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CSHL Cancer Center - Gene Regulation & Cell Proliferation

The Gene Regulation & Cell Proliferation Program is an interdisciplinary effort focused on understanding the mechanisms that govern both normal and cancerous cell growth. The researchers in this program combine traditional experimental biology with cutting-edge technology to gain significant insights into DNA replication, epigenetics, and RNA biology. 

Program Co-leaders
David L. Spector, Ph.D.           Christopher Vakoc, M.D, Ph.D.

Camila
Camila dos Santos - Assistant Professor

Studies the epigenetic regulation of normal and malignant mammary gland development, with an emphasis on the alterations brought upon by pregnancy. A recent finding showed that mammary glands react differently to a second pregnancy compared to the first, with associated changes in DNA methylation. Further research is examining how pregnancy-induced epigenetic changes might influence cell transformation and the risk of breast cancer.
Thomas
Thomas Gingeras - Professor

Examines how genomes are organized and regulated using high-throughput technologies and computational approaches, focusing on the regulation and function of non-protein coding RNAs within and outside of cells. These efforts help explain the biological and clinical effects of disease-causing gene mutations in humans and other organisms.
 
Molly
Molly Hammell - Assistant Professor

Uses computational and experimental approaches to study gene networks and how they adapt to changes. Current cancer focus relates to mechanisms underlying acquired resistance to BRAF targeted therapies in melanoma. Studying the global changes in gene regulation that enable melanoma cells to bypass these therapies could lead to identification of clinically relevant pathways of interest for new therapeutic approaches.
Leemor
Leemor Joshua-Tor - Professor & HHMI Investigator

Uses the tools of structural biology and biochemistry to study the molecular basis of cell regulatory processes, focusing on protein complexes involved in nucleic acid regulatory processes. Areas of focus include gene silencing mechanisms via RNA interference (RNAi) and molecular mechanisms of DNA replication.
Justin
Justin Kinney - Assistant Professor

Combines theory, computation, and experiment to quantitatively define relationships between sequence and function in molecular biology. Current research focuses on developing next-generation sequencing as a tool for dissecting the biophysical basis of transcriptional regulation.  
Adrian
Adrian Krainer - Professor

Studies the mechanisms and regulation of RNA splicing - how splicing is disrupted in disease and how this can be corrected. His team used antisense technology to correct a splicing defect associated with spinal muscular atrophy (SMA), and the resulting antisense drug is currently in phase-3 clinical trials. Their work has also shed light on the role of splicing factors in cancer, showing that dysregulated SRSF1 functions as an oncoprotein, e.g., in the context of breast cancer.
Rob
Rob Martienssen - Professor & HHMI Investigator

Uses plants and yeast as model organisms to investigate the epigenetic mechanisms that control gene expression, transposon silencing, and stem cell fate. Currently employing methods in functional genomics and developmental genetics to gain insight into how defects in the epigenome cause disease.
David
David Spector - Professor & Director of Research

Studies the spatial organization and regulation of gene expression, focusing on long non-coding RNAs (lncRNAs) and nuclear organization/function. Current research has revealed that altered levels of a specific lncRNA, Malat1, impacts breast cancer progression and metastasis. Studies are currently underway to elucidate the mechanism of action of Malat1, and to identify and characterize newly identified lncRNAs as therapeutic targets in breast cancer.
Arne
Arne Stenlund - Associate Professor

Focuses on the DNA replication properties of human papillomaviruses, which are still the leading cause of cervical cancer in women. In particular, he works on processes required for replication initiation, including site-specific recognition of the origin of replication, local strand separation or distortion, and loading of a replication helicase.
 
Bruce
Bruce Stillman - President & Professor

Investigates the mechanism and control of DNA replication in yeast and human cells, with a current focus on replication initiation. Also exploring the role of DDX5, an RNA helicase that controls the expression of DNA replication protein, in breast cancer and acute myeloid leukemia. The Stillman lab is  currently assessing DDX5 inhibitors as possible therapeutics. 
Christopher
Christopher Vakoc - Associate Professor

Investigates how transcription factors and chromatin regulators control gene expression and maintain the cancer cell state in leukemias and other cancer types. Develops innovative and state-of-art genetic screens to reveal vulnerabilities in cancer cells for subsequent target development. Recently identified the factor BRD4 as a potential target for treating leukemia, a finding that has motivated an ongoing clinical trial.
Lingbo
Lingbo Zhang - CSHL Fellow

Focuses on normal and malignant progenitor and stem cells in the blood-forming system, specifically early erythroid progenitors and leukemic stem cells. Currently using a reverse-genetic approach to uncover critical genes regulating progenitor self-renewal, with the goal of identifying new treatments for unresponsive anemias and many cancer types.

