Weiran Feng, PhD

Feng W*, Ladewig E*, Salsabeel N, Zhao H, Lee YS, Gopalan A, Luo H, Kang K, Fan N, Rosiek E, Masilionis I, Chaligne R, de Stanchina E, Chen Y, Carver BS, Leslie CS, Sawyers CL. (2023) ERG-driven prostate cancer emerges from basal-luminal hybrid cells. BioRxiv.

https://www.biorxiv.org/content/10.1101/2023.05.15.540839v1.full

• Prostate cancer (PCa) is the most frequent cancer and the second leading cause of cancer death among American men. The oncogenic ERG translocation (activating the ERG transcription factor) occurs in 50% of PCas. However, how ERG drives PCa remains unclear.

• To gain mechanistic insights, I performed single-cell profiling and lineage tracing in an autochthonous ERG-driven PCa model, combined with organoid modeling and fresh cell transplantation to delineate cell fate decisions at an early stage of disease initiation.

• Contrast to the striking luminal histology of PCa, I discovered that ERG does not initiate cancer from luminal cells, but from a subset of basal cells via a highly proliferative basal-luminal intermediate state that retains the ability to rapidly differentiate to luminal cells 

• My studies: • Discovered the previously overlooked heterogeneity within prostate basal cells. 

• Defined the intermediate state as a key transition in PCa initiation. 

• Helped resolve the preexisting debate about the cell of origin of PCa. 

• I led the study, while the co-first author Erik Ladewig provided computational expertise..

2. Feng W*, Cao Z*, Lim PX, Zhao H, Luo H, Mao N, Lee YS, Rivera AA, Choi D, Wu C, Han T, Romero R, de Stanchina E, Carver BS, Wang Q, Jasin M, Sawyers CL. (2021) Rapid interrogation of cancer cell of origin through CRISPR editing. Proc Natl Acad Sci., 118 (32) e2110344118.. https://pubmed.ncbi.nlm.nih.gov/34353917/ • The increasing complexity of different cell types revealed by single-cell analysis of tissues presents challenges in efficiently elucidating their functions. 

• I developed a rapid and efficient approach to CRISPR edit freshly isolated primary prostate cells or organoids. • Large intrachromosomal (∼2 Mb) or multigenic deletions can be engineered efficiently without the need for selection. 

• The freshly edited cells can be directly transplanted to host prostates as an edited population without any intermediate culture step, allowing for rapid generation of genetic models in vivo from an expanded repertoire of cell types. 

• I developed the approach and led the study, while the co-first author Zhen Cao implemented the approach for a subset of applications.

3. Feng W, Jasin M. (2018) 53BP1 nuclear body-marked replication stress in a human mammary cell model of BRCA2 deficiency. BioRxiv, 462119. https://www.biorxiv.org/content/10.1101/462119v1.abstract • Elucidated the causes and consequences of replication stresses upon BRCA2 inactivation.

 • As the single junior author on the paper, I led the study and performed all experiments..

4. Feng W, Jasin M. (2017) BRCA2 suppresses replication stress-induced mitotic and G1 abnormalities through homologous recombination. Nat Commun., 8, 525. PMCID: PMC5597640. https://www.ncbi.nlm.nih.gov/pubmed/28904335 

• BRCA2 is a well-known breast and ovarian tumor suppressor that functions by maintaining genome integrity. Given the tissue tropism of BRCA2-mutated cancers, key insights on the tumor suppressor function of BRCA2 are lacking due to a paucity of genetic models from a normal and disease-related background. • I engineered the first series of BRCA2 conditional knockout models in a non-transformed human mammary cell line. 

• I discovered for the first time a DNA under replication-53BP1 nuclear body formation-G1 arrest axis as the primary source of genome instability of BRCA2 deficiency. • BRCA2 loss confers hypersensitivity to PARP inhibition. BRCA2 plays a key role in two processes: a well-known homology-directed repair, and a newly recognized replication fork protection pathway. Knowledge on how each repair pathway contributes to genome integrity is critically needed for improving therapy responses.

 • I dissected BRCA2 functions by creating complementary separation-of-function systems 

• I demonstrated that replication stress and cell lethality due to BRCA2 deficiency is mainly attributed to a lack of homology-directed repair, but not replication fork protection, providing clear answers to a heavily debated topic. 

• As the single junior author on the paper, I led the study and performed all experiments..