September 2019: Dalerba Lab
Background:
What is the main focus of your lab?
The main focus of our laboratory is to understand the role of epithelial stem cells in the origin and biology of human malignancies, such as colon cancer, breast cancer and some aggressive forms of salivary gland cancer. A central focus of our current research is the use modern single-cell RNA-seq technologies to de-convolute the cell composition of malignant tissues (e.g. colon cancer, breast cancer, adenoid cystic carcinomas of the salivary gland) and identify novel biomarkers of their “cancer stem cell” populations, to be used as: 1) novel predictive biomarkers to improve treatment algorithms; 2) novel pharmacological targets for the development of innovative anti-tumor drugs.
How long have you had your lab? When did you join Columbia University?
I joined Columbia University in the summer of 2014.
How big is your lab currently?
Our laboratory currently consists of two graduate students (William J. Raab, Sara Viragova), two post-doctoral fellows (Junko Mukohyama, Emily Rinebold), a technician (Luis Valencia) and a grant-writing assistant (Seetha V. Srinivasan).
Where is your lab located?
Our laboratory has recently relocated to the 9th floor of the Irving Cancer Research Center (ICRC) in Room 916.
Current affairs:
What are the most exciting projects/directions in the lab at this moment?
Research in our laboratory is currently unfolding along three major directions: 1) the identification of novel surface markers for the ex vivo purification of epithelial stem/progenitor cell populations of the salivary gland, and for the differential isolation of “cancer stem cell” populations in human salivary gland malignancies (Sara Viragova; PhD student); 2) the elucidation of a new molecular mechanism responsible for colon cancer resistance to anti-EGFR monoclonal antibodies (William J. Raab, PhD student; Luis Enrique Valencia-Salazar, laboratory technician); 3) the elucidation of the cellular origins of CDX2neg colon carcinomas and of the molecular mechanisms responsible for their enhanced sensitivity to cytotoxic drugs used in conventional chemotherapy regimens (Junko Mukohyama, post-doctoral fellow; William J. Raab, PhD student); 4) the development of novel experimental models to investigate the causes of the recent and dramatic increase in incidence of Rectal Cancer among young people (Emily Rinebold, post-doctoral fellow).
What are the biggest accomplishments that your lab recently had?
Over the last three years, the most important accomplishment of our laboratory is the identification of CDX2 as a predictive biomarker for benefit from adjuvant chemotherapy in Stage-II colon cancer patients (Dalerba et al., CDX2 as a prognostic biomarker in Stage-II and Stage-III colon cancer, NEJM, 374:211-222. 2016).
Technology:
What are the model systems that your lab is using?
Our laboratory leverages a large collection of patient-derived xenograft (PDX) models established from human primary colorectal carcinomas (CRCs) and human adenoid cystic carcinomas (ACCs) of the salivary glands. We also established tissue-culture protocols that enable the in vitro study and serial propagation of stem/progenitor and “cancer stem cell” populations as three-dimensional (3D) “organoids”, grown within the thickness of gelatinous matrices.
What are the key techniques that your lab is using? Are you open to training scientists from other labs?
The key techniques used in our laboratory include fluorescence activated cell sorting (FACS), “single-cell genomics” techniques (including single-cell RT-qPCR and single-cell RNA-seq), in vivo xeno-transplantation experiments and three-dimensional (3D) “organoid” cultures.
What facilities or equipment does your absolutely lab rely upon? Do you use CSCI cores?
We are frequent users of flow cytometry cores, especially those managed by the Columbia Stem Cell Initiative (CSCI) and the Columbia Center for Translational Immunology (CCTI). We also make extensive use of utilize the services provided by the J.P. Sulzberger Columbia Genome Center, the Molecular Pathology Shared Resource (MPSR), the Confocal and Specialized Microscopy Shared Resource (CSMSR), the Oncology Precision Therapeutics & Imaging Core (OPTIC) and the Digital and Computational Pathology Laboratory (DCPL).
Training:
What's your best approach to mentoring trainees in the lab?
In essence, I believe that the mission of a mentor is two-fold: “to ignite” and “to empower”. To ignite means to help students visualize an important challenge, and understand its intellectual and/or social value. To empower means to help students craft a method to engage such challenge successfully, with self-confidence and intellectual pleasure. In this process, the role of the mentor is delicate, as it evolves during the relationship. It is frequently on the mentor to make the first move, to take the initiative and open the discussion on a new idea, to provide a sketch of a new problem, of which the student is unaware. However, as the interest and the proficiency of the student grow, the mentor must take a step back, and let the student take the driving seat. In this second phase, the mentor becomes a “sparring partner”, who actively challenges the models and methods drafted in the student’s mind, and tries to highlight hidden problems or non-intuitive pitfalls, until the ultimate solution is achieved by the students themselves (a maiuetic process).
Who were your most influential mentors/role models in science and what did you learn from them?