2016

Focus on quiescent cells brings to light the essential role of RNA interference in transcription control | November 9, 2016
Using simple fission yeast as a model, researchers discovered that mutants lacking RNAi were unable to enter, maintain, or exit quiescence. Without RNAi, yeast could survive only if they were in the process of dividing.
Non-coding portions of genome are found to play role in cancer | September 27, 2016
CSHL scientists screened thousands of non-coding RNAs to find those that were expressed at high levels in aggressive breast cancer. When they reduced the level of the most over-expressed of these RNAs from mammary tumor samples, cancer spread much more slowly.
Why calling childhood cancers “rare” is missing the point | September 19, 2016
Childhood cancer is rare, and that categorization can dissuade researchers from studying. But to CSHL’s Chris Vakoc, a cancer researcher who also trained as a medical doctor, the rarity of childhood cancer is not what’s really important.
To divide or not: a cellular feedback loop that enables new cells to make a fateful decision | July 26, 2016
New research from the laboratory of Professor Bruce Stillman, Ph.D., president of Cold Spring Harbor Laboratory (CSHL), sheds light on a critical decision that every newly born cell makes: whether to continue to proliferate or to exit the cell-division cycle.
Academic-industry collaboration generates elegant way of pinpointing how a new drug exerts beneficial effects | July 5, 2016
Research demonstrates a new, highly accurate way of proving how certain classes of drugs work -- extremely valuable information in the risky business of drug development. 

2015

Unusual drug target and drug generate exciting preclinical results in mouse models of metastatic breast cancer | December 22, 2015
Preclinical data based on experiments conducted in mice suggest the promise of a novel drug directed against a novel target in malignant mammary tumors. 
New method prevents cells from prematurely halting protein production in certain genetic illnesses | December 14, 2015
Improperly formed proteins can cause a host of serious illnesses but, sometimes, inhibiting the pathway (called NMD) that acts as a quality control mechanism can actually be beneficial. 
Unassuming “Swiss Army knife”-like protein proves lynchpin in a new cancer drug’s therapeutic action | November 30, 2015
Researchers at Cold Spring Harbor Laboratory report a surprising mechanism through which an important new candidate drug against leukemia exerts its therapeutic effect. 
Breast Cancer Survivors Show Camila dos Santos What’s Important About Her Research | November 17, 2015
Biology has always felt personal to Assistant Professor Camila dos Santos. Looking back on high school biology, she remembers, “it was just so interesting to me that there was a field of research that makes you understand how your body works.”
Rhabdomyosarcoma (RMS) research bolstered by $50,000 gift from Friends of TJ | October 20, 2015
The Friends of TJ Foundation, a group dedicated to research for an RMS cure, presented a check for $50,000 to spur RMS research at CSHL. 
Research connects specific variations in RNA splicing with breast cancer causation | October 1, 2015
Researchers have identified cellular changes that may play a role in converting normal breast cells into tumors. Targeting these changes could potentially lead to therapies for some forms of breast cancer...
Scientists discover how a promising anti-leukemia drug harms cancer cells | May 14, 2015
Inhibiting a protein called BRD4 critical to the survival of acute myeloid leukemia (AML) cells has shown to be an effective therapeutic strategy. But the mechanism that explains how the protein works has remained a mystery. Now, scientists at Cold Spring Harbor Laboratory (CSHL) have discovered the larger cancer-causing...
Using CRISPR, biologists find a way to comprehensively identify anti-cancer drug targets | May 11, 2015
Imagine having a complete catalog of the best drug targets to hit in a particularly deadly form of cancer. Imagine having a master catalog of such targets for all the major cancer types and subtypes. Scientists at Cold Spring Harbor Laboratory (CSHL) today publish in Nature Biotechnology a method of compiling just such a catalog...
Scientists show the mammary gland ‘remembers’ prior pregnancy, spurring milk production | May 7, 2015
Anecdotal reports of nursing mothers have long suggested that giving milk is a lot easier in second and subsequent pregnancies, compared with a first pregnancy. Now, researchers at Cold Spring Harbor Laboratory (CSHL) are able to explain why...
Cancer researcher Dr. Chris Vakoc to receive AACR’s Outstanding Achievement Award | April 17, 2015
The American Association for Cancer Research (AACR) will honor CSHL Assistant Professor Christopher R. Vakoc, M.D., Ph.D., with the 35th annual AACR Outstanding Achievement in Cancer Research Award. The award will be given at the AACR Annual Meeting 2015, which convenes in Philadelphia on Saturday, April 18th.
Twin copies of a gene pair up in embryonic stem cells at a critical moment in their differentiation | March 5, 2015
Imagine a pair of twins that everyone believed to be estranged, who turn out to be closer than anyone knew. A genetic version of this heartwarming tale might be taking place in our cells. We and other mammals have two copies of each gene, one from each parent. Each copy, or “allele,” was thought to remain physically apart...
In a role reversal, RNAs proofread themselves | January 29, 2015
Building a protein is a lot like a game of telephone: information is passed along from one messenger to another, creating the potential for errors every step of the way. There are separate, specialized enzymatic machines that proofread at each step, ensuring that the instructions encoded in our DNA are faithfully translated into...
Christina Renna Foundation Raises $30,000 for pediatric cancer research at CSHL | January 26, 2015
The Christina Renna Foundation presented $30,000 to Cold Spring Harbor Laboratory (CSHL) at their 8th annual Angel's Wish Gala held on January 16, 2015. These funds will be used to support a new Sarcoma Research Project that will look into a rare and often fatal cancer, Rhabdomosarcoma (RMS)...

