Lectures and seminars OnkPat Friday Seminar: Genetic approaches to understanding carcinoma metastasis

Host: Susanne Schlisio, Department of Oncology-Pathology

About the speaker

Chris Lengner is the Harriet Ellison Woodward Professor and Chair of the Department of Biomedical Sciences at the University of Pennsylvania (Penn) School of Veterinary Medicine, where his lab uses molecular genetics and genomic tools to understand the organization of adult stem cell compartments and their oncogenic transformation.  The Lengner lab currently focuses on endodermal organs and disease states, including understanding the fundamental organization of the intestinal stem cell compartment and how its dysregulation initiates tumorigenesis, how telomere biology disorders impact stem cell function and crosstalk with the microenvironment, and how new genetic tools can be harnessed to understand lineage in tissue regeneration and cancer metastases.  

Prior to assuming the role of Department Chair, Dr. Lengner acted as the Co-Director, along with Dr. Jeremy Wang, of Penn Vet’s Center for Animal Transgenesis from 2014-2023.  Dr. Lengner also served as the Associate Director of the Institute for Regenerative Medicine at the University of Pennsylvania  from 2017-2023.

Talk abstract

Metastatic outgrowth requires that cancer cells delaminate from the primary tumor, intravasate, survive in circulation, extravasate, migrate to, and proliferate at a distal site. Recurrent genetic drivers of metastasis remain elusive, suggesting that unlike the early steps of oncogenesis, metastasis drivers may be variable.  Here, we discuss two approaches to understand the metastasis of carcinoma cells.  First, we describe a framework for identifying metastasis regulators using CRISPR/Cas9-based screening in a genetically defined organoid model of colorectal adenocarcinoma. In vitro screens for invasion and migration alongside orthotopic, in vivo screens for gain of metastasis in a syngeneic mouse model highlight the importance of using in vivomodels that capture all metastatic stages. We identify suppressors of metastasis that govern anoikis, motility, and the immune microenvironment.  

Next, we develop genetic tools to probe transcriptional states linked to metastatic success in a model of pancreatic cancer. By employing a CRISPR-Cas9-based evolving lineage recorder with highly efficient single-cell capture of both transcriptome and barcode, we can generate large lineage phylogenies annotated with cell state information for tens of thousands of carcinoma cells isolated from primary tumors and metastatic sites.  Clonal and subclonal reconstruction reveal that metastatic potential peaks in rare, late-hybrid EMT states, which are aggressively selected from a predominately epithelial ancestral pool. The gene signatures of these late-hybrid EMT states are predictive of reduced survival in both human pancreatic and lung cancer patients, highlighting their relevance to clinical disease progression.  These studies demonstrate the power of novel genetic tools to reveal the complex biology of carcinoma metastasis with unprecedented resolution.
 

Selected publications

Mapping and modeling human colorectal carcinoma interactions with the tumor microenvironment.
Li N, Zhu Q, Tian Y, Ahn KJ, Wang X, Cramer Z, Jou J, Folkert IW, Yu P, Adams-Tzivelekidis S, Sehgal P, Mahmoud NN, Aarons CB, Roses RE, Thomas-Tikhonenko A, Furth EE, Stanger BZ, Rustgi A, Haldar M, Katona BW, Tan K, Lengner CJ
Nat Commun 2023 Nov;14(1):7915

Calorie Restriction Governs Intestinal Epithelial Regeneration through Cell-Autonomous Regulation of mTORC1 in Reserve Stem Cells.
Yousefi M, Nakauka-Ddamba A, Berry CT, Li N, Schoenberger J, Bankler-Jukes D, Simeonov KP, Cedeno RJ, Yu Z, Lengner CJ
Stem Cell Reports 2023 Apr;18(4):1048

Single-cell lineage tracing of metastatic cancer reveals selection of hybrid EMT states.
Simeonov KP, Byrns CN, Clark ML, Norgard RJ, Martin B, Stanger BZ, Shendure J, McKenna A, Lengner CJ
Cancer Cell 2021 Aug;39(8):1150-1162.e9