High mobility group AT-hook 2 (HMGA2) has been associated with increased cell proliferation and cell cycle dysregulation, leading to the ontogeny of varied tumor types and their metastatic potentials, a frequently used index of disease prognosis. In this review, we deepen our understanding of HMGA2 pathogenicity by exploring the mechanisms by which HMGA2 misexpression and ectopic expression induces mesenchymal and epithelial tumorigenesis respectively and distinguish the pathogenesis of benign from malignant mesenchymal tumors. Importantly, we highlight the regulatory role of let-7 microRNA family of tumor suppressors in determining HMGA2 misexpression events leading to tumor pathogenesis and focused on possible mechanisms by which HMGA2 could propagate lymphangioleiomyomatosis (LAM), benign mesenchymal tumors of the lungs. Lastly, we discuss potential therapeutic strategies for epithelial and mesenchymal tumorigenesis based on targeting the HMGA2 signaling pathway.

Macrophage infiltration is common to both emphysema and atherosclerosis, and cigarette smoke down‐regulates the macrophage cholesterol efflux transporter ATP binding cassette (ABC)A1. This decreased cholesterol efflux results in lipid‐laden macrophages. We hypothesize that cigarette smoke adversely affects cholesterol transport via an ABCA1‐dependent mechanism in macrophages, enhancing TLR4/myeloid differentiation primary response gene 88 (Myd88) signaling and resulting in matrix metalloproteinase (MMP) up‐regulation and exacerbation of pulmonary inflammation. ABCA1 is significantly down‐regulated in the lung upon smoke exposure conditions. Macrophages exposed to cigarette smoke in vivo and in vitro exhibit impaired cholesterol efflux correlating with significantly decreased ABCA1 expression, up‐regulation of the TLR4/Myd88 pathway, and downstream MMP‐9 and MMP‐13 expression. Treatment with liver X receptor (LXR) agonist restores ABCA1 expression after short‐term smoke exposure and attenuates the inflammatory response; after long‐term smoke exposure, there is also attenuated physiologic and morphologic changes of emphysema. In vitro , treatment with LXR agonist decreases macrophage inflammatory activation in wild‐type but not ABCA1 knockout mice, suggesting an ABCA1‐dependent mechanism of action. These studies demonstrate an important association between cigarette smoke exposure and cholesterol‐mediated pathways in the macrophage inflammatory response. Modulation of these pathways through manipulation of ABCA1 activity effectively blocks cigarette smoke–induced inflammation and provides a potential novel therapeutic approach for the treatment of chronic obstructive pulmonary disease.—Sonett, J., Goldklang, M., Sklepkiewicz, P., Gerber, A., Trischler, J., Zelonina, T., Westerterp, M., Lemaître, V., Okada, V., D’Armiento, J. A critical role for ABC transporters in persistent lung inflammation in the development of emphysema after smoke exposure. FASEB J. 32, 6724–6736 (2018). www.fasebj.org

Tuberous sclerosis (TSC) is a tumor suppressor gene syndrome that is associated with the widespread development of mesenchymal tumor types. Genetically, TSC is said to occur through a classical biallelic inactivation of either TSC genes (TSC1, hamartin or TSC2, tuberin), an event that is implicated in the induction of the mTOR pathway and subsequent tumorigenesis. High Mobility Group A2 (HMGA2), an architectural transcription factor, is known to regulate mesenchymal differentiation and drive mesenchymal tumorigenesis in vivo. Here, we investigated the role of HMGA2 in the pathogenesis of TSC using the TSC2+/− mouse model that similarly mirrors human disease and human tumor samples. We show that HMGA2 expression was detected in 100% of human and mouse TSC tumors and that HMGA2 activation was required for TSC mesenchymal tumorigenesis in genetically engineered mouse models. In contrast to the current dogma, the mTOR pathway was not activated in all TSC2+/− tumors and was elevated in only 50% of human mesenchymal tumors. Moreover, except for a subset of kidney tumors, tuberin was expressed in both human and mouse tumors. Therefore, haploinsufficiency of one TSC tumor suppressor gene was required for tumor initiation, but further tumorigenesis did not require the second hit, as previously postulated. Collectively, these findings demonstrate that tissue-specific genetic mechanisms are employed to promote tumor pathogenesis in TSC and identify a novel, critical pathway for potential therapeutic targeting. Cancer Res; 76(4); 844–54. ©2016 AACR.

The present study tested the hypothesis that maternal smoke exposure results in fetal lung growth retardation due to dysregulation in various signaling pathways, including the Wnt (wingless‐related integration site)/β‐catenin pathway. Pregnant female C57BL/6J mice were exposed to cigarette smoke (100–150 mg/m ³ ) or room air, and offspring were humanely killed on 12.5, 14.5, 16.5, and 18.5 d post coitum (dpc). We assessed lung stereology with Cavalieri estimation; apoptosis with proliferating cell nuclear antigen, TUNEL, and caspase assays; and gene expression with quantitative PCR (qPCR) and RNA sequencing on lung epithelium and mesenchyme retrieved by laser capture microdissection. Results demonstrated a significant decrease in body weight and lung volume of smoke‐exposed embryos. At 16.5 dpc, the reduction in lung volume was due to loss of lung mesenchymal tissue correlating with a decrease in cell proliferation ( n = 10; air: 61.65% vs. smoke: 44.21%, P < 0.05). RNA sequence analysis demonstrated an alteration in the Wnt pathway, and qPCR confirmed an increased expression of secreted frizzled‐related protein 1 (sFRP‐1) [ n = 12; relative quantification (RQ) 1 vs. 2.33, P < 0.05] and down‐regulation of Cyclin D1 (n = 7; RQ 1 vs. 0.61, P < 0.05) in mesenchymal tissue. Furthermore, genome expression studies revealed a smoke‐induced up‐regulation of Rho‐GTPase‐dependent actin cytoskeletal signaling that can lead to loss of tissue integrity.—Unachukwu, U., Trischler, J., Goldklang, M., Xiao, R., D'Armiento, J. Maternal smoke exposure decreases mesenchymal proliferation and modulates Rho‐GTPase‐dependent actin cytoskeletal signaling in fetal lungs. FASEB J. 31, 2340–2351 (2017). www.fasebj.org

Bronchoalveolar stem cells (BASCs) are mobilized during injury and identified as lung progenitor cells, but the molecular regulation of this population of cells has not been elucidated. Secreted frizzled‐related protein 1 (SFRP1) is a critical molecule involved in alveolar duct formation in the lung and here we demonstrate its importance in controlling cell differentiation during lung injury. Mice lacking SFRP1 exhibited a rapid repair response leading to aberrant proliferation of differentiated cells. Furthermore, SFRP1 treatment of BASCs maintained these cells in a quiescent state. In vivo overexpression of SFRP1 after injury suppressed differentiation and resulted in the accumulation of BASCs correlating with in vitro studies. These findings suggest that SFRP1 expression in the adult maintains progenitor cells within their undifferentiated state and suggests that manipulation of this pathway is a potential target to augment the lung repair process during disease.—Shiomi, T., Sklepkiewicz, P., Bodine, P. V. N., D'Armiento, J. M., Maintenance of the bronchial alveolar stem cells in an undifferentiated state by secreted frizzled‐related protein 1. FASEB J. 28, 5242–5249 (2014). www.fasebj.org