Chakrabortty, S. K. and Prakash, A. and Nechooshtan, G. and Hearn, S. and Gingeras, T. R. (2015) Extracellular vesicle-mediated transfer of processed and functional RNY5 RNA. RNA 21(11) pp. 1966-1979.

Kinney, J. B. (2015) Unification of field theory and maximum entropy methods for learning probability densities. Physical Review E 92(3)

Bergmann, J. H. and Li, J. and Eckersley-Maslin, M. A. and Rigo, F. and Freier, S. M. and Spector, D. L. (2015) Regulation of the ESC transcriptome by nuclear long non-coding RNAs. Genome Res 25(9) pp. 1336-1346.

Burke, S. L. and Hammell, M. and Ambros, V. (2015) Robust Distal Tip Cell Pathfinding in the Face of Temperature Stress Is Ensured by Two Conserved microRNAS in Caenorhabditis elegans. Genetics 200(4) pp. 1201-18.

Wasik, K. A. and Tam, O. H. and Knott, S. R. and Falciatori, I. and Hammell, M. and Vagin, V. V. and Hannon, G. J. (2015) RNF17 blocks promiscuous activity of PIWI proteins in mouse testes. Genes Dev 29(13) pp. 1403-1415.

Roe, Jae-Seok and Mercan, Fatih and Rivera, Keith and Pappin, Darryl J and Vakoc, Christopher R (2015) BET Bromodomain Inhibition Suppresses the Function of Hematopoietic Transcription Factors in Acute Myeloid Leukemia. Molecular Cell 58(6) pp. 1028-1036.

Akerman, M. and Fregoso, O. I. and Das, S. and Ruse, C. and Jensen, M. A. and Pappin, D. J. and Zhang, M. Q. and Krainer, A. R. (2015) Differential connectivity of splicing activators and repressors to the human spliceosome. Genome Biol 16(1) pp. 119.

Shi, J. and Wang, E. and Milazzo, J. P. and Wang, Z. and Kinney, J. B. and Vakoc, C. R. (2015) Discovery of cancer drug targets by CRISPR-Cas9 screening of protein domains. Nat Biotechnol 33(6) pp. 661-67.

Kara, N. and Hossain, M. and Prasanth, S. G. and Stillman, B. (2015) Orc1 Binding to Mitotic Chromosomes Precedes Spatial Patterning During G1 Phase and Assembly of the Origin Recognition Complex in Human Cells. J Biol Chem 290(19) pp. 12355-12369.

