Abstract:
:Lymphangioleiomyomatosis (LAM) is a progressive destructive neoplasm of the lung associated with inactivating mutations in the TSC1 or TSC2 tumor suppressor genes. Cell or animal models that accurately reflect the pathology of LAM have been challenging to develop. Here, we generated a robust human cell model of LAM by reprogramming TSC2 mutation-bearing fibroblasts from a patient with both tuberous sclerosis complex (TSC) and LAM (TSC-LAM) into induced pluripotent stem cells (iPSC), followed by selection of cells that resemble those found in LAM tumors by unbiased in vivo differentiation. We established expandable cell lines under smooth muscle cell (SMC) growth conditions that retained a patient-specific genomic TSC2+/- mutation and recapitulated the molecular and functional characteristics of pulmonary LAM cells. These include multiple indicators of hyperactive mTORC1 signaling, presence of specific neural crest and SMC markers, expression of VEGF-D and female sex hormone receptors, reduced autophagy, and metabolic reprogramming. Intriguingly, the LAM-like features of these cells suggest that haploinsufficiency at the TSC2 locus contributes to LAM pathology, and demonstrated that iPSC reprogramming and SMC lineage differentiation of somatic patient cells with germline mutations was a viable approach to generate LAM-like cells. The patient-derived SMC lines we have developed thus represent a novel cellular model of LAM that can advance our understanding of disease pathogenesis and develop therapeutic strategies against LAM. Cancer Res; 77(20); 5491-502. ©2017 AACR.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Julian LM,Delaney SP,Wang Y,Goldberg AA,Doré C,Yockell-Lelièvre J,Tam RY,Giannikou K,McMurray F,Shoichet MS,Harper ME,Henske EP,Kwiatkowski DJ,Darling TN,Moss J,Kristof AS,Stanford WLdoi
10.1158/0008-5472.CAN-17-0925subject
Has Abstractpub_date
2017-10-15 00:00:00pages
5491-5502issue
20eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-17-0925journal_volume
77pub_type
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