characterizing the cellular and genetic heterogeneity within tumours, to ultimately trace the origins of metastatic cells in different cancers.

Tracing the origins of metastasis.

Cancer has long been compared to the aberrant development of human tissues. It was in the mid-19th century writings of Rudolf Virchow and Joseph Recamier that malignant tissue was first proposed to originate from embryonal cells. More contemporary perspectives on malignant progression are founded on the tenant that tumors emerge from somatic tissues. Yet examples linking the biological properties of cancer to developmental processes, both aberrant and normal, abound. In this review, we will discuss how the developmental lineage of tumor cells can influence the course of cancer metastasis. As new molecular mechanisms that control cell fate in various tissues are being rapidly uncovered, understanding how these well orchestrated programs can be subverted in human diseases should provide intriguing avenues for fundamental biological discoveries and new therapeutic opportunities in cancer.

Cell lineage specification in tumor progression and metastasis.

Molecular programs that mediate normal cell differentiation are required for oncogenesis and tumor cell survival in certain cancers. How cell-lineage-restricted genes specifically influence metastasis is poorly defined. In lung cancers, we uncovered a transcriptional program that is preferentially associated with distal airway epithelial differentiation and lung adenocarcinoma (ADC) progression. This program is regulated in part by the lineage transcription factors GATA6 and HOPX. These factors can cooperatively limit the metastatic competence of ADC cells, by modulating overlapping alveolar differentiation and invasogenic target genes. Thus, GATA6 and HOPX are critical nodes in a lineage-selective pathway that directly links effectors of airway epithelial specification to the inhibition of metastasis in the lung ADC subtype.

Control of Alveolar Differentiation by the Lineage Transcription Factors GATA6 and HOPX Inhibits Lung Adenocarcinoma Metastasis.

Programmes mol&eacute;culaires m&eacute;diateurs de la diff&eacute;renciation des cellules normales sont n&eacute;cessaires pour la survie des cellules oncogen&egrave;se et tumeur dans certains cancers. Comment les g&egrave;nes cell lineage-restriction influencent sp&eacute;cifiquement m&eacute;tastase est mal d&eacute;finie. Cancers du poumon, que nous avons d&eacute;couverts un programme transcriptionnel pr&eacute;f&eacute;rentiellement associ&eacute; &agrave; la diff&eacute;renciation &eacute;pith&eacute;liale des voies a&eacute;riennes distales et progression d&#39;ad&eacute;nocarcinome (ADC) du poumon. Ce programme est r&eacute;gul&eacute; en partie par les facteurs de transcription de lign&eacute;e GATA6 et HOPX. Ces facteurs peuvent en collaboration limiter la comp&eacute;tence m&eacute;tastatique des cellules de l&#39;ADC, en modulante la diff&eacute;renciation alv&eacute;olaire qui se chevauchent et g&egrave;nes cibles invasogenic. Ainsi, GATA6 et HOPX sont des n&oelig;uds critiques dans une voie de lign&eacute;e s&eacute;lectif qui effecteurs de sp&eacute;cification &eacute;pith&eacute;liales des voies respiratoires est directement li&eacute; &agrave; l&#39;inhibition des m&eacute;tastases dans le sous-type de poumon ADC.

Facteurs de contr&ocirc;le de la diff&eacute;renciation alv&eacute;olaire par la Transcription de la lign&eacute;e GATA6 et HOPX inhibe les m&eacute;tastases d&#39;ad&eacute;nocarcinome pulmonaire.

MET amplification as a mechanism of acquired resistance to EGF receptor (EGFR)-targeted therapies in non-small cell lung carcinoma (NSCLC) led to investigation of novel combinations of EGFR and MET kinase inhibitors. However, promiscuous interactions between MET and ERBB family members have made it difficult to evaluate the effects of MET on EGFR signaling, both independent of drug treatment and in the context of drug resistance. We addressed this issue by establishing a 32D model cell system wherein ERBBs or MET are expressed alone and in combination. Using this model, we determined that EGFR signaling is sufficient to induce MET phosphorylation, although MET activation is enhanced by coexpression of ERBB3. EGFR-MET cross-talk was not direct, but occurred by a combined regulation of MET levels and intermediary signaling through mitogen-activated protein kinases (MAPK). In NSCLCs harboring either wild-type or mutant EGFR, inhibiting EGFR or MAPK reduced MET activation and protein levels. Furthermore, MET signaling promoted EGFR-driven migration and invasion. Finally, EGFR-MET signaling was enhanced in a highly metastatic EGFR-mutant cell subpopulation, compared with the indolent parental line, and MET attenuation decreased the incidence of brain metastasis. Overall, our results establish that EGFR-MET signaling is critical for aggressive behavior of NSCLCs and rationalize its continued investigation as a therapeutic target for tumors harboring both wild-type and mutant EGFR at early stages of progression.

EGF receptor activates MET through MAPK to enhance non-small cell lung carcinoma invasion and brain metastasis.