Dos Santos, C. O. and Dolzhenko, E. and Hodges, E. and Smith, A. D. and Hannon, G. J. (2015) An Epigenetic Memory of Pregnancy in the Mouse Mammary Gland. Cell Reports

Wang, E. and Kawaoka, S. and Roe, J. S. and Shi, J. and Hohmann, A. F. and Xu, Y. and Bhagwat, A. S. and Suzuki, Y. and Kinney, J. B. and Vakoc, C. R. (2015) The transcriptional cofactor TRIM33 prevents apoptosis in B lymphoblastic leukemia by deactivating a single enhancer. Elife 4

Naguib, Adam and Bencze, Gyula and Cho, Hyejin and Zheng, Wu and Tocilj, Ante and Elkayam, Elad and Faehnle, Christopher R and Jaber, Nadia and Pratt, Christopher P and Chen, Muhan and Zong, Wei-Xing and Marks, Michael S and Joshua-Tor, Leemor and Pappin, Darryl J and Trotman, Lloyd C (2015) PTEN Functions by Recruitment to Cytoplasmic Vesicles. Molecular Cell 58(2) pp. 255-268.

Hogan, Megan S and Parfitt, David-Emlyn and Zepeda-Mendoza, Cinthya J and Shen, Michael M and Spector, David L (2015) Transient Pairing of Homologous Oct4 Alleles Accompanies the Onset of Embryonic Stem Cell Differentiation. Cell Stem Cell 16(3) pp. 275-288.

Yu, J. R. and Tai, Y. and Jin, Y. and Hammell, M. C. and Wilkinson, J. E. and Roe, J. S. and Vakoc, C. R. and Van Aelst, L. (2015) TGF-beta/Smad signaling through DOCK4 facilitates lung adenocarcinoma metastasis. Genes Dev 29(3) pp. 250-61.

Kuhn, C. D. and Wilusz, J. E. and Zheng, Y. and Beal, P. A. and Joshua-Tor, L. (2015) On-Enzyme Refolding Permits Small RNA and tRNA Surveillance by the CCA-Adding Enzyme. Cell 160(4) pp. 644-658.

Pervouchine, D. D. and Djebali, S. and Breschi, A. and Davis, C. A. and Barja, P. P. and Dobin, A. and Tanzer, A. and Lagarde, J. and Zaleski, C. and See, L. H. and Fastuca, M. and Drenkow, J. and Wang, H. and Bussotti, G. and Pei, B. and Balasubramanian, S. and Monlong, J. and Harmanci, A. and Gerstein, M. and Beer, M. A. and Notredame, C. and Guigo, R. and Gingeras, T. R. (2015) Enhanced transcriptome maps from multiple mouse tissues reveal evolutionary constraint in gene expression. Nat Commun 6pp. 5903.

Hua, Y. and Liu, Y. H. and Sahashi, K. and Rigo, F. and Bennett, C. F. and Krainer, A. R. (2015) Motor neuron cell-nonautonomous rescue of spinal muscular atrophy phenotypes in mild and severe transgenic mouse models. Genes Dev 29(3) pp. 288-297.

Shen, C. and Vakoc, C. R. (2015) Gain-of-function mutations in chromatin regulators as a tumorigenic mechanism and opportunity for therapeutic intervention. Current Opinion in Oncology 27(1) pp. 57-63.

Boj, Sylvia F and Hwang, Chang-Il and Baker, Lindsey A and Chio, Iok In Christine and Engle, Dannielle D and Corbo, Vincenzo and Jager, Myrthe and Ponz-Sarvise, Mariano and Tiriac, Hervé and Spector, Mona S and Gracanin, Ana and Oni, Tobiloba and Yu, Kenneth H and van Boxtel, Ruben and Huch, Meritxell and Rivera, Keith D and Wilson, John P and Feigin, Michael E and Öhlund, Daniel and Handly-Santana, Abram and Ardito-Abraham, Christine M and Ludwig, Michael and Elyada, Ela and Alagesan, Brinda and Biffi, Giulia and Yordanov, Georgi N and Delcuze, Bethany and Creighton, Brianna and Wright, Kevin and Park, Youngkyu and Morsink, Folkert H M. and Molenaar, I.  Quintus and Borel Rinkes, Inne H and Cuppen, Edwin and Hao, Yuan and Jin, Ying and Nijman, Isaac J and Iacobuzio-Donahue, Christine and Leach, Steven D and Pappin, Darryl J and Hammell, Molly and Klimstra, David S and Basturk, Olca and Hruban, Ralph H and Offerhaus, George Johan and Vries, Robert G J. and Clevers, Hans and Tuveson, David A (2015) Organoid Models of Human and Mouse Ductal Pancreatic Cancer. Cell 160(1-2) pp. 324-338.

Schuck, S. and Stenlund, A. (2015) A conserved regulatory module at the C-terminus of the papillomavirus E1 helicase domain controls E1 helicase assembly. Journal of Virology 89(2) pp. 1129-1142.

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