![Lindsay M. LaFave](https://assets.montefioreeinstein.org/profiles/images/LaFave_Lindsay_2x.jpg)
Lindsay M. LaFave, Ph.D.
- Assistant Professor, Department of Cell Biology
Area of research
- lung cancer, lung stem cells, cancer predisposition, chromatin biology, single-cell epigenomics, chromatin plasticity, intratumoral heterogeneity, lung adenocarcinoma, gene regulatory networks, spatial profiling, transcription factor biology
Phone
Location
- Albert Einstein College of Medicine Jack and Pearl Resnick Campus 1300 Morris Park Avenue Chanin Building 606 Bronx, NY 10461
Research Profiles
Professional Interests
Lung adenocarcinoma (LUAD) is the most common subtype of non-small cell lung cancer and remains a leading cause of cancer-related death. Next-generation sequencing studies have identified a number of recurrent genetic drivers (such as mutations in KRAS and TP53); however, this somatic variation does not fully explain key features of cancer evolution including progression toward metastasis and intratumoral heterogeneity. Our group aims to understand how non-genetic mechanisms contribute to lung cancer initiation and progression through the lens of chromatin biology.
In genetically engineered mouse modeling studies, cell-type specific transformation of alveolar type II (AT2) cells with KrasG12D and loss of Tp53 lead to a natural cancer evolution process that recapitulates phenotypic hallmarks of human disease. Using this model, our recent work employed single-cell epigenomics to study dysregulation of chromatin state across lung cancer evolution. We identified a continuum of heterogeneous chromatin states with reproducible epigenomic features across individual lung tumors, suggesting conserved routes of cancer progression. Using both functional and computational approaches, we annotated transcription factor (TF) regulators and downstream gene programs associated with these diverse chromatin profiles. These discernable gene regulatory modules were linked to certain aspects of cancer progression including loss of cellular identity, inflammation, and metastasis. Our work also identified the emergence of a pre-metastatic gene regulatory program that arises in a rare cell population in primary tumors and primes cells for metastatic seeding.
Cellular identity is dictated by chromatin structure, which is maintained by a complex network of cis- (e.g., enhancer, promoters, and insulators), and trans- (e.g., chromatin modifiers, TFs, and adaptors) factors. Our previous work found that early stages of LUAD progression are associated with the loss of AT2 identity and the acquisition of epigenomic states similar to developmentally related cell types. We seek to further understand how lung cancer initiation ultimately leads to decoupling from an AT2 cell identity and increased epigenomic plasticity. In addition, we are interested in investigating how disruption of the tumor microenvironment influences LUAD cell state. To address these questions, we pair lung cancer modeling with epigenomic technologies (including single-cell ATAC-sequencing, single-cell multiomic analysis, and spatial approaches) to dissect mechanisms important for the maintenance and persistence of dysregulated cell states in lung cancer. We flexibly utilize genetically engineered mouse models, alveolar human and murine organoids, and cell-based assays to perform functional studies. We continue to expand our technological and modeling toolkit to study early and late stages of lung cancer progression with the overarching goal of better understanding and targeting lung cancer progression.
Selected Publications
Journal articles
Naranjo S^, Cabana CM^, LaFave LM, Westcott MK, Romero R, Ghosh A, Liao LX, Schenkel JM, Del Priore I, Bhutkar A, Yang D, Jacks T. Modeling diverse genetic subtypes of lung adenocarcinoma with a next-generation alveolar type 2 organoid platform.
Zhao T^, Chiang ZD^, Morriss JW, LaFave LM, Murray EM, Del Priore, Meli K, Lareau CA, Nadaf NM, Li J, Earl AS, Macosko EZ, Jacks T, Buenrostro JD*, Chen F*. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature. 2022 Jan;601(7891):85-91. doi: 10.1038/s41586-021-04217-4. PMID: 34912115.
Concepcion C, Ma S#, LaFave LM#, Bhutkar A#, Liu M, DeAngelo LP, Kim JY, Del Priore I, Schoenfeld AJ, Miller M, Kartha VK, Westcott PMK, Sanchez-Rivera FJ, Meli K, Gupta M, Bronson RT, Riely GJ, Rekhtman N, Rudin CM, Kim CF, Regev A, Buenrostro JD, Jacks T. Smarca4 inactivation promotes lineage-specific transformation and early metastatic features in the lung. Cancer Discovery. 2021 Sep 24:candisc.0248.2021. doi: 10.1158/2159-8290.CD-21-0248. Epub ahead of print. PMID: 34561242.
Del Priore I^, Ma S^, Strecker J, Jacks T, LaFave LM*, Buenrostro JD*. Protocol for single-cell ATAC sequencing using combinatorial indexing in mouse lung adenocarcinoma. STAR Protocols. 2021 Jun 3;2(2):100583. doi: 10.1016/j.xpro.2021.100583. PMID: 34142101; PMCID: PMC8185305.
Ma S, Bing Z, LaFave LM, Chiang Z, Hu Y, Ding J, Brack A, Kartha VK, Law T, Lareau C, Hsu Y, Regev* A, Buenrostro JD*. Chromatin-mediated lineage priming and chromatin potential identified by shared single cell profiling of RNA and chromatin. Cell. 2020 Oct 20:S0092-8674(20)31253-8. PMID: 33098772.
LaFave LM, Kartha VK#, Ma S#, Meli K, Del Priore I, Lareau C, Naranjo S, Westcott P, Duarte FM, Sankar V, Chiang Z, Brack A, Law T, Hauck H, Okimoto A, Regev A, Buenrostro JD*, Jacks T*. Epigenomic state transitions characterize tumor progression in mouse lung adenocarcinoma. Cancer Cell. 2020 Aug 10;38(2):212-228.e13. PMID: 32707078.
