Small cell lung cancer (SCLC) is an especially virulent form of lung cancer that is only transiently responsive to therapy and kills about 30,000 Americans each year. Based on a more general interest in understanding why certain kinds of cancers have characteristic genotypes, we are developing methods for studying the initiation of human cancers by genetically modifying cells at discrete stages of differentiation after chemical induction of specific lineages from human embryonic stem cells (hESCs). We have extended recently published methods for inducing hESCs to form parts of the pulmonary lineage by perturbing NOTCH signaling and reducing expression of the RB1 gene (one of the two genes commonly inactivated in SCLC); in this way, we have prepared cultures with high proportions of pulmonary neuroendocrine cells (PNECs), the putative precursors of SCLC. Moreover, by also reducing expression of P53, the other gene commonly inactivated in SCLC, PNEC-containing cultures are able to produce small tumors resembling SCLC when implanted in immune-deficient mice. We now propose to expand our studies of this promising model for studying the origins of SCLC in several ways: by determining the mechanisms by which interference with NOTCH and RB1 generates PNECs; by exploring several possible assays for the SCLC-like phenotype we have recently observed; by defining the similarities between the genetic and physiological features of the SCLCs derived from hESCs and the SCLCs arising in human patients; and by making induced pleuropotent stem cells (iPSCs) from normal and tumor cells from patients with lung cancer, especially SCLC, in an effort to seek genetic risk factors for SCLC. Through these studies, we expect to generate new information and ideas about risk assessment, prevention, diagnosis, and treatment for SCLC. !
Small cell lung cancer (SCLC) remains a major challenge in public health because of its frequency, its lethality, and the paucity of convenient models for exploring its pathogenesis and potential therapeutic strategies. As part of our efforts to understand how and why certain constellations of genetic changes drive cancer in specialized cell lineages, we have developed early but strong evidence that we can induce from human embryonic stem cells (hESCs) the lung cell type (a neuro-endocrine cell) that has been proposed to initiate SCLC, and we have produced early stage SCLC-like tumors from these cells after genetic changes. We now propose to expand these findings to make an effective model for development of SCLC that can be used to explore new opportunities to diagnose, categorize, treat, and possibly even prevent SCLC more effectively. !
| Zhou, Ting; Kim, Tae Wan; Chong, Chi Nok et al. (2018) A hPSC-based platform to discover gene-environment interactions that impact human ?-cell and dopamine neuron survival. Nat Commun 9:4815 |