As for most scientists, my scientific trajectory has been shaped by many mentors, along the various stages of my career and across different institutions. I credit Catia Traversari and Vincenzo Russo (Ospedale San Raffaele, Milano, Italy) for having first taught me the pleasure of rigorous craftsmanship in the conceptual design and technical execution of laboratory experiments (i.e. a well-executed experiment is intellectually beautiful). I credit Chiara Castelli and Giorgio Parmiani (Istituto Nazionale Tumori, Milano, Italy) for having taught me a sense of responsibility and respect towards, not only colleagues in the workshop, but also the whole community of scientists (i.e. the tapestry of science is woven by a big loom, through the effort of many investigators, all citizens of the same world). I credit Michael F. Clarke (Stanford University) for having taught me to be fearless in the pursuit of important and transformative goals, but also to maintain rigorous control on the intellectual framework of my ideas (i.e. to “dream big”, but always chart carefully your path).
What would be your career advice for students/postdocs?
My main advice for students (PhD students, post-doctoral fellows) is to “always pursue a scientific question that you perceive as exciting and meaningful” (i.e. a question to which you really would like to know the answer, be it in basic or translational science). The path of the researcher is, by its very definition, beset by systematic failure (i.e. if the next step in the progress of knowledge was self-evident, no effort would be required to attain it). Only the pleasure of pursuing a meaningful question (i.e. to be engaged in a worthy “adventure”) will sustain you through a long series of technical setbacks and negative results. If, during the course of your studies, a new question emerges, a question that you find exceptionally meaningful, don’t be shy of embracing it. In my personal experience, the most important findings have, very often, emerged as the result of side-projects, and usually required a courageous choice: a change of research direction (in consultation, of course, with my academic mentors).
Lab management:
How do members of your lab celebrate accomplishments?
We usually celebrate lab accomplishments (or special events) by going out together, for either lunch or dinner.
What was the most exciting part about starting your new lab?
The most exciting aspect of setting-up a new laboratory was the opportunity to “design” a work environment (a workshop) that can empower a team of researchers in their quest to pursue meaningful scientific questions, in a collaborative and efficient manner. I often think of this idea as analogous to equipping a research vessel to explore a new sea. It was also very exciting to meet, one-by-one, the various prospective members of my laboratory, secure their recruitment and then witness the high quality of the research work that they set in motion.
What has been your greatest challenge in managing your lab?
The greatest challenge is, without any doubt, the need of constantly secure sufficient funding to enable the progress of our studies. It is painful sometimes, to be unable to recruit a talented student, or pursue a valuable scientific question, because of insufficient funding.
Stem Cell Directions
What are the most important recent developments in the stem cell field?
The field of stem cell biology is currently in a phase of rapid acceleration, on many fronts. The possibility of growing three-dimensional (3D) “organoids” from human stem cells purified ex vivo, and then use CRISPR/Cas9 technologies to correct harmful genetic mutations, is breathing new life into the fields of gene therapy and regenerative medicine. The same holds true for the possibility of using animal chimeras to create new organs. In the field cancer biology, it is becoming increasingly clear that many of the functional traits once considered as unique to the malignant phenotype (e.g. immortality, metastasis) can be interpreted as abnormal manifestations of physiological properties that are specific to stem cells (i.e. self-renewal, migration and tissue repair).
CSCI:
What was the main reason of you joining CSCI?
Being part of the CSCI community is absolutely critical to the success of our laboratory, for many reasons: 1) it gives us the opportunity to learn about the work of colleagues who share our interests in stem cells biology, and provides us with formal venues to interact with them (e.g. the CSCI retreat) in order to exchange ideas and explore formal collaborations; 2) it gives us subsidized access to specialized core facilities and their cutting-edge scientific equipment (e.g. Flow Cytometry Core, Stem Cell Core) thus enabling experiments that would be otherwise impossible, or exceedingly difficult, for us to perform alone (e.g. “index sorting” by FACS, single-cell RT-qPCR, generation of iPSC lines); 3) it allows us to attend seminars by international leaders in stem cell biology, thus ensuring that we remain up-to-date on some of the field’s most important advances; 4) it provides our trainees with a formal venue to discuss their ongoing work (i.e. the “work-in-progress” seminar series), where they get valuable feedback from experienced faculty regarding their career trajectory and communication skills; and 5) it gives us access to funding opportunities specifically designed to support stem cell research (e.g. CSCI pilot grants, pre-doctoral and post-doctoral fellowships from the NYSTEM training grant).
What do you plan to bring to the CSCI community?
Our laboratory is interested in understanding the role played by stem cells in the origin of human tumors, and in applying the “conceptual framework” of stem cell biology to the study of malignant tissues, which we interpret as a “caricatures” of normal developmental processes. Over the years, we have become increasingly proficient in the study of various types of epithelial stem cells (e.g. intestinal, mammary and salivary gland stem cells) and of their mutated counterparts in malignant tissues (e.g. “cancer stem cell” populations in human colon, breast and salivary gland carcinomas). We have now developed in-depth expertise in the use of three-dimensional (3D) “organoid” tissue-culture techniques, patient-derived xenograft (PDX) lines (i.e. human malignant tissues serially transplanted in immune-deficient mice) and in single-cell genomics technologies (single-cell RT-qPCR, single-cell RNA-seq), which we use to deconvolute the cell composition of solid tissues, and “hunt” for novel stem cell populations.