A fundamental goal in cancer biology is to identify the cells and signalling pathways that are keys to induce tumour regression. Here we use a spontaneously self-regressing tumour, cutaneous keratoacanthoma (KAs), to identify physiological mechanisms that drive tumour regression. By using a mouse model system that recapitulates the behaviour of human KAs, we show that self-regressing tumours shift their balance to a differentiation programme during regression. Furthermore, we demonstrate that developmental programs utilized for skin hair follicle regeneration, such as Wnt, are hijacked to sustain tumour growth and that the retinoic acid (RA) signalling pathway promotes tumour regression by inhibiting Wnt signalling. Finally, we find that RA signalling can induce regression of malignant tumours that do not normally spontaneously regress, such as squamous cell carcinomas. These findings provide new insights into the physiological mechanisms of tumour regression and suggest therapeutic strategies to induce tumour regression. 

Spontaneous tumour regression in keratoacanthomas is driven by Wnt/retinoic acid signalling cross-talk.

The recently identified claudin-low subtype of breast cancer is enriched for cells with stem-like and mesenchymal-like characteristics. This subtype is most often triple-negative (lacking the estrogen and progesterone receptors (ER, PR) as well as lacking epidermal growth factor 2 (HER2) amplification) and has a poor prognosis. There are few targeted treatment options available for patients with this highly aggressive type of cancer.

Significance of glioma-associated oncogene homolog 1 (GLI1) expression in claudin-low breast cancer and crosstalk with the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway.

Defining the molecular networks that drive breast cancer has led to therapeutic interventions and improved patient survival. However, the aggressive triple-negative breast cancer subtype (TNBC) remains recalcitrant to targeted therapies because its molecular etiology is poorly defined. In this study, we used a forward genetic screen to discover an oncogenic network driving human TNBC. SCYL1, TEX14, and PLK1 ("STP axis") cooperatively trigger degradation of the REST tumor suppressor protein, a frequent event in human TNBC. The STP axis induces REST degradation by phosphorylating a conserved REST phospho-degron and bridging REST interaction with the ubiquitin-ligase βTRCP. Inhibition of the STP axis leads to increased REST protein levels and impairs TNBC transformation, tumor progression, and metastasis. Expression of the STP axis correlates with low REST protein levels in human TNBCs and poor clinical outcome for TNBC patients. Our findings demonstrate that the STP-REST axis is a molecular driver of human TNBC.

The oncogenic STP axis promotes triple-negative breast cancer via degradation of the REST tumor suppressor.

The receptor tyrosine kinase ERBB4, a member of the epidermal growth factor receptor (EGFR) family, is unusual in that ERBB4 can undergo intramembrane proteolysis, releasing a soluble intracellular domain (ICD) that modulates transcription in the nucleus. We found that ERBB4 activated the transcriptional coactivator YAP, which promotes organ and tissue growth and is inhibited by the Hippo tumor-suppressor pathway. Overexpressing ERBB4 in cultured mammary epithelial cells or adding the ERBB4 ligand neuregulin 1 (NRG1) to breast cancer cell cultures promoted the expression of genes regulated by YAP, such as CTGF. Knocking down YAP or ERBB4 prevented the induction of CTGF expression by NRG1, as did treating cells with the ERBB inhibitors lapatinib or erlotinib, which reduced ERBB4 cleavage. NRG1 stimulated YAP activity to an extent comparable to that of EGF (epidermal growth factor) or LPA (lysophosphatidic acid), known activators of YAP. NRG1 stimulated YAP-dependent cell migration in breast cancer cell lines. These observations connect the unusual nuclear function of a growth factor receptor with a mechanosensory pathway and suggest that NRG1-ERBB4-YAP signaling contributes to the aggressive behavior of tumor cells. 

Neuregulin 1-activated ERBB4 interacts with YAP to induce Hippo pathway target genes and promote cell migration.

Glycosylation is one of the most predominant forms of cell-surface protein modifications, yet its deregulation in cancer and contribution to tumor microenvironment interactions remain poorly understood. In this issue of Cancer Discovery, Reticker-Flynn and Bhatia characterize an enzymatic switch in lung cancer cells that triggers aberrant surface protein glycosylation patterns, adhesion to lectins on the surface of inflammatory cells, and subsequent metastatic colonization of the liver.

Sweets for a bitter end: lung cancer cell-surface protein glycosylation mediates metastatic colonization.

Mechanisms underlying the propensity of latent lung adenocarcinoma (LUAD) to relapse are poorly understood. In this study, we show how differential expression of a network of extracellular matrix (ECM) molecules and their interacting proteins contributes to risk of relapse in distinct LUAD subtypes. Overexpression of the hyaluronan receptor HMMR in primary LUAD was associated with an inflammatory molecular signature and poor prognosis. Attenuating HMMR in LUAD cells diminished their ability to initiate lung tumors and distant metastases. HMMR upregulation was not required for dissemination , but enhanced ECM-mediated signaling, LUAD cell survival, and micrometastasis expansion in hyaluronan-rich microenvironments in the lung and brain metastatic niches. Our findings reveal an important mechanism by which disseminated cancer cells can coopt the inflammatory ECM to persist, leading to brain metastatic outgrowths. .

Don X. Nguyen

Department of Pathology,
Department of Medical Oncology

Yale University School of Medicine

Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment

Don X. Nguyen

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pathology,Department of Medical Oncology

Yale University School of Medicine

Pre-Conditioning the Airways of Mice with Bleomycin Increases the Efficiency of Orthotopic Lung Cancer Cell Engraftment

Department of Pathology,
Department of Medical Oncology