Kristin Baldwin | The Scripps Research Institute, USA
René Bernards | Netherlands Cancer Institute (NKI), Netherlands
In my lecture, I will focus on two new concepts in the treatment of cancer. First, I will discuss how we can identify acquired vulnerabilities of drug-resistant cancers. Based on the notion that every acquired strength (i.e. drug resistance) must have an associated weakness, we have searched for acquired vulnerabilities when BRAF mutant melanomas become resistant to the combination of BRAF and MEK inhibitors. Our pre-clinical findings indicate a major acquired sensitivity of such drug resistant melanomas for HDAC inhibitors. Initial results from a clinical trial in our center confirm our pre-clinical findings.
Second, I will discuss how we can use sequential drug treatment to deliver a “one-two punch” lethal blow to cancer cells. In this scenario, we use the first drug to expose a major new vulnerability of the cancer cells that is subsequently targeted by the second drug. Examples of effective sequential drug treatments based on the induction of senescence in liver cancer followed by killing of senescent cells with a senolytic agent will be presented.
Mina J. Bissell | Lawrence Berkeley National Laboratory, USA
To understand initiation of breast tumors, one must consider the health of the entire organ within the context of the individual: the age of the individual and the medical condition, not only the cells that become, or have become, malignant but the entire tissue and the microenvironment of the cells that have been targeted to become tumors.
I will discuss three fundamental questions: 1) How do epithelial cells know to stop growing and why malignant cells don’t? 2) What is the basis of tissue- and organ- specificity? And 3) how physical and biochemical signals help make a tissue?
We have shown that unless the architecture of the tissue is severely compromised, the cells will not become malignant or invade. Indeed we can revert the malignant cells to ‘normal phenotype’ despite myriads of mutations, deletions and amplifications if we restore the architecture. We now have discovered new pathways that regulate growth and quiescence in human breast cells(1), an intricate mechanism by which the ECM and cytoskeletal connections may interact with nucleus and chromatin(2), and how the morphogenetic signaling loop in breast epithelial tissue is maintained.(3)?
This is a tale of how form and function integrate: From laminins to lamins, P53, HOX D10 and back to laminins. See you there!
1) Cell Report, 2017
2) J. Cell Science, 2017
3) E.Life (in Press)
Bissell earned her doctorate in microbiology and molecular genetics from Harvard Medical School, won an American Cancer Society fellowship for her postdoctoral studies, and soon after joined LBNL. She was the founding Director of the Cell and Molecular Biology Division and later the Associate Laboratory Director for all Life Sciences at Berkeley Lab where she recruited outstanding scientists and developed a strong program in cell and molecular biology and breast cancer.
Bissell has published more than 400 publications and is one of the most sought-after speakers in the field. She has received numerous honors and awards, which include: U.S. Department of Energy’s E.O. Lawrence Award, AACR’s G.H.A. Clowes Memorial Award, the Pezcoller Foundation-AACR International Award, Susan G. Komen Foundation’s Brinker Award, BCRF Foundation’s Jill Rose Award, Berkeley Lab’s inaugural Lifetime Achievement Prize, American Cancer Society’s Medal of Honor, MD Anderson Cancer Center’s highest honor – the Ernst W. Bertner Award, the Honorary Medal from the Signaling Societies in Germany, ASCB’s highest honor – the E.B. Wilson Medal, and the 2017 AACR Award for Lifetime Achievement in Cancer Research. Bissell is an inspiring mentor and in her honor, the University of Porto, Portugal established the Mina J. Bissell Award which is given every three years to a person who has dramatically changed a field. She is the recipient of Honorary Doctorates from both Pierre & Marie Curie University in Paris, France and University of Copenhagen in Denmark. Bissell is not only an elected Fellow of most U.S. honorary scientific academies, including National Academy of Sciences (NAS), National Academy of Medicine (NAM), and American Philosophical Society (APS), but she also sits on many national and international scientific boards and continues to engage in full-time research, among other scientific activities.
Don W. Cleveland | University of California San Diego, USA
Maike Sander | University of California San Diego, USA
Jan van Deursen | Mayo Clinic, USA
Erwin Wagner | Spanish National Cancer Research Centre (CNIO), Spain
I will focus in my talk on recent studies towards understanding skin and lung pathologies at the cross-road between chronic inflammation and cancer. A major systemic complication of cancer is Cancer-Associated-Cachexia (CAC), where chronic inflammation, metabolic dysfunction and increased metabolic rate have been described. We showed that a phenotypic switch from white adipose tissue (WAT) to brown fat, termed WAT browning, takes place at the initial stages of CAC, before skeletal muscle atrophy. Recent results suggest that liver metabolism, the immune system and endocrine organs are dysregulated in CAC, which will also be discussed.
Marius Wernig | Stanford University, USA
Unlike reprogramming towards other lineages such as iPS cell reprogramming, the iN cell reprogramming process is very efficient (up to 20%) and deterministic. We previously found a molecular explanation in that Ascl1, a transcriptional activator, can access its physiological targets in fibroblasts even though these sites are in a closed chromatin state, thus robustly inducing a neuronal transcriptional program and rearranging the local chromatin. Surprisingly, Ascl1 alone is sufficient to induce fully functional iN cells, but in the majority of cells activates also non-neuronal programs. We further show, that Myt1l, a zinc finger domain protein, primarily functions as transcriptional repressor suppressing the fibroblast and other non-neuronal programs. This suggests that the physiological role of Myt1l is to ensure maintenance of neuronal identity by repressing many transcriptional program except neuronal genes, thereby functioning in exactly the inverse way as REST which blocks neuronal genes in many non-neuronal cell types. In summary, our data suggest that for optimal reprogramming results it may be important to use a combination of specific activators of the target cell program and specific repressors of the donor and other non-target cell programs.
Dr. Wernig’s lab is interested in pluripotent stem cell biology and the molecular determinants of neural cell fate decisions. His laboratory was the first to generate functional neuronal cells reprogrammed directly from skin fibroblasts, which he termed induced neuronal (iN) cells. The lab is now working on identifying the molecular mechanisms underlying induced lineage fate changes, the phenotypic consequences of disease-causing mutations in human neurons and other neural lineages as well as the development of novel therapeutic gene targeting and cell transplantation-based strategies for a variety of monogenetic diseases.
Maximina H. Yun | Center for Regenerative Therapies TU Dresden, Germany
Selected Short Talks
Scientists and clinicians at any career stage working on innovative projects with potential relevance for translation and systems medicine were invited to submit their abstracts in order to present their own research at BIH Symposium 2018. Abstract submission was open to all research fields.
The scientific organizing committee reviews all abstracts to ensure that the topic of the submission is consistent with the scope of the topics covered at the symposium. The most exciting contributions are selected for short talks and/or poster presentation. A condition of submission is that, if accepted, the talk and/or poster will be presented at the symposium by one of the authors.