Honors & Awards
Tobacco-Related Disease Research Program (TRDRP) Postdoctoral Fellow, University of California (2018-2021)
Huck Graduate Dissertation Research Award, The Huck Institutes of Life Sciences, The Pennsylvania State University (2014-2017)
Outstanding CMIND research seminar presentations, Center for Molecular Investigation of Neurological Disorders, The Pennsylvania State University (2015)
Bachelor of Science, Tsinghua University (2008)
Master of Science, Tsinghua University (2011)
Doctor of Philosophy, Pennsylvania State University (2017)
LKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer.
2022; 13 (1): 1090
LKB1 is among the most frequently altered tumor suppressors in lung adenocarcinoma. Inactivation of Lkb1 accelerates the growth and progression of oncogenic KRAS-driven lung tumors in mouse models. However, the molecular mechanisms by which LKB1 constrains lung tumorigenesis and whether the cancer state that stems from Lkb1 deficiency can be reverted remains unknown. To identify the processes governed by LKB1 in vivo, we generated an allele which enables Lkb1 inactivation at tumor initiation and subsequent Lkb1 restoration in established tumors. Restoration of Lkb1 in oncogenic KRAS-driven lung tumors suppressed proliferation and led to tumor stasis. Lkb1 restoration activated targets of C/EBP transcription factors and drove neoplastic cells from a progenitor-like state to a less proliferative alveolar type II cell-like state. We show that C/EBP transcription factors govern a subset of genes that are induced by LKB1 and depend upon NKX2-1. We also demonstrate that a defining factor of the alveolar type II lineage, C/EBPalpha, constrains oncogenic KRAS-driven lung tumor growth in vivo. Thus, this key tumor suppressor regulates lineage-specific transcription factors, thereby constraining lung tumor development through enforced differentiation.
View details for DOI 10.1038/s41467-022-28619-8
View details for PubMedID 35228570
Tumor suppressor pathways shape EGFR-driven lung tumor progression and response to treatment.
Molecular & cellular oncology
2022; 9 (1): 1994328
In vivo modeling combined with CRISPR/Cas9-mediated somatic genome editing has contributed to elucidating the functional importance of specific genetic alterations in human tumors. Our recent work uncovered tumor suppressor pathways that affect EGFR-driven lung tumor growth and sensitivity to tyrosine kinase inhibitors and reflect the mutational landscape and treatment outcomes in the human disease.
View details for DOI 10.1080/23723556.2021.1994328
View details for PubMedID 35252550
View details for PubMedCentralID PMC8890383
- Tumor suppressor pathways shape EGFR-driven lung tumor progression and response to treatment MOLECULAR & CELLULAR ONCOLOGY 2021
Quantitative in vivo analyses reveal a complex pharmacogenomic landscape in lung adenocarcinoma.
The lack of knowledge about the relationship between tumor genotypes and therapeutic responses remains one of the most critical gaps in enabling the effective use of cancer therapies. Here we couple a multiplexed and quantitative experimental platform with robust statistical methods to enable pharmacogenomic mapping of lung cancer treatment responses in vivo. The complex map of genotype-specific treatment responses uncovered that over 20% of possible interactions show significant resistance or sensitivity. Known and novel interactions were identified, and one of these interactions, the resistance of KEAP1 mutant lung tumors to platinum therapy, was validated using a large patient response dataset. These results highlight the broad impact of tumor suppressor genotype on treatment responses and define a strategy to identify the determinants of precision therapies.
View details for DOI 10.1158/0008-5472.CAN-21-0716
View details for PubMedID 34215621
Genetic determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo.
In lung adenocarcinoma, oncogenic EGFR mutations co-occur with many tumor suppressor gene alterations, however the extent to which these contribute to tumor growth and response to therapy in vivo remains largely unknown. By quantifying the effects of inactivating ten putative tumor suppressor genes in a mouse model of EGFR-driven Trp53-deficient lung adenocarcinoma, we found that Apc, Rb1, or Rbm10 inactivation strongly promoted tumor growth. Unexpectedly, inactivation of Lkb1 or Setd2 - the strongest drivers of growth in a Kras-driven model - reduced EGFR-driven tumor growth. These results are consistent with mutational frequencies in human EGFR- and KRAS-driven lung adenocarcinomas. Furthermore, Keap1 inactivation reduced the sensitivity of EGFR-driven tumors to the EGFR inhibitor osimertinib and mutations in the KEAP1 pathway were associated with decreased time on tyrosine kinase inhibitor treatment in patients. Our study highlights how the impact of genetic alterations differ across oncogenic contexts and that the fitness landscape shifts upon treatment.
View details for DOI 10.1158/2159-8290.CD-20-1385
View details for PubMedID 33707235
A functional taxonomy of tumor suppression in oncogenic KRAS-driven lung cancer.
Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multi-step process, however the importance and specific roles of many of these genes during tumor initiation, growth and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of forty-eight known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo. Inactivation of some genes substantially increased growth, while the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression.
View details for DOI 10.1158/2159-8290.CD-20-1325
View details for PubMedID 33608386