Highlight: Drapkin, BJ and Minna JD. Studying Lineage Plasticity One Cell at a Time. Cancer Cell. 2020 Aug (2); 150-152.
LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, Papalexi E, Keller M, Hricik T, Konstantinoff K, Micol JB, Durham B, Knutson SK, Campbell JE, Blum G, Shi X, Doud EH, Krivtsov A, Chung YR, Khodos I, DeStanchina A, Ouerfelli O, Adusumilli P, Thomas PM, Kelleher NL, Luo M, Keilhack H, Abdel-Wahab O, Melnick A, Armstrong S, Levine RL. Reply to “Uveal melanoma cells are resistant to EZH2 inhibition regardless of BAP1 status.” Nature Medicine 2016 Jun 578-9; PMID: 27270773.
Meyer SC, Keller MD, Woods BA, LaFave LM, Bastian L, Kleppe M, Bhagwat N, Marubayashki S, Levine RL. Genetic studies reveal an unexpected negative regulatory role for Jak2 in thrombopoiesis. Blood. 2014 Oct 2;124(14):2280-4; PMID 25115888.
Abdel-Wahab O, Gao J, Adli M, Dey A, Trimarchi T, Chung YR, Kuscu C, Hricik T, Ndiaye-Lobry D, LaFave LM, Koche R, Shih AH, Guryanova OA, Kim E, Li S, Pandey S, Shin JY, Telis L, Liu J, Bhatt PK, Monette S, Zhao X, Mason CE, Park CY, Bernstein BE, Aifantis I, Levine RL. Deletion of ASXL1 results in myelodysplasia and severe developmental defects in vivo. J Exp Med. 2013 Nov; 210(12):2641-59; PMID 24218140
Abdel-Wahab O^, Adli M^, LaFave LM^, Gao, J, Hricik T, Shih AH, Pandey S, Patel J, Perna F, Zhao X, Taylor JE, Park CY, Carrol M, Melnick A, Nimer SD, Jaffe JD, Aifantis I, Bernstein BE, Levine RL. ASXL1 Mutations Promote Myeloid Transformation Through Loss of PRC2-Mediated Gene Repression. Cancer Cell. 2012 Aug; 22(2); 180-93; PMID 22897849
Dey, A, Seshasayee, D, Noubade R, French D, Liu J, Kirkpatrick D, Pham V, Lill J, Bakalarski C, Wu J, Katavolos P, LaFave LM, Modrusan Z, Seshagiri S, Dong K, Lin Z, Balazs M, Suriben R, Newton K, Hymowitz S, Garcia-Manero G, Martin F, Levine RL, Dixit V. Loss of tumor suppressor BAP1 promotes myeloid transformation. Science. 2012 Sep; 337(6101); 1541-6; PMID 22878500
Koppikar P, Bhagwat N, Kilpivaara O, Manshouri T, Adli M, Hricik T, Liu F, Saunders L, Mullaly A, Abdel-Wahab O, Leung L, Weinstein A, Marubayashi S, Goel A, Gonen M, Estrov Z, Ebert, BL, Chiosis G, Nimer SD, Bernstein BE, Verstovsek S, Levine RL. Heterodimeric JAK-STAT Activation as a Mechanism of Persistence to JAK2 Inhibitor Therapy. Nature. 2012 Sep; 489(7414); 155-9. PMID: 22820254
Dawson MS, Bannister AJ, Saunders L, Wahab OA, Liu F, Nimer SD, Levine RL, Gottgens B, Kouzarides T, Green AR. Nuclear JAK2. Blood. 2011 Dec; 118(26):6987-8; PMID 22194397.
Abuzeid WM, Davis S, Tang AL, Saunders L, Brenner JC, Lin J, Fuchs JR, Light E, Bradford CR, Prince ME, Carey TE. Sensitization of head and neck cancer to Cisplatin through the use of a novel curcumin analog. Arch Otolaryngol Head Neck Surg. 2011 May; 137(5):499-507; PMID: 21576562
Brenner JC, Graham MP, Kumar B, Saunders LM, Kupfer R, Lyons RH, Bradford CR, Carey TE. Genotyping of 73 UM-SCC head and neck squamous cell carcinoma cell lines. Head Neck. 2010 Apr; 32(4):417-26; PMID 19760794.
Reviews and commentaries
Bayin NS*, McKinley KL, LaFave LM*. Research vision workshopping: Peer mentoring to support the transition to independence. Cell. 2023 Mar 30;186(7):1295-1299. doi: 10.1016/j.cell.2023.03.002. PMID: 37001493.
LaFave LM*, Savage RE, Buenrostro JD*. Single-cell Epigenomics Reveals Mechanisms of Cancer Progression. Annual Review of Cancer Biology. Ahead of Print. Vol 6.
LaFave LM*, Buenrostro JD*. Unlocking PDAC initiation with AP-1. Nature Cancer 2, 14–15 (2021).
LaFave LM, Levine RL. Targeting a regulator of protein homeostasis in myeloproliferative neoplasms. Nature Medicine. 2016 Jan (1); 20-1; PMID: 26735404.
LaFave LM, Levine RL. Mining the epigenetic landscape in ALL. Nat Genet. 2013 Nov;45(11):1269-70; PMID 24165727
LaFave LM, Levine RL. JAK2 the future: therapeutic strategies for JAK-dependent malignancies. Trends in Pharmacol Sci. 2012 Nov; 33(11); 574-82. PMID: 